Phase-1 study of vamotinib (PF-114), a 3rd generation BCR::ABL1 tyrosine kinase-inhibitor, in chronic myeloid leukaemia

Phase-1 study of vamotinib (PF-114), a 3rd generation BCR::ABL1 tyrosine kinase-inhibitor, in chronic myeloid leukaemia | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Phase-1 study of vamotinib (PF-114), a 3rd generation BCR::ABL1 tyrosine kinase-inhibitor, in chronic myeloid leukaemia Anna Turkina, Olga Vinogradova, Elza Lomaia, Evgeniya Shatokhina, and 16 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5341421/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 29 Apr, 2025 Read the published version in Annals of Hematology → Version 1 posted 11 You are reading this latest preprint version Abstract Vamotinib (PF-114) is a 3 rd -generation, ATP-competitive oral tyrosine kinase inhibitor (TKI) active against wild-type and mutated BCR::ABL1 isoforms including BCR::ABL1 T315I . We present final results of a phase-1 vamotinib dose-escalation study to identify maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) followed by expansion cohorts. 51 subjects with chronic myeloid leukaemia (CML) failing ≥ 1 2 nd generation TKI or with BCR::ABL1 T315I were enrolled. Subjects received vamotinib, 50-750 mg/d, continuously. Median exposure was 6 months (range, <1 - 52 months). Median CML duration pre-study was 10 years (range, <1 - 23 years). 36 subjects received ≥ 3 prior TKIs and 16 had BCR::ABL1 T315I . The MTD was 600 mg with the Grade-3 psoriasis-like skin toxicity as the DLT. There were no vascular occlusive events nor deviations of ankle-brachial index. Complete haematologic response (CHR) was achieved in 14 of 30 subjects, major cytogenetic response (MCyR) in 14 of 44 subjects, complete cytogenetic response (CCyR) in 10 of 50 and major molecular response (MMR) in 7 of 51 subjects who did not have a CHR, MCyR, CCyR or MMR at enrollment. The best safety/efficacy dose was 300 mg with MCyR achieved in 6 of 7 subjects, CCyR in 5 of 9 and MMR in 4 of 9 subjects who did not have a MCyR, CCyR or MMR at enrollment. 5 of 16 subjects with BCR::ABL1 T315I responded including 3 achieving a CHR, 1, a MCyR, and 1,a CCyR. 2 of 5 subjects failing ponatinib achieved a CHR. Vamotinib dose for further phase-3 study is 300 mg/d. CTR: NCT02885766, August 26, 2016 Chronic myeloid leukaemia tyrosine kinase inhibitor PF-114 vamotinib Figures Figure 1 Introduction Six tyrosine kinase inhibitors (TKIs) are approved to treat BCR::ABL1 positive chronic myeloid leukemia ( BCR::ABL1 + CML) [ 1 – 6 ]. However, there remains a need for new TKIs because of resistance and intolerance [ 7 – 25 ]. Vamotinib (PF-114) mesylate is a potent, highly specific 3rd generation BCR::ABL1 -inhibitor for oral use. Vamotinib is rationally designed to avoid inhibition of vascular endothelial growth factor receptor-2 ( VEGFR2 ) and other off-target kinases [ 26 – 27 ]. Vamotinib is active against wild-type and mutant BCR::ABL1 isoforms including BCR::ABL1 T315I . In pre-clinical studies in animals there were few adverse events including no arterial occlusive events. We present the results of a phase-1 trial of vamotinib in subjects with BCR::ABL1 -positive CML failing ≥ 2nd generation TKIs (2G-TKIs) or with BCR::ABL1 T315I . Methods Study oversight The study was designed by Fusion Pharma, LLC, in collaboration with the principal investigators from each clinical centre participating in the study and members of the sponsor's Scientific Advisory Board. Data were collected, analyzed and interpreted by OCT ( https://oct-clinicaltrials.com/ ) a clinical contract research organization (CRO). Principal investigators verified data accuracy and completeness at their site and integrity of the analyses and study conducted consistent with the study protocol. Subjects Study subjects ≥ 18 years with BCR::ABL1 positive CML in chronic (CP) or accelerated phase (AP) using the European LeukemiaNet 2013 guidelines [ 28 ]. Subjects, had to have failed ≥ 1 TKIs or intolerance to ≥ 2 TKIs or have BCR::ABL1 T315I . Other eligibility criteria included ECOG performance score 0–2; QTcF interval ≤ 470 milliseconds and resolution of all prior therapy-associated adverse event to ≤ Grade-1 according to NCI CTC AE v4 criteria [ 29 ]. Study design Open-label phase-1 study at 3 clinical centers with dose-escalation using a 3 + 3 scheme with a starting dose of 50 mg/d given continuously. A 28-days of therapy was defined as a cycle. Dose escalation for the subsequent cohort depended on the results of the safety assessment of subjects in the preceding cohort during the 28 days of therapy. Once an MTD was identified expanded cohorts of 10–15 subjects were recruited at doses of interest below the MTD. A modified accelerated dose-escalation regimen was used up to a dose of 400 mg. Dose could be increased for subjects in whom the dose was reduced because of an adverse drug reaction (ADR). Severity of adverse events was assessed using NCI CTC AE v4 [ 28 ]. The primary objective was to determine the MTD and DLT of vamotinib during the 1st cycle of therapy. Secondary objectives were to assess the safety and tolerability of vamotinib, determine pharmacokinetics and determine efficacy by response criteria according to 2013 ELN [ 29 ]. Pharmaco-kinetics and -dynamics Blood samples were obtained to evaluate pharmacokinetics and pharmacodynamics (Tables S1, S1.1, S1.2). Data on phosphorylated CrkL protein (pCrkL) concentration were evaluated in samples from 4 subjects. Efficacy Haematological response evaluations were done on the first day of each therapy; molecular response on the first day of cycles 1, 2, 4, 7, 10, 13 and then every three months; cytogenetic response – at screening and on the first days of cycles 4, 7, 13 and every three months thereafter, provided that there was no major molecular response. Cytogenetic response was assessed by differential staining of chromosomes and if uninformative, by fluorescent in situ hybridization (FISH). Mutations in BCR::ABL1 were assessed by Sanger and next generation sequencing (NGS). Sanger sequencing was done at each center; NGS analyses were done in the laboratory of Prof. Susan Branford, University of Adelaide. Discordances were resolved as described in Table S2. Molecular response was assessed using the ratio of BCR::ABL1 to ABL1 measured according to the IS [ 9 ]. RESULTS Subjects and baseline co-variates 54 subjects were screened between July, 2016 and January, 2019, 51 of whom were enrolled. The starting dose of vamotinib was 50 mg/d (n = 3). Subsequent subjects were sequentially recruited into cohorts at doses of 100 mg (n = 3), 200 mg (n = 11), 400 mg (n = 12), 500 mg (n = 3), 600 mg (n = 6), 750 mg (n = 4), and 300 mg (n = 9). All subjects treated at 300 mg daily and 6 subjects at 400 mg were enrolled after the MTD was determined. The cut-off date of the analysis is July 30, 2019. Baseline co-variates and therapy state of subjects as are displayed in Table 1 . Mean follow-up is 27 w (range 0.1–31 w, IQR 65 w). 36 subjects previously received ≥ 3TKIs. 35 subjects had ≥ 1 BCR::ABL1 kinase domain mutation the most common of which was BCR::ABL1 T315I in 16 (Table S2.1). All subjects discontinued from the study 1 of whom died later from blast transformation. Table 1 Baseline co-variates and therapy state Cohort 1 50 mg (N = 3) Cohort 2 100 mg (N = 3) Cohort 3 200 mg (N = 11) Cohort 4 400 mg (N = 12) Cohort 5 500 mg (N = 3) Cohort 6 600 mg (N = 6 ) Cohort 7 750 mg (N = 4) Cohort 8 300 mg (N = 9) All (N = 51) Time on treatment , median (range) –days 308 (28–707) 394 (280–1592) 261 (45-1549) 162 (14–539) 54 (23–79) 102 (31-1002) 35 (13–364) 805 (77-1093) 199 (13-1592) Therapy state Discontinued 3 3 11 12 3 6 4 9 51 Disease progression or need to change therapy in the opinion of the investigator 2 0 2 7 2 3 1 3 20 Adverse event 0 1 1 2 0 1 0 1 6 Intolerable adverse drug reaction in the opinion of the investigator 0 1 0 1 0 0 0 0 2 Withdrawal of informed consent 0 0 0 1 1 1 2 0 5 Participation in another clinical study or additional therapy 1 0 1 1 0 0 0 0 3 Lost to follow-up 0 0 1 0 0 0 0 1 2 Sponsor's decision to terminate the study 0 1 2 0 0 1 0 3 7 Other 0 0 4 0 0 0 1 1 6 ECOG performance-status score 0 3 2 8 9 2 5 2 9 40 1 0 1 3 3 0 1 2 0 10 2 0 0 0 0 1 0 0 0 1 No. of previous TKIs 1 0 0 1 4 0 0 0 0 5 2 1 2 5 1 2 2 1 5 19 ≥ 3 2 1 6 8 1 6 6 6 36 Previous TKI Imatinib 3 3 11 12 3 5 3 9 49 Nilotinib 2 2 4 7 2 5 4 6 32 Dasatinib 2 2 7 6 2 5 4 5 33 Bosutinib 1 0 4 1 0 2 3 3 14 Ponatinib 0 0 1 2 0 1 0 1 5 BCR::ABL1 transcript p 210 3 3 11 11 3 6 4 9 50 p 190 0 0 0 1 0 0si 0 0 1 Safety There was no DLT in cohorts at doses < 400 mg/d. At a dose of 400 mg/d 1 subject developed a Grade-3 psoriasiform dermatitis (Table 2 ). There were no DLTs at doses of 500 mg/d and 600 mg/d. At a dose of 750 mg/d all 3 subjects treated developed skin DLTs, therefore 600 mg/d was defined as the MTD. Additional subjects were enrolled in the 400 mg/d, 300 mg/d, and 200 mg/d cohorts. Therapy duration was briefer at a dose of 400 md/d. Rates of dose-reductions and therapy-interruptions were higher for 400 mg/d compared with lower doses (Table 2 ) Table 2 Subjects’ treatment and dose-limiting toxicities. Cohorts Cohort 1 50 mg (N = 3) Cohort 2 100 mg (N = 3) Cohort 3 200 mg (N = 11) Cohort 4 400 mg (N = 12) Cohort 5 500 mg (N = 3) Cohort 6 600 mg (N = 6) Cohort 7 750 mg (N = 4) Cohort 8 300 mg (N = 9) All subjects, (N = 51) Time on treatment, median (range) – days 308 (28–707) 394 (280–1592) 261 (45-1549) 162 (14–539) 54 (23–79) 102 (31-1002) 35 (13–364) 805 (77-1093) 199 (13-1592) DLTs 0 0 0 1 0 0 3 0 4 Subjects with dose delay, n 1 2 6 6 1 4 3 4 27 Subjects with dose reduction, n 1 1 3 4 1 2 3 0 15 The most common non-hematological adverse event was psoriasiform dermatitis in 19 subjects 4 of which were Grade-3/-4 (Table 3 ). There was diarrhea in 14 subjects, all < Grade-3. Dry skin and rash occurred in 8 subjects 6 subjects had a Grade-3/-4 toxic skin rash. 6 subjects had serious adverse events (Table S3). Haematological adverse events were common but usually Grade-1/-2 (Table 3 ). No cardio-vascular or arterial occlusive adverse events were reported at any dose, including no cases of occlusion of large peripheral blood vessels and no clinically significant deviations of the ankle-brachial index from its normal range 1.00-1.29 [ 30 ]. Table 3 Most common adverse events. Adverse Events All grades (N = 51) Grade 3–4 * Number of subjects (percent) Skin and subcutaneous tissue disorders 32 (63) 11 (22) Dermatitis psoriasiform 19 (37) 4 (8) Toxic skin eruption 9 (18) 7 (14) Dry skin 9 (18) Pruritus 5 (10) 1 (2) Erythema 4 (8) Rash papular 2 (4) Gastrointestinal disorders 17 (33) Diarrhoea 14 (28) Nausea 6 (12) Abdominal pain upper 4 (8) Abdominal pain 2 (4) Anal fissure 2 (4) Dyspepsia 2 (4) Blood and lymphatic system disorders 12 (24) 7 (14) Thrombocytopenia 8 (16) 4 (8) Neutropenia 5 (10) 3 (6) Anaemia 2 (4) 1 (2) Leukopenia 1 (2) 1 (2) gInvestigations 7 (14) 1 (2) Blood cholesterol increased 3 (6) Cardiac disorders 3 (6) Eye disorders 3 (6) Alanine aminotransferase increased 2 (4) Low density lipoprotein increased 2 (4) Transaminases increased 1 (2) 1 (2) Hepato-biliary disorders 1 (2) 1 (2) Hepatitis toxic 1 (2) 1 (2) * Dermatitis psoriasiform – 2 subjects on 400 mg; 2 subjects on 600 mg; Toxic skin eruption – 1 subject on 300 mg; 1 subject on 400 mg; 2 subjects on 500 mg; 1 subject on 600 mg; 2 subjects on 750 mg; Pruritus – 1 subject on 600 mg; Hepatitis toxic – 1 subject on 400 mg; Thrombocytopenia – 1 subject on 200 mg; 1 subject on 500 mg; 1 subject on 600 mg; 1 subject on 750 mg; Neutropenia – 2 subjects on 400 mg; 1 subject on 500 mg; Anaemia – 1 subject on 200 mg; Leukopenia – 1 subject on 400 mg. Rash Rashes were the most common non-haematological adverse event and were seen in 32 subjects (Table 4 ). Grade-3 rash occurred in 10 subjects at doses ≥ 400 mg/d. Rash was the reason for dose-reduction (n = 9) and study withdrawal (n = 6). No rash was coded as a serious adverse events. The most common rash was psoriasiform with erythema, lymphoplasmacytic infiltration of derma and desquamation of well-defined foci. Rashes were often in sites of friction and stretching and painless but occasionally associated with paresthesia. Other types of rashes included dryness and redness mainly in the setting of development or regression of psoriasiform rashes. Toxicity resolved within 1–2 weeks after discontinuation of the drug. Lipoic acid (tablets), vitamin E, and topical agents such as tacrolimus 0.1, betamethasone 0.05, calcipotriol, hydrocortisone 0.5 eye ointment, urea 10, thermal water were used to manage skin lesions. After 4–6 months of taking the drug, adaptation of the skin to its effects was noted. Table 4 Skin toxicity. Severity Cohort 1 50 mg Cohort 2 100 mg Cohort 3 200 mg Cohort 4 400 mg Cohort 5 500 mg Cohort 6 600 mg Cohort 7 750 mg Cohort 8 300 mg Overall N = 3 N = 3 N = 11 N = 12 N = 3 N = 6 N = 4 N = 9 N = 51 Psoriasiform dermatitis, n Grade 3 0 0 1 2 0 1 0 0 4 Total 1 3 4 8 0 1 0 2 19 Dry skin, n Grade 3 0 0 0 0 0 0 0 0 0 Total 0 1 1 4 1 1 0 1 9 Erythema, n Grade 3 0 0 0 0 0 0 0 0 0 Total 0 0 0 2 1 1 0 0 4 Pruritus, n Grade 3 0 0 0 0 0 1 0 0 1 Total 0 0 0 3 0 2 0 0 5 Toxic skin eruption, n Grade 3 0 0 1 1 1 1 3 0 7 Total 0 0 1 1 1 3 3 0 9 Rash papular, n Grade 3 0 0 0 0 0 0 0 0 0 Total 1 0 0 1 0 0 0 0 2 Pharmacokinetics Pharmacokinetic measurements were done days 1 and 29–30 of treatment. The time to reach C max was approximately 4 hours, the half-life of 13.5 hours, which confirmed the validity of the once a day regimen. Steady-state was reached after 8 days of dosing, Fig. 1 . The concentration-time profiles suggest linear or near-linear pharmacokinetics of vamotinib over the entire dose range studied (50–750 mg). Dose proportionality assessment showed a less than dose-dependent increase in AUC and C max of vamotinib (Table S4). Starting from a dose of 200 mg, the concentration of vamotinib in the blood during the day exceeds 75 nM, corresponding to the IC50 of cytotoxicity for BaF3 cells expressing BCR::ABL1 T315I [ 26 ]. Analysis of changes in blood pCrkL done for subjects with leukocytosis on days 1, 8 and 29 of therapy but was uninformative due to poor quality of samples. Efficacy Efficacy and best responses to treatment are summarized in Table 5 and Table S6. 30 subjects did not have a complete hematological response (CHR) at baseline 14 of whom achieved a CHR (Table 5 ). Median time to achieving a CHR was 3.8 months, (range, 1–4 months); all instances of CHR were maintained at least for 12 months of therapy. Of the 44 and 50 subjects who did not have a major cytogenetic response (MCyR) and a complete cytogenetic response (CCyR) at the start of therapy, respectively, 14 (32%) achieved MCyR and 10 (20%) achieved CCyR during therapy. The median time to achievement of MCyR and CCyR were 4.5 months (range 1.9–19.4) and 5.6 months (range 2.8–15), respectively. None of the 51 subjects had a major molecular response (MMR) at study entry, and 7 (13.7%) subjects achieved MMR during therapy. One subject on a dose of 300 mg achieved a deep molecular response of MR4.5. The median time to MMR was 5,6 months (range 2.8–22.2), and no subject has lost after 24 months. One subject, treated at a dose of 300 mg, achieved a MR4.5. Most molecular and cytogenetic responses were observed at doses of 300 and 200 mg. The lower number of responses at doses of 400 mg and above may be explained by the fact that the resulting (skin) toxicity prevented long-term treatment of subjects at these doses. Table 5 Efficacy Cohort 1 50 mg Cohort 2 100 mg Cohort 3 200 mg Cohort 4 400 mg Cohort 5 500 mg Cohort 6 600 mg Cohort 7 750 mg Cohort 8 300 mg Total N = 3 N = 3 N = 11 N = 12 N = 3 N = 6 N = 4 N = 9 N = 51 Absence of CHR at baseline – no. (%) 2 (67) 0 5 (46) 7 (58) 2 (67) 6 (100) 4 (100) 4 (44) 30 (59) CHR at treatment – no. (%) 1 (50) 0 2 (40) 4 (57) 0 2 (33) 1 (25) 4 (100) 14 (47) CHR by the 3 months – no. (%) 0 0 2 (40) 2 (29) 0 2 (33) 1 (25) 4 (100) 11 (37) CHR by the 6th months – no. (%) 0 0 2 (40) 2 (29) 0 2 (33) 1 (25) 4 (100) 11 (37) CHR by the 12th months – no. (%) 1 (50) 0 2 (40) 4 (57) 0 2 (33) 1 (25) 4 (100) 14 (47) Subjects with loss of CHR – no. (%) 0 0 2 (100) 4 (100) 0 0 0 2 (50) 8 (57) Absence of MCyR at baseline – no. (%) 3 (100) 2 (67) 8 (73) 11 (92) 3 (100) 6 (100) 4 (100) 7 (78) 44 (86) MCyR at treatment – no. (%) 0 2 (67) 4 (50) 2 (19) 0 0 0 6 (86) 14 (32) MCyR by 6 months – no. (%) 0 1 (33) 3 (38) 2 (19) 0 0 0 4 (57) 10 (23) MCyR by 12 months – no. (%) 0 1 (33) 3 (38) 2 (19) 0 0 0 5 (83) 11 (25) Subjects with loss of MCyR – no. (%) 0 0 1 (25) 0 0 0 0 1 (17) 2 (14) Absence of CCyR at baseline – no. (%) 3 (100) 3 (100) 10 (91) 12 (100) 3 (100) 6 (100) 4 (100) 9 (100) 50 (98) CCyR at treatment – no. (%) 0 1 (33) 3 (30) 1 (8) 0 0 0 5 (56) 10 (20) CCyR by 6 months – no. (%) 0 0 2 (20) 1 (8) 0 0 0 3 (33) 6 (12) CCyR by 12 months – no. (%) 0 0 2 (20) 1 (8) 0 0 0 4 (44) 7 (14) Subjects with loss of CCyR – no. (%) 0 0 1 (33) 0 0 0 0 1 (20) 2 (20) Absence of MMR at baseline – no. (%) 3 (100) 3 (100) 11 (100) 12 (100) 3 (100) 6 (100) 4 (100) 9 (100) 51 (100) MMR at treatment – no. (%) 0 1 (33) 2 (18) 0 0 0 0 4 (44) 7 (14) MMR by 6 months – no. (%) 0 0 1 (9) 0 0 0 0 3 (33) 4 (8) MMR by 12 months – no. (%) 0 0 1 (9) 0 0 0 0 3 (33) 4 (8) MMR by 24 months – no. (%) 0 1 (33) 2 (18) 0 0 0 0 4 (44) 7 (14) Subjects with loss of MMR – no. (%) 0 0 0 0 0 0 0 0 0 Of the 16 subjects with BCR::ABL1 T315I , 12 did not have CHR at study entry; 3 of them achieved CHR during vamotinib therapy. Of the 15 subjects without MCyR and 16 without CCyR, 2 and 1 subjects achieved responses, respectively (Table 6 ). Responses to vamotinib in subjects with BCR::ABL1 T315I were transient, lasting 2.8 months (MCyR) and 2.8 months (CCyR). Most subjects with BCR::ABL1 T315I were treated at doses of 400 mg and above, which were characterized by premature withdrawal from the study due to toxicity. No subject with BCR::ABL1 T315I was included in the 300 mg dose cohort, which performed optimally in terms of efficacy and safety. Five subjects had received prior therapy ponatinib. None had CHR at study entry and 2 achieved CHR; however, none achieved MCyR or CCyR (Table 6 ). Five subjects with advanced phase CML (4 in AP and 1 in blast phase, BP) were treated. 2 achieved a CHR but none achieved MCyR or CCyR. 1 subject continued on therapy (Table 6 ). A subject with myeloid variant M0 blast crisis was treated with vamotinib due to the lack of other available at that time therapies [ 31 – 32 ]. BP was identified on enrollment and accompanied by i(17) and BCR::ABL1 T315I . A CHR was achieved after 5 weeks of vamotinib lasting for 18 months with no cytogenetic response. At 1 year there was extra-medullary relapse and the CHR was lost and vamotinib discontinued. Table 6 Subjects with the BCR::ABL1 T315I , resistance/intolerance to ponatinib or in accelerated phase. Variable Subjects with BCR::ABL1 T315I (N = 16) Subjects after ponatinib (N = 5) Advanced phase CML (N = 5) Median follow-up (range), days 78 (17–987) 53 (8-266) 150 (15–539) CHR no./total no. 3/12 * 2/5 2/5 MCyR no./total no. 2/15 ** 0/5 0/5 CCyR no./total no. 1/16 0/5 * 0/5 MMR no./total no. 0/16 0/5 * 0/5 * 4 subjects had a CHR at enrollment ** 1subject had a MCyR at enrollment Discussion Vamotinib is safe and effective in people with CML resistant and/or intolerance to 1st and 2nd generation TKIs, ponatinib and in those with BCR::ABL1 T315I . The MTD is 600 mg with rash the dose-limiting and most common DLT and adverse event. Rash was seen in pre-clinical toxicology studies in rats and dogs [ 26 ]. There were no arterial-occlusive events despite the close structural similarity with ponatinib [ 23 – 24 ]. This correlates with a more selective kinase inhibition profile of vamotinib in EPHA6, EPHA7, TAK1, TIE2, VEGFR2, ZAK kinases and no cardio-vascular findings in pre-clinical toxicology studies [ 26 ]. The study has its limitations due to the relatively small sample size, heterogeneous pretreatment status of the enrolled patients, and the lack of reliable pharmacodynamic readouts. In conclusion, v amotinib is safe and effective in subjects failing ≥ 2 TKIs, ponatinib and with BCR::ABL1 T315I . The dose selected for further study is 300 mg/d. Declarations Acknowledgements The work of Scientific Advisory Board of Fusion Pharma was significantly contributed by Prof. Michele Baccarani, University of Bologna, who left us untimely. Special thanks to the patients and their families, to study support clinical stuff and to the OCT clinical contract research organization for clinical trial documents, reports, statistical analyses. RPG acknowledges support from the UK National Institute of Health Research (NIHR). Author contribution AT, EC, OS, Vasily Shuvaev, Veronika Shulgina, AH, OO, JC, RPG and GC conceptualized and developed the clinical trial protocol. AT, EC, OV, EL, ES, OS, DS, IN, , AP, AB and NS conducted the clinical trial. GC drafted the typescript, edited by AT, JC and RPG. IM drafted the tables, All authors read, reviewed and approved the final version of the manuscript. Funding The study was conducted by Fusion Pharma, LLC with a grant support from the Skolkovo Foundation https://sk.ru/. Data availability Fusion Pharma will consider requests for disclosure of raw data underlying the tables and figures in the current manuscript. Qualified academic investigators may request such data for their use solely for non-commercial purposes by applying to the corresponding author’s e-mail address [email protected] Ethics approval The protocol was approved by the ethics committee of the Ministry of Health of Russian Federation and by the participating clinical sites’ ethics committees. The study was conducted in accordance with the 1964 Declaration of Helsinki and the Good Clinical Practice Guidelines of the International Conference on Harmonization. All patients provided written informed consent. Consent for publication Not applicable Trial registration The trial is registered at clinicaltrials.gov . The registration number is NCT02885766. Competing interests AT – speaker: Novartis, Pfizer, R-Pharm, consultancy/advisory board: Novartis; OV: no competing interests to declare; EL has received fees for lecturing and expert opinion from Novartis, Pfizer, Sotex, Pharmstandard and Fusion Pharma; ES: no competing interests to declare; OS: no competing interests to declare; EC – speaker: Novartis, Pfizer, R-Pharm, consultancy: Ascentage Pharma; DS: no competing interests to declare; IN: no competing interests to declare; AP: speaker: Novartis, Alexpharm; AB: no competing interests to declare; NS: no competing interests to declare; Vasily Shuvaev received fees for lecturing and expert opinion from Novartis, Pfizer, Amgen, and AbbVie; IM: no competing interests to declare; FN was employed by Fusion Pharma; Veronika Shulgina: was employed by Fusion Pharma; AH: Honoraria and research funding (Novartis, Incyte); research funding (Bristol Myers Squibb, Pfizer, MSD); OO: Amgen, Incyte, Celgene, Roche, Fusion Pharma, Novartis: honoraria. 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Cancer Cell 37(4):530–542. https://doi.org/10.1016/j.ccell.2020.03.006 Lipton JH, Chuah C, Guerci-Bresler A et al (2016) Ponatinib versus imatinib for newly diagnosed chronic myeloid leukaemia: an international, randomised, open-label, phase 3 trial. Lancet Oncol 17(5):612-621. https://doi.org/10.1016/s1470-2045(16)00080-2 Moslehi JJ, Deininger M (2015) Tyrosine Kinase Inhibitor-Associated Cardiovascular Toxicity in Chronic Myeloid Leukemia. J Clin Oncol 33(35):4210-4218. https://doi.org/10.1200/jco.2015.62.4718 Steegmann JL, Baccarani M, Breccia M et al (2016) European LeukemiaNet recommendations for the management and avoidance of adverse events of treatment in chronic myeloid leukaemia. Leukemia. 30(8):1648-1671. https://doi.org/10.1038/leu.2016.104 Saydam G, Ali R, Demir AM et al (2022) The effect of comorbidities on the choice of tyrosine kinase inhibitors in patients with chronic myeloid leukemia. Int J Hematol Oncol 11(1):IJH38. https://doi.org/10.2217/ijh-2021-0010 Soverini S, Colarossi S, Gnani A et al (2006) GIMEMA Working Party on Chronic Myeloid Leukemia. Contribution of ABL kinase domain mutations to imatinib resistance in different subsets of Philadelphia-positive patients: by the GIMEMA Working Party on Chronic Myeloid Leukemia. Clin Cancer Res 12(24):7374-7379. https://doi.org/10.1158/1078-0432.ccr-06-1516 Etienne G, Dulucq S, Huguet F et al (2019) Incidence and outcome of BCR-ABL mutated chronic myeloid leukemia patients who failed to tyrosine kinase inhibitors. Cancer Med 8(11):5173-5182. https://doi.org/10.1002/cam4.2410 Réa D, Mauro MJ, Boquimpani C et al (2021) A phase 3, open-label, randomized study of asciminib, a STAMP inhibitor, vs bosutinib in CML after 2 or more prior TKIs. Blood 138(21):2031-2041. https://doi.org/10.1182/blood.2020009984 Cortes JE, Kim D-W, Pinilla-Ibarz J et al (2013) A phase 2 trial of ponatinib in Philadelphia chromosome-positive leukemias. N Engl J Med 369(19):1783–1796. https://doi.org/10.1056/nejmoa1306494 Cortes JE, Kim D-W, Pinilla-Ibarz J et al (2018) Ponatinib efficacy and safety in Philadelphia chromosome-positive leukemia: final 5-year results of the phase 2 PACE trial. Blood 132(4):393–404. https://doi.org/10.1182/blood-2016-09-739086 Valent P, Hadzijusufovic E, Schernthaner G-H et al (2015) Vascular safety issues in CML patients treated with BCR/ABL1 kinase inhibitors. Blood 125(6):901–906. https://doi.org/10.1182/blood-2014-09-594432 Januzzi JL, Garasic JM, Kasner SE et al (2022) Retrospective analysis of arterial occlusive events in the PACE trial by an independent adjudication committee. J Hematol Oncol 15(1):1-25. doi: 10.1186/s13045-021-01221-z. Pulte ED, Chen H, Price LSL et al (2022) FDA Approval Summary: Revised Indication and Dosing Regimen for Ponatinib Based on the Results of the OPTIC Trial. Oncologist 27(2):149-157. https://doi.org/10.1093/oncolo/oyab040 Mian AA, Rafiei A, Haberbosch I et al (2015) PF-114, a potent and selective inhibitor of native and mutated BCR/ABL is active against Philadelphia chromosome-positive (Ph+) leukemias harboring the T315I mutation. Leukemia 29(5):1104–1114. https://doi.org/10.1038/leu.2014.326 Ivanova ES, Tatarskiy VV, Yastrebova MA et al (2019) PF‑114, a novel selective inhibitor of BCR‑ABL tyrosine kinase, is a potent inducer of apoptosis in chronic myelogenous leukemia cells. Int J Oncol 55(1):289-297. https://doi.org/10.3892/ijo.2019.4801 National Cancer Institute Common Terminology Criteria for Adverse Events 4.03, 14 June 2010. https://www.eortc.be/services/doc/ctc/ctcae_4.03_2010-06-14_quickreference_5x7.pdf Baccarani M, Deininger MW, Rosti G et al (2013) European LeukemiaNet recommendations for the management of chronic myeloid leukemia: 2013. Blood 122(6):872–884. https://doi.org/10.1182/blood-2013-05-501569 McDermott MM, Liu K, Criqui MH et al (2005) Ankle-Brachial Index and Subclinical Cardiac and Carotid Disease The Multi-Ethnic Study of Atherosclerosis, Am J Epidemiol 162:33–41. https://doi.org/10.1093/aje/kwi167 Copland M (2022) Treatment of blast phase chronic myeloid leukaemia: A rare and challenging entity. Br J Haematol 199(5):665-678. https://doi.org/10.1111/bjh.18370 Jain P, Kantarjian HM, Ghorab A et al (2017) Prognostic factors and survival outcomes in patients with chronic myeloid leukemia in blast phase in the tyrosine kinase inhibitor era: Cohort study of 477 patients. Cancer 123(22):4391-4402. https://doi.org/10.1002/cncr.30864 Additional Declarations Competing interest reported. AT – speaker: Novartis, Pfizer, R-Pharm, consultancy/advisory board: Novartis; OV: no competing interests to declare; EL has received fees for lecturing and expert opinion from Novartis, Pfizer, Sotex, Pharmstandard and Fusion Pharma; ES: no competing interests to declare; OS: no competing interests to declare; EC – speaker: Novartis, Pfizer, R-Pharm, consultancy: Ascentage Pharma; DS: no competing interests to declare; IN: no competing interests to declare; AP: speaker: Novartis, Alexpharm; AB: no competing interests to declare; NS: no competing interests to declare; Vasily Shuvaev received fees for lecturing and expert opinion from Novartis, Pfizer, Amgen, and AbbVie; IM: no competing interests to declare; FN was employed by Fusion Pharma; Veronika Shulgina: was employed by Fusion Pharma; AH: Honoraria and research funding (Novartis, Incyte); research funding (Bristol Myers Squibb, Pfizer, MSD); OO: Amgen, Incyte, Celgene, Roche, Fusion Pharma, Novartis: honoraria. Amgen, Incyte, and Celgene: research funding; JC: Consultancy (Pfizer, Takeda, Nerviano, Sun Pharma, Novartis, Biopath Holdings, Tigel); research funding (Ascentage, Novartis, Sun Pharma, Tern Pharma, Abbvie); membership on an entity’s board of directors or advisory committees (BioPath Holdings); RPG is a consultant to Antengene Biotech LLC, Ascentage Pharma Group and NexImmune Inc.; Medical Director, FFF Enterprises Inc.; A speaker for Janssen Pharma and Hengrui Pharma; Board of Directors: Russian Foundation for Cancer Research Support; and Scientific Advisory Boards, Nanexa AB and StemRad Ltd.; GC is employed by Fusion Pharma Supplementary Files Vamotinibphase1AnnHematolv1SupplementaryInformation.docx Cite Share Download PDF Status: Published Journal Publication published 29 Apr, 2025 Read the published version in Annals of Hematology → Version 1 posted Editorial decision: Revision requested 25 Nov, 2024 Reviews received at journal 24 Nov, 2024 Reviews received at journal 20 Nov, 2024 Reviews received at journal 17 Nov, 2024 Reviewers agreed at journal 13 Nov, 2024 Reviewers agreed at journal 13 Nov, 2024 Reviewers agreed at journal 11 Nov, 2024 Reviewers invited by journal 11 Nov, 2024 Editor assigned by journal 06 Nov, 2024 Submission checks completed at journal 06 Nov, 2024 First submitted to journal 27 Oct, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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AT – speaker: Novartis, Pfizer, R-Pharm, consultancy/advisory board: Novartis; OV: no competing interests to declare; EL has received fees for lecturing and expert opinion from Novartis, Pfizer, Sotex, Pharmstandard and Fusion Pharma; ES: no competing interests to declare; OS: no competing interests to declare; EC – speaker: Novartis, Pfizer, R-Pharm, consultancy: Ascentage Pharma; DS: no competing interests to declare; IN: no competing interests to declare; AP: speaker: Novartis, Alexpharm; AB: no competing interests to declare; NS: no competing interests to declare; Vasily Shuvaev received fees for lecturing and expert opinion from Novartis, Pfizer, Amgen, and AbbVie; IM: no competing interests to declare; FN was employed by Fusion Pharma; Veronika Shulgina: was employed by Fusion Pharma; AH: Honoraria and research funding (Novartis, Incyte); research funding (Bristol Myers Squibb, Pfizer, MSD); OO: Amgen, Incyte, Celgene, Roche, Fusion Pharma, Novartis: honoraria. Amgen, Incyte, and Celgene: research funding; JC: Consultancy (Pfizer, Takeda, Nerviano, Sun Pharma, Novartis, Biopath Holdings, Tigel); research funding (Ascentage, Novartis, Sun Pharma, Tern Pharma, Abbvie); membership on an entity’s board of directors or advisory committees (BioPath Holdings); RPG is a consultant to Antengene Biotech LLC, Ascentage Pharma Group and NexImmune Inc.; Medical Director, FFF Enterprises Inc.; A speaker for Janssen Pharma and Hengrui Pharma; Board of Directors: Russian Foundation for Cancer Research Support; and Scientific Advisory Boards, Nanexa AB and StemRad Ltd.; GC is employed by Fusion Pharma","formattedTitle":"Phase-1 study of vamotinib (PF-114), a 3rd generation BCR::ABL1 tyrosine kinase-inhibitor, in chronic myeloid leukaemia","fulltext":[{"header":"Introduction","content":"\u003cp\u003eSix tyrosine kinase inhibitors (TKIs) are approved to treat \u003cem\u003eBCR::ABL1\u003c/em\u003e positive chronic myeloid leukemia (\u003cem\u003eBCR::ABL1\u003c/em\u003e\u0026thinsp;+\u0026thinsp;CML) [\u003cspan additionalcitationids=\"CR2 CR3 CR4 CR5\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. However, there remains a need for new TKIs because of resistance and intolerance [\u003cspan additionalcitationids=\"CR8 CR9 CR10 CR11 CR12 CR13 CR14 CR15 CR16 CR17 CR18 CR19 CR20 CR21 CR22 CR23 CR24\" citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. Vamotinib (PF-114) mesylate is a potent, highly specific 3rd generation \u003cem\u003eBCR::ABL1\u003c/em\u003e-inhibitor for oral use. Vamotinib is rationally designed to avoid inhibition of vascular endothelial growth factor receptor-2 (\u003cem\u003eVEGFR2\u003c/em\u003e) and other off-target kinases [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. Vamotinib is active against wild-type and mutant \u003cem\u003eBCR::ABL1\u003c/em\u003e isoforms including \u003cem\u003eBCR::ABL1\u003c/em\u003e\u003csup\u003e\u003cem\u003eT315I\u003c/em\u003e\u003c/sup\u003e. In pre-clinical studies in animals there were few adverse events including no arterial occlusive events. We present the results of a phase-1 trial of vamotinib in subjects with \u003cem\u003eBCR::ABL1\u003c/em\u003e-positive CML failing\u0026thinsp;\u0026ge;\u0026thinsp;2nd generation TKIs (2G-TKIs) or with \u003cem\u003eBCR::ABL1\u003c/em\u003e\u003csup\u003eT315I\u003c/sup\u003e.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy oversight\u003c/h2\u003e \u003cp\u003e The study was designed by Fusion Pharma, LLC, in collaboration with the principal investigators from each clinical centre participating in the study and members of the sponsor's Scientific Advisory Board. Data were collected, analyzed and interpreted by OCT (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://oct-clinicaltrials.com/\u003c/span\u003e\u003cspan address=\"https://oct-clinicaltrials.com/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e) a clinical contract research organization (CRO). Principal investigators verified data accuracy and completeness at their site and integrity of the analyses and study conducted consistent with the study protocol.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eSubjects\u003c/h3\u003e\n\u003cp\u003eStudy subjects\u0026thinsp;\u0026ge;\u0026thinsp;18 years with \u003cem\u003eBCR::ABL1\u003c/em\u003e positive CML in chronic (CP) or accelerated phase (AP) using the European LeukemiaNet 2013 guidelines [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. Subjects, had to have failed\u0026thinsp;\u0026ge;\u0026thinsp;1 TKIs or intolerance to \u0026ge;\u0026thinsp;2 TKIs or have \u003cem\u003eBCR::ABL1\u003c/em\u003e\u003csup\u003eT315I\u003c/sup\u003e. Other eligibility criteria included ECOG performance score 0\u0026ndash;2; QTcF interval\u0026thinsp;\u0026le;\u0026thinsp;470 milliseconds and resolution of all prior therapy-associated adverse event to \u0026le;\u0026thinsp;Grade-1 according to NCI CTC AE v4 criteria [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e].\u003c/p\u003e\n\u003ch3\u003eStudy design\u003c/h3\u003e\n\u003cp\u003eOpen-label phase-1 study at 3 clinical centers with dose-escalation using a 3\u0026thinsp;+\u0026thinsp;3 scheme with a starting dose of 50 mg/d given continuously. A 28-days of therapy was defined as a cycle. Dose escalation for the subsequent cohort depended on the results of the safety assessment of subjects in the preceding cohort during the 28 days of therapy. Once an MTD was identified expanded cohorts of 10\u0026ndash;15 subjects were recruited at doses of interest below the MTD. A modified accelerated dose-escalation regimen was used up to a dose of 400 mg. Dose could be increased for subjects in whom the dose was reduced because of an adverse drug reaction (ADR). Severity of adverse events was assessed using NCI CTC AE v4 [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe primary objective was to determine the MTD and DLT of vamotinib during the 1st cycle of therapy. Secondary objectives were to assess the safety and tolerability of vamotinib, determine pharmacokinetics and determine efficacy by response criteria according to 2013 ELN [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e].\u003c/p\u003e\n\u003ch3\u003ePharmaco-kinetics and -dynamics\u003c/h3\u003e\n\u003cp\u003eBlood samples were obtained to evaluate pharmacokinetics and pharmacodynamics (Tables S1, S1.1, S1.2). Data on phosphorylated CrkL protein (pCrkL) concentration were evaluated in samples from 4 subjects.\u003c/p\u003e\n\u003ch3\u003eEfficacy\u003c/h3\u003e\n\u003cp\u003eHaematological response evaluations were done on the first day of each therapy; molecular response on the first day of cycles 1, 2, 4, 7, 10, 13 and then every three months; cytogenetic response \u0026ndash; at screening and on the first days of cycles 4, 7, 13 and every three months thereafter, provided that there was no major molecular response.\u003c/p\u003e \u003cp\u003eCytogenetic response was assessed by differential staining of chromosomes and if uninformative, by fluorescent \u003cem\u003ein situ\u003c/em\u003e hybridization (FISH). Mutations in \u003cem\u003eBCR::ABL1\u003c/em\u003e were assessed by Sanger and next generation sequencing (NGS). Sanger sequencing was done at each center; NGS analyses were done in the laboratory of Prof. Susan Branford, University of Adelaide. Discordances were resolved as described in Table S2. Molecular response was assessed using the ratio of \u003cem\u003eBCR::ABL1\u003c/em\u003e to \u003cem\u003eABL1\u003c/em\u003e measured according to the IS [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e].\u003c/p\u003e"},{"header":"RESULTS","content":"\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003eSubjects and baseline co-variates\u003c/h2\u003e \u003cp\u003e54 subjects were screened between July, 2016 and January, 2019, 51 of whom were enrolled. The starting dose of vamotinib was 50 mg/d (n\u0026thinsp;=\u0026thinsp;3). Subsequent subjects were sequentially recruited into cohorts at doses of 100 mg (n\u0026thinsp;=\u0026thinsp;3), 200 mg (n\u0026thinsp;=\u0026thinsp;11), 400 mg (n\u0026thinsp;=\u0026thinsp;12), 500 mg (n\u0026thinsp;=\u0026thinsp;3), 600 mg (n\u0026thinsp;=\u0026thinsp;6), 750 mg (n\u0026thinsp;=\u0026thinsp;4), and 300 mg (n\u0026thinsp;=\u0026thinsp;9). All subjects treated at 300 mg daily and 6 subjects at 400 mg were enrolled after the MTD was determined. The cut-off date of the analysis is July 30, 2019.\u003c/p\u003e \u003cp\u003eBaseline co-variates and therapy state of subjects as are displayed in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. Mean follow-up is 27 w (range 0.1\u0026ndash;31 w, IQR 65 w). 36 subjects previously received\u0026thinsp;\u0026ge;\u0026thinsp;3TKIs. 35 subjects had\u0026thinsp;\u0026ge;\u0026thinsp;1 \u003cem\u003eBCR::ABL1\u003c/em\u003e kinase domain mutation the most common of which was \u003cem\u003eBCR::ABL1\u003c/em\u003e\u003csup\u003eT315I\u003c/sup\u003e in 16 (Table S2.1). All subjects discontinued from the study 1 of whom died later from blast transformation.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eBaseline co-variates and therapy state\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"10\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c10\" colnum=\"10\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCohort 1\u003c/p\u003e \u003cp\u003e50 mg\u003c/p\u003e \u003cp\u003e(N\u0026thinsp;=\u0026thinsp;3)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCohort 2\u003c/p\u003e \u003cp\u003e100 mg\u003c/p\u003e \u003cp\u003e(N\u0026thinsp;=\u0026thinsp;3)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eCohort 3\u003c/p\u003e \u003cp\u003e200 mg\u003c/p\u003e \u003cp\u003e(N\u0026thinsp;=\u0026thinsp;11)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eCohort 4\u003c/p\u003e \u003cp\u003e400 mg\u003c/p\u003e \u003cp\u003e(N\u0026thinsp;=\u0026thinsp;12)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eCohort 5\u003c/p\u003e \u003cp\u003e500 mg\u003c/p\u003e \u003cp\u003e(N\u0026thinsp;=\u0026thinsp;3)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eCohort 6\u003c/p\u003e \u003cp\u003e600 mg\u003c/p\u003e \u003cp\u003e(N\u0026thinsp;=\u0026thinsp;6 )\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003eCohort 7\u003c/p\u003e \u003cp\u003e750 mg\u003c/p\u003e \u003cp\u003e(N\u0026thinsp;=\u0026thinsp;4)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c9\"\u003e \u003cp\u003eCohort 8\u003c/p\u003e \u003cp\u003e300 mg\u003c/p\u003e \u003cp\u003e(N\u0026thinsp;=\u0026thinsp;9)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c10\"\u003e \u003cp\u003eAll\u003c/p\u003e \u003cp\u003e(N\u0026thinsp;=\u0026thinsp;51)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eTime on treatment\u003c/b\u003e, median (range) \u0026ndash;days\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e308 (28\u0026ndash;707)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e394 (280\u0026ndash;1592)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e261 (45-1549)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e162 (14\u0026ndash;539)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e54 (23\u0026ndash;79)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e102 (31-1002)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e35 (13\u0026ndash;364)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e805 (77-1093)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e199 (13-1592)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"10\" nameend=\"c10\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eTherapy state\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDiscontinued\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e51\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDisease progression or need to change therapy in the opinion of the investigator\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e20\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAdverse event\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIntolerable adverse drug reaction in the opinion of the investigator\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWithdrawal of informed consent\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eParticipation in another clinical study or additional therapy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLost to follow-up\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSponsor's decision to terminate the study\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOther\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"10\" nameend=\"c10\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eECOG performance-status score\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e40\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"10\" nameend=\"c10\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eNo. of previous TKIs\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e19\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026ge;\u0026thinsp;3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e36\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"10\" nameend=\"c10\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePrevious TKI\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eImatinib\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e49\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNilotinib\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e32\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDasatinib\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e33\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBosutinib\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e14\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePonatinib\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"10\" nameend=\"c10\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eBCR::ABL1\u003c/b\u003e \u003cb\u003etranscript\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ep 210\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e50\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ep 190\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0si\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eSafety\u003c/h3\u003e\n\u003cp\u003eThere was no DLT in cohorts at doses\u0026thinsp;\u0026lt;\u0026thinsp;400 mg/d. At a dose of 400 mg/d 1 subject developed a Grade-3 psoriasiform dermatitis (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). There were no DLTs at doses of 500 mg/d and 600 mg/d. At a dose of 750 mg/d all 3 subjects treated developed skin DLTs, therefore 600 mg/d was defined as the MTD. Additional subjects were enrolled in the 400 mg/d, 300 mg/d, and 200 mg/d cohorts. Therapy duration was briefer at a dose of 400 md/d. Rates of dose-reductions and therapy-interruptions were higher for 400 mg/d compared with lower doses (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e)\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eSubjects\u0026rsquo; treatment and dose-limiting toxicities.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"10\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c10\" colnum=\"10\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCohorts\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCohort 1\u003c/p\u003e \u003cp\u003e50 mg\u003c/p\u003e \u003cp\u003e(N\u0026thinsp;=\u0026thinsp;3)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCohort 2\u003c/p\u003e \u003cp\u003e100 mg\u003c/p\u003e \u003cp\u003e(N\u0026thinsp;=\u0026thinsp;3)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eCohort 3\u003c/p\u003e \u003cp\u003e200 mg\u003c/p\u003e \u003cp\u003e(N\u0026thinsp;=\u0026thinsp;11)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eCohort 4\u003c/p\u003e \u003cp\u003e400 mg\u003c/p\u003e \u003cp\u003e(N\u0026thinsp;=\u0026thinsp;12)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eCohort 5\u003c/p\u003e \u003cp\u003e500 mg\u003c/p\u003e \u003cp\u003e(N\u0026thinsp;=\u0026thinsp;3)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eCohort 6\u003c/p\u003e \u003cp\u003e600 mg\u003c/p\u003e \u003cp\u003e(N\u0026thinsp;=\u0026thinsp;6)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003eCohort 7\u003c/p\u003e \u003cp\u003e750 mg\u003c/p\u003e \u003cp\u003e(N\u0026thinsp;=\u0026thinsp;4)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c9\"\u003e \u003cp\u003eCohort 8\u003c/p\u003e \u003cp\u003e300 mg\u003c/p\u003e \u003cp\u003e(N\u0026thinsp;=\u0026thinsp;9)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c10\"\u003e \u003cp\u003eAll subjects,\u003c/p\u003e \u003cp\u003e(N\u0026thinsp;=\u0026thinsp;51)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTime on treatment, median\u003c/p\u003e \u003cp\u003e(range) \u0026ndash;\u003c/p\u003e \u003cp\u003edays\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e308\u003c/p\u003e \u003cp\u003e(28\u0026ndash;707)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e394\u003c/p\u003e \u003cp\u003e(280\u0026ndash;1592)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e261\u003c/p\u003e \u003cp\u003e(45-1549)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e162\u003c/p\u003e \u003cp\u003e(14\u0026ndash;539)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e54\u003c/p\u003e \u003cp\u003e(23\u0026ndash;79)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e102\u003c/p\u003e \u003cp\u003e(31-1002)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e35\u003c/p\u003e \u003cp\u003e(13\u0026ndash;364)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e805\u003c/p\u003e \u003cp\u003e(77-1093)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e199\u003c/p\u003e \u003cp\u003e(13-1592)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDLTs\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSubjects with dose delay, n\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e27\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSubjects with dose reduction, n\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e15\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eThe most common non-hematological adverse event was psoriasiform dermatitis in 19 subjects 4 of which were Grade-3/-4 (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). There was diarrhea in 14 subjects, all \u0026lt;\u0026thinsp;Grade-3. Dry skin and rash occurred in 8 subjects 6 subjects had a Grade-3/-4 toxic skin rash. 6 subjects had serious adverse events (Table S3).\u003c/p\u003e \u003cp\u003eHaematological adverse events were common but usually Grade-1/-2 (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). No cardio-vascular or arterial occlusive adverse events were reported at any dose, including no cases of occlusion of large peripheral blood vessels and no clinically significant deviations of the ankle-brachial index from its normal range 1.00-1.29 [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e].\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eMost common adverse events.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAdverse Events\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAll grades\u003c/p\u003e \u003cp\u003e(N\u0026thinsp;=\u0026thinsp;51)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eGrade 3\u0026ndash;4\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e\u003cem\u003eNumber of subjects (percent)\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSkin and subcutaneous tissue disorders\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e32 (63)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e11 (22)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDermatitis psoriasiform\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e19 (37)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4 (8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eToxic skin eruption\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9 (18)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7 (14)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDry skin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9 (18)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePruritus\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5 (10)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eErythema\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4 (8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRash papular\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eGastrointestinal disorders\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e17 (33)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDiarrhoea\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e14 (28)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNausea\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6 (12)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAbdominal pain upper\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4 (8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAbdominal pain\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAnal fissure\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDyspepsia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eBlood and lymphatic system disorders\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e12 (24)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e7 (14)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eThrombocytopenia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8 (16)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4 (8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNeutropenia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5 (10)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3 (6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAnaemia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLeukopenia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003egInvestigations\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e7 (14)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e1 (2)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBlood cholesterol increased\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCardiac disorders\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEye disorders\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAlanine aminotransferase increased\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLow density lipoprotein increased\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTransaminases increased\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eHepato-biliary disorders\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e1 (2)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e1 (2)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHepatitis toxic\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003csup\u003e*\u003c/sup\u003eDermatitis psoriasiform \u0026ndash; 2 subjects on 400 mg; 2 subjects on 600 mg; Toxic skin eruption \u0026ndash; 1 subject on 300 mg; 1 subject on 400 mg; 2 subjects on 500 mg; 1 subject on 600 mg; 2 subjects on 750 mg; Pruritus \u0026ndash; 1 subject on 600 mg; Hepatitis toxic \u0026ndash; 1 subject on 400 mg; Thrombocytopenia \u0026ndash; 1 subject on 200 mg; 1 subject on 500 mg; 1 subject on 600 mg; 1 subject on 750 mg; Neutropenia \u0026ndash; 2 subjects on 400 mg; 1 subject on 500 mg; Anaemia \u0026ndash; 1 subject on 200 mg; Leukopenia \u0026ndash; 1 subject on 400 mg.\u003c/p\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eRash\u003c/h2\u003e \u003cp\u003eRashes were the most common non-haematological adverse event and were seen in 32 subjects (Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). Grade-3 rash occurred in 10 subjects at doses\u0026thinsp;\u0026ge;\u0026thinsp;400 mg/d. Rash was the reason for dose-reduction (n\u0026thinsp;=\u0026thinsp;9) and study withdrawal (n\u0026thinsp;=\u0026thinsp;6). No rash was coded as a serious adverse events. The most common rash was psoriasiform with erythema, lymphoplasmacytic infiltration of derma and desquamation of well-defined foci. Rashes were often in sites of friction and stretching and painless but occasionally associated with paresthesia. Other types of rashes included dryness and redness mainly in the setting of development or regression of psoriasiform rashes. Toxicity resolved within 1\u0026ndash;2 weeks after discontinuation of the drug. Lipoic acid (tablets), vitamin E, and topical agents such as tacrolimus 0.1, betamethasone 0.05, calcipotriol, hydrocortisone 0.5 eye ointment, urea 10, thermal water were used to manage skin lesions. After 4\u0026ndash;6 months of taking the drug, adaptation of the skin to its effects was noted.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eSkin toxicity.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"11\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c10\" colnum=\"10\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c11\" colnum=\"11\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSeverity\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCohort 1 50 mg\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eCohort 2 100 mg\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eCohort 3 200 mg\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eCohort 4 400 mg\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eCohort 5 500 mg\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003eCohort 6 600 mg\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c9\"\u003e \u003cp\u003eCohort 7 750 mg\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c10\"\u003e \u003cp\u003eCohort 8 300 mg\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c11\"\u003e \u003cp\u003eOverall\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eN\u0026thinsp;=\u0026thinsp;3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eN\u0026thinsp;=\u0026thinsp;3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eN\u0026thinsp;=\u0026thinsp;11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eN\u0026thinsp;=\u0026thinsp;12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eN\u0026thinsp;=\u0026thinsp;3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eN\u0026thinsp;=\u0026thinsp;6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eN\u0026thinsp;=\u0026thinsp;4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eN\u0026thinsp;=\u0026thinsp;9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003eN\u0026thinsp;=\u0026thinsp;51\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003ePsoriasiform dermatitis, n\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eGrade 3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTotal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e19\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eDry skin, n\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eGrade 3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTotal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eErythema, n\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eGrade 3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTotal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003ePruritus, n\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eGrade 3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTotal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eToxic skin eruption, n\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eGrade 3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTotal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eRash papular, n\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eGrade 3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTotal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003ePharmacokinetics\u003c/h2\u003e \u003cp\u003ePharmacokinetic measurements were done days 1 and 29\u0026ndash;30 of treatment. The time to reach C\u003csub\u003emax\u003c/sub\u003e was approximately 4 hours, the half-life of 13.5 hours, which confirmed the validity of the once a day regimen. Steady-state was reached after 8 days of dosing, Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. The concentration-time profiles suggest linear or near-linear pharmacokinetics of vamotinib over the entire dose range studied (50\u0026ndash;750 mg). Dose proportionality assessment showed a less than dose-dependent increase in AUC and C\u003csub\u003emax\u003c/sub\u003e of vamotinib (Table S4). Starting from a dose of 200 mg, the concentration of vamotinib in the blood during the day exceeds 75 nM, corresponding to the IC50 of cytotoxicity for BaF3 cells expressing \u003cem\u003eBCR::ABL1\u003c/em\u003e\u003csup\u003e\u003cem\u003eT315I\u003c/em\u003e\u003c/sup\u003e [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e].\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eAnalysis of changes in blood pCrkL done for subjects with leukocytosis on days 1, 8 and 29 of therapy but was uninformative due to poor quality of samples.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eEfficacy\u003c/h2\u003e \u003cp\u003eEfficacy and best responses to treatment are summarized in Table\u0026nbsp;\u003cspan refid=\"Tab5\" class=\"InternalRef\"\u003e5\u003c/span\u003e and Table S6. 30 subjects did not have a complete hematological response (CHR) at baseline 14 of whom achieved a CHR (Table\u0026nbsp;\u003cspan refid=\"Tab5\" class=\"InternalRef\"\u003e5\u003c/span\u003e). Median time to achieving a CHR was 3.8 months, (range, 1\u0026ndash;4 months); all instances of CHR were maintained at least for 12 months of therapy. Of the 44 and 50 subjects who did not have a major cytogenetic response (MCyR) and a complete cytogenetic response (CCyR) at the start of therapy, respectively, 14 (32%) achieved MCyR and 10 (20%) achieved CCyR during therapy. The median time to achievement of MCyR and CCyR were 4.5 months (range 1.9\u0026ndash;19.4) and 5.6 months (range 2.8\u0026ndash;15), respectively. None of the 51 subjects had a major molecular response (MMR) at study entry, and 7 (13.7%) subjects achieved MMR during therapy. One subject on a dose of 300 mg achieved a deep molecular response of MR4.5. The median time to MMR was 5,6 months (range 2.8\u0026ndash;22.2), and no subject has lost after 24 months. One subject, treated at a dose of 300 mg, achieved a MR4.5. Most molecular and cytogenetic responses were observed at doses of 300 and 200 mg. The lower number of responses at doses of 400 mg and above may be explained by the fact that the resulting (skin) toxicity prevented long-term treatment of subjects at these doses.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab5\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 5\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eEfficacy\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"10\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c10\" colnum=\"10\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCohort 1 50 mg\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCohort 2\u003c/p\u003e \u003cp\u003e100 mg\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eCohort 3\u003c/p\u003e \u003cp\u003e200 mg\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eCohort 4\u003c/p\u003e \u003cp\u003e400 mg\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eCohort 5\u003c/p\u003e \u003cp\u003e500 mg\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eCohort 6\u003c/p\u003e \u003cp\u003e600 mg\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003eCohort 7\u003c/p\u003e \u003cp\u003e750 mg\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c9\"\u003e \u003cp\u003eCohort 8\u003c/p\u003e \u003cp\u003e300 mg\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c10\"\u003e \u003cp\u003eTotal\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eN\u0026thinsp;=\u0026thinsp;3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eN\u0026thinsp;=\u0026thinsp;3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eN\u0026thinsp;=\u0026thinsp;11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eN\u0026thinsp;=\u0026thinsp;12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eN\u0026thinsp;=\u0026thinsp;3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eN\u0026thinsp;=\u0026thinsp;6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eN\u0026thinsp;=\u0026thinsp;4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eN\u0026thinsp;=\u0026thinsp;9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eN\u0026thinsp;=\u0026thinsp;51\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAbsence of CHR at baseline \u0026ndash; no. (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (67)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e5 (46)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e7 (58)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e2 (67)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e6 (100)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e4 (100)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e4 (44)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e30 (59)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCHR at treatment \u0026ndash; no.\u0026nbsp;(%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (50)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2 (40)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e4 (57)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e2 (33)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e1 (25)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e4 (100)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e14 (47)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCHR by the 3 months \u0026ndash; no.\u0026nbsp;(%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2 (40)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2 (29)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e2 (33)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e1 (25)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e4 (100)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e11 (37)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCHR by the 6th months \u0026ndash; no. (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2 (40)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2 (29)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e2 (33)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e1 (25)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e4 (100)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e11 (37)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCHR by the 12th months \u0026ndash; no.\u0026nbsp;(%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (50)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2 (40)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e4 (57)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e2 (33)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e1 (25)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e4 (100)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e14 (47)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSubjects with loss of CHR \u0026ndash; no.\u0026nbsp;(%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2 (100)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e4 (100)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e2 (50)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e8 (57)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAbsence of MCyR at baseline \u0026ndash; no. (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (100)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (67)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e8 (73)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e11 (92)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e3 (100)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e6 (100)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e4 (100)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e7 (78)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e44 (86)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMCyR at treatment \u0026ndash; no. (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (67)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4 (50)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2 (19)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e6 (86)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e14 (32)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMCyR by 6\u0026nbsp;months \u0026ndash; no.\u0026nbsp;(%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (33)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3 (38)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2 (19)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e4 (57)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e10 (23)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMCyR by 12\u0026nbsp;months \u0026ndash; no.\u0026nbsp;(%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (33)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3 (38)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2 (19)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e5 (83)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e11 (25)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSubjects with loss of MCyR \u0026ndash; no.\u0026nbsp;(%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1 (25)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e1 (17)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e2 (14)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAbsence of CCyR at baseline \u0026ndash; no. (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (100)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3 (100)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e10 (91)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e12 (100)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e3 (100)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e6 (100)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e4 (100)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e9 (100)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e50 (98)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCCyR at treatment \u0026ndash; no.\u0026nbsp;(%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (33)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3 (30)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1 (8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e5 (56)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e10 (20)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCCyR by 6\u0026nbsp;months \u0026ndash; no.\u0026nbsp;(%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2 (20)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1 (8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e3 (33)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e6 (12)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCCyR by 12\u0026nbsp;months \u0026ndash; no.\u0026nbsp;(%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2 (20)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1 (8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e4 (44)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e7 (14)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSubjects with loss of CCyR \u0026ndash; no.\u0026nbsp;(%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1 (33)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e1 (20)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e2 (20)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAbsence of MMR at baseline \u0026ndash; no. (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (100)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3 (100)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e11 (100)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e12 (100)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e3 (100)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e6 (100)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e4 (100)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e9 (100)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e51 (100)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMMR at treatment \u0026ndash; no. (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (33)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2 (18)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e4 (44)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e7 (14)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMMR by 6 months \u0026ndash; no.\u0026nbsp;(%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1 (9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e3 (33)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e4 (8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMMR by 12 months \u0026ndash; no.\u0026nbsp;(%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1 (9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e3 (33)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e4 (8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMMR by 24 months \u0026ndash; no.\u0026nbsp;(%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (33)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2 (18)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e4 (44)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e7 (14)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSubjects with loss of MMR \u0026ndash; no.\u0026nbsp;(%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eOf the 16 subjects with \u003cem\u003eBCR::ABL1\u003c/em\u003e\u003csup\u003eT315I\u003c/sup\u003e, 12 did not have CHR at study entry; 3 of them achieved CHR during vamotinib therapy. Of the 15 subjects without MCyR and 16 without CCyR, 2 and 1 subjects achieved responses, respectively (Table\u0026nbsp;\u003cspan refid=\"Tab6\" class=\"InternalRef\"\u003e6\u003c/span\u003e). Responses to vamotinib in subjects with \u003cem\u003eBCR::ABL1\u003c/em\u003e\u003csup\u003eT315I\u003c/sup\u003e were transient, lasting 2.8 months (MCyR) and 2.8 months (CCyR). Most subjects with \u003cem\u003eBCR::ABL1\u003c/em\u003e\u003csup\u003eT315I\u003c/sup\u003e were treated at doses of 400 mg and above, which were characterized by premature withdrawal from the study due to toxicity. No subject with \u003cem\u003eBCR::ABL1\u003c/em\u003e\u003csup\u003eT315I\u003c/sup\u003e was included in the 300 mg dose cohort, which performed optimally in terms of efficacy and safety. Five subjects had received prior therapy ponatinib. None had CHR at study entry and 2 achieved CHR; however, none achieved MCyR or CCyR (Table\u0026nbsp;\u003cspan refid=\"Tab6\" class=\"InternalRef\"\u003e6\u003c/span\u003e). Five subjects with advanced phase CML (4 in AP and 1 in blast phase, BP) were treated. 2 achieved a CHR but none achieved MCyR or CCyR. 1 subject continued on therapy (Table\u0026nbsp;\u003cspan refid=\"Tab6\" class=\"InternalRef\"\u003e6\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eA subject with myeloid variant M0 blast crisis was treated with vamotinib due to the lack of other available at that time therapies [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]. BP was identified on enrollment and accompanied by i(17) and \u003cem\u003eBCR::ABL1\u003c/em\u003e\u003csup\u003eT315I\u003c/sup\u003e. A CHR was achieved after 5 weeks of vamotinib lasting for 18 months with no cytogenetic response. At 1 year there was extra-medullary relapse and the CHR was lost and vamotinib discontinued.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab6\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 6\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eSubjects with the \u003cem\u003eBCR::ABL1\u003c/em\u003e\u003csup\u003eT315I\u003c/sup\u003e, resistance/intolerance to ponatinib or in accelerated phase.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVariable\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSubjects with \u003cem\u003eBCR::ABL1\u003c/em\u003e\u003csup\u003eT315I\u003c/sup\u003e\u0026nbsp; \u003c/p\u003e \u003cp\u003e(N\u0026thinsp;=\u0026thinsp;16)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSubjects after ponatinib\u003c/p\u003e \u003cp\u003e(N\u0026thinsp;=\u0026thinsp;5)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eAdvanced phase CML\u003c/p\u003e \u003cp\u003e(N\u0026thinsp;=\u0026thinsp;5)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMedian follow-up (range), days\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e78 (17\u0026ndash;987)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e53 (8-266)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e150 (15\u0026ndash;539)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCHR no./total no.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3/12\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2/5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2/5\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMCyR no./total no.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2/15\u003csup\u003e**\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0/5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0/5\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCCyR no./total no.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1/16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0/5\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0/5\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMMR no./total no.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0/16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0/5\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0/5\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003csup\u003e*\u003c/sup\u003e 4 subjects had a CHR at enrollment\u003c/p\u003e \u003cp\u003e \u003csup\u003e**\u003c/sup\u003e 1subject had a MCyR at enrollment\u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eVamotinib is safe and effective in people with CML resistant and/or intolerance to 1st and 2nd generation TKIs, ponatinib and in those with \u003cem\u003eBCR::ABL1\u003c/em\u003e\u003csup\u003eT315I\u003c/sup\u003e. The MTD is 600 mg with rash the dose-limiting and most common DLT and adverse event. Rash was seen in pre-clinical toxicology studies in rats and dogs [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. There were no arterial-occlusive events despite the close structural similarity with ponatinib [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. This correlates with a more selective kinase inhibition profile of vamotinib in EPHA6, EPHA7, TAK1, TIE2, VEGFR2, ZAK kinases and no cardio-vascular findings in pre-clinical toxicology studies [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe study has its limitations due to the relatively small sample size, heterogeneous pretreatment status of the enrolled patients, and the lack of reliable pharmacodynamic readouts.\u003c/p\u003e \u003cp\u003eIn conclusion, \u003cem\u003ev\u003c/em\u003eamotinib is safe and effective in subjects failing\u0026thinsp;\u0026ge;\u0026thinsp;2 TKIs, ponatinib and with \u003cem\u003eBCR::ABL1\u003c/em\u003e\u003csup\u003eT315I\u003c/sup\u003e. The dose selected for further study is 300 mg/d.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe work of Scientific Advisory Board of Fusion Pharma was significantly contributed by Prof. Michele Baccarani, University of Bologna, who left us untimely. Special thanks to the patients and their families, to study support clinical stuff and to the OCT clinical contract research organization for clinical trial documents, reports, statistical analyses. RPG acknowledges support from the UK National Institute of Health Research (NIHR).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contribution\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAT, EC, OS, Vasily Shuvaev, Veronika Shulgina, AH, OO, JC, RPG and GC conceptualized and developed the clinical trial protocol. AT, EC, OV,\u003csup\u003e\u0026nbsp;\u003c/sup\u003eEL,\u003csup\u003e\u0026nbsp;\u003c/sup\u003eES,\u003csup\u003e\u0026nbsp;\u003c/sup\u003eOS, DS,\u003csup\u003e\u0026nbsp;\u003c/sup\u003eIN,\u003csup\u003e,\u0026nbsp;\u003c/sup\u003eAP,\u003csup\u003e\u0026nbsp;\u003c/sup\u003eAB\u003csup\u003e\u0026nbsp;\u003c/sup\u003eand NS conducted the clinical trial. GC drafted the typescript, edited by AT, JC and RPG. IM drafted the tables, All authors read, reviewed and approved the final version of the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study was conducted by Fusion Pharma, LLC with a grant support from the Skolkovo Foundation https://sk.ru/.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFusion Pharma will consider requests for disclosure of raw data underlying the tables and figures in the current manuscript. Qualified academic investigators may request such data for their use solely for non-commercial purposes by applying to the corresponding author\u0026rsquo;s e-mail address [email protected]\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe protocol was approved by the ethics committee of the Ministry of Health of Russian Federation and by the participating clinical sites\u0026rsquo; ethics committees. The study was conducted in accordance with the 1964 Declaration of Helsinki and the Good Clinical Practice Guidelines of the International Conference on Harmonization. All patients provided written informed consent.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTrial registration\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe trial is registered at \u003cem\u003eclinicaltrials.gov\u003c/em\u003e. The registration number is NCT02885766.\u003c/p\u003e\n\u003ch3\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/h3\u003e\n\u003cp\u003eAT \u0026ndash; speaker: Novartis, Pfizer, R-Pharm, consultancy/advisory board: Novartis; OV: no competing interests to declare; EL has received fees for lecturing and expert opinion from Novartis, Pfizer, Sotex, Pharmstandard and Fusion Pharma; ES: no competing interests to declare; OS: no competing interests to declare; EC \u0026ndash; speaker: Novartis, Pfizer, R-Pharm, consultancy: Ascentage Pharma; DS: no competing interests to declare; IN: no competing interests to declare; AP: speaker: Novartis, Alexpharm; AB: no competing interests to declare; NS: no competing interests to declare; Vasily Shuvaev received fees for lecturing and expert opinion from Novartis, Pfizer, Amgen, and AbbVie; IM: no competing interests to declare; FN was employed by Fusion Pharma; Veronika Shulgina: was employed by Fusion Pharma; AH: Honoraria and research funding (Novartis, Incyte); research funding (Bristol Myers Squibb, Pfizer, MSD); OO: Amgen, Incyte, Celgene, Roche, Fusion Pharma, Novartis: honoraria. Amgen, Incyte, and Celgene: research funding; JC: Consultancy (Pfizer, Takeda, Nerviano, Sun Pharma, Novartis, Biopath Holdings, Tigel); research funding (Ascentage, Novartis, Sun Pharma, Tern Pharma, Abbvie); membership on an entity\u0026rsquo;s board of directors or advisory committees (BioPath Holdings); RPG is a consultant to Antengene Biotech LLC, Ascentage Pharma Group and NexImmune Inc.; Medical Director, FFF Enterprises Inc.; A speaker for Janssen Pharma and Hengrui Pharma; Board of Directors: Russian Foundation for Cancer Research Support; and Scientific Advisory Boards, Nanexa AB and StemRad Ltd.; GC is employed by Fusion Pharma\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eDruker BJ, Guilhot F, O\u0026rsquo;Brien SG et al (2006) Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N Engl J Med 355:2408-2417. https://doi.org/10.1056/NEJMoa062867 \u003c/li\u003e\n\u003cli\u003eKantarjian H, Shah NP, Hochhaus A et al (2010) Dasatinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med 362:2260-2270. https://doi.org/10.1056/nejmoa1002315\u003c/li\u003e\n\u003cli\u003eSaglio G, Kim DW, Issaragrisil S et al (2010) Nilotinib versus imatinib for newly diagnosed chronic myeloid leukemia. N Engl J Med 362:2251-2259. https://doi.org/10.1056/nejmoa0912614 \u003c/li\u003e\n\u003cli\u003eCortes JE, Gambacorti-Passerini C, Deininger MW (2017) Bosutinib Versus Imatinib for Newly Diagnosed Chronic Myeloid Leukemia: Results From the Randomized BFORE Trial, J Clin Oncol 36:231-237. https://doi.org/10.1200/jco.2017.74.7162 \u003c/li\u003e\n\u003cli\u003eCortes JE, Kantarjian H, Shah NP et al (2012) Ponatinib in refractory Philadelphia chromosome\u0026ndash;positive leukemias. N Engl J Med 367: 2075-2088. https://doi.org/10.1056/nejmoa1205127 \u003c/li\u003e\n\u003cli\u003eHughes TP, Mauro MJ, Cortes JE et al (2019) Asciminib in Chronic Myeloid Leukemia after ABL Kinase Inhibitor Failure. N Engl J Med 381:2315-2326. https://doi.org/10.1056/nejmoa1902328 \u003c/li\u003e\n\u003cli\u003eShah NP, Nicoll JM, Nagar B et al (2002) Multiple BCR-ABL kinase domain mutations confer polyclonal resistance to the tyrosine kinase inhibitor imatinib (STI571) in chronic phase and blast crisis chronic myeloid leukemia. Cancer Cell 2:117-125. https://doi.org/10.1016/s1535-6108(02)00096-x \u003c/li\u003e\n\u003cli\u003eBranford S, Rudzki Z, Walsh S et al (2003) Detection of BCR-ABL mutations in patients with CML treated with imatinib is virtually always accompanied by clinical resistance, and mutations in the ATP phosphate-binding loop (P-loop) are associated with a poor prognosis. Blood. 102(1):276\u0026ndash;283. https://doi.org/10.1182/blood-2002-09-2896 \u003c/li\u003e\n\u003cli\u003eHughes T, Deininger M, Hochhaus A et al (2006) Monitoring CML patients responding to treatment with tyrosine kinase inhibitors: review and recommendations for harmonizing current methodology for detecting BCR-ABL transcripts and kinase domain mutations and for expressing results. \u003cem\u003eBlood\u003c/em\u003e. 108(1):28\u0026ndash;37. https://doi.org/10.1182/blood-2006-01-0092 \u003c/li\u003e\n\u003cli\u003eO\u0026rsquo;Hare T, Eide CA, Deininger MWN (2007) Bcr-Abl kinase domain mutations, drug resistance, and the road to a cure for chronic myeloid leukemia. \u003cem\u003eBlood \u003c/em\u003e110(7):2242\u0026ndash;2249. https://doi.org/10.1182/blood-2007-03-066936\u003c/li\u003e\n\u003cli\u003eCortes J, Jabbour E, Kantarjian H et al (2007) Dynamics of BCR-ABL kinase domain mutations in chronic myeloid leukemia after sequential treatment with multiple tyrosine kinase inhibitors. Blood; 110: 4005-4011. https://doi.org/10.1182/blood-2007-03-080838 \u003c/li\u003e\n\u003cli\u003eHughes TP, Saglio G, Quint\u0026aacute;s-Cardama A et al (2015) BCR-ABL1 mutation development during first-line treatment with dasatinib or imatinib for chronic myeloid leukemia in chronic phase. Leukemia 29:1832-1838. https://doi.org/10.1038/leu.2015.168 \u003c/li\u003e\n\u003cli\u003eBraun TP, Eide CA, Druker BJ (2020) Response and Resistance to BCR-ABL1-Targeted Therapies. \u003cem\u003eCancer Cell\u003c/em\u003e 37(4):530\u0026ndash;542. https://doi.org/10.1016/j.ccell.2020.03.006 \u003c/li\u003e\n\u003cli\u003eLipton JH, Chuah C, Guerci-Bresler A et al (2016) Ponatinib versus imatinib for newly diagnosed chronic myeloid leukaemia: an international, randomised, open-label, phase 3 trial. Lancet Oncol 17(5):612-621. https://doi.org/10.1016/s1470-2045(16)00080-2 \u003c/li\u003e\n\u003cli\u003eMoslehi JJ, Deininger M (2015) Tyrosine Kinase Inhibitor-Associated Cardiovascular Toxicity in Chronic Myeloid Leukemia. J Clin Oncol 33(35):4210-4218. https://doi.org/10.1200/jco.2015.62.4718\u003c/li\u003e\n\u003cli\u003eSteegmann JL, Baccarani M, Breccia M et al (2016) European LeukemiaNet recommendations for the management and avoidance of adverse events of treatment in chronic myeloid leukaemia. Leukemia. 30(8):1648-1671. https://doi.org/10.1038/leu.2016.104 \u003c/li\u003e\n\u003cli\u003eSaydam G, Ali R, Demir AM et al (2022) The effect of comorbidities on the choice of tyrosine kinase inhibitors in patients with chronic myeloid leukemia. Int J Hematol Oncol 11(1):IJH38. https://doi.org/10.2217/ijh-2021-0010 \u003c/li\u003e\n\u003cli\u003eSoverini S, Colarossi S, Gnani A et al (2006) GIMEMA Working Party on Chronic Myeloid Leukemia. Contribution of ABL kinase domain mutations to imatinib resistance in different subsets of Philadelphia-positive patients: by the GIMEMA Working Party on Chronic Myeloid Leukemia. Clin Cancer Res 12(24):7374-7379. https://doi.org/10.1158/1078-0432.ccr-06-1516 \u003c/li\u003e\n\u003cli\u003eEtienne G, Dulucq S, Huguet F et al (2019) Incidence and outcome of BCR-ABL mutated chronic myeloid leukemia patients who failed to tyrosine kinase inhibitors. Cancer Med 8(11):5173-5182. https://doi.org/10.1002/cam4.2410 \u003c/li\u003e\n\u003cli\u003eR\u0026eacute;a D, Mauro MJ, Boquimpani C et al (2021) A phase 3, open-label, randomized study of asciminib, a STAMP inhibitor, vs bosutinib in CML after 2 or more prior TKIs. Blood 138(21):2031-2041. https://doi.org/10.1182/blood.2020009984 \u003c/li\u003e\n\u003cli\u003eCortes JE, Kim D-W, Pinilla-Ibarz J et al (2013) A phase 2 trial of ponatinib in Philadelphia chromosome-positive leukemias. \u003cem\u003eN Engl J Med \u003c/em\u003e369(19):1783\u0026ndash;1796. https://doi.org/10.1056/nejmoa1306494 \u003c/li\u003e\n\u003cli\u003eCortes JE, Kim D-W, Pinilla-Ibarz J et al (2018) Ponatinib efficacy and safety in Philadelphia chromosome-positive leukemia: final 5-year results of the phase 2 PACE trial. \u003cem\u003eBlood\u003c/em\u003e 132(4):393\u0026ndash;404. https://doi.org/10.1182/blood-2016-09-739086 \u003c/li\u003e\n\u003cli\u003eValent P, Hadzijusufovic E, Schernthaner G-H et al (2015) Vascular safety issues in CML patients treated with BCR/ABL1 kinase inhibitors. \u003cem\u003eBlood\u003c/em\u003e 125(6):901\u0026ndash;906. https://doi.org/10.1182/blood-2014-09-594432 \u003c/li\u003e\n\u003cli\u003eJanuzzi JL, Garasic JM, Kasner SE et al (2022) Retrospective analysis of arterial occlusive events in the PACE trial by an independent adjudication committee. J Hematol Oncol 15(1):1-25. doi: 10.1186/s13045-021-01221-z. \u003c/li\u003e\n\u003cli\u003ePulte ED, Chen H, Price LSL et al (2022) FDA Approval Summary: Revised Indication and Dosing Regimen for Ponatinib Based on the Results of the OPTIC Trial. Oncologist 27(2):149-157. https://doi.org/10.1093/oncolo/oyab040 \u003c/li\u003e\n\u003cli\u003eMian AA, Rafiei A, Haberbosch I et al (2015) PF-114, a potent and selective inhibitor of native and mutated BCR/ABL is active against Philadelphia chromosome-positive (Ph+) leukemias harboring the T315I mutation. Leukemia 29(5):1104\u0026ndash;1114. https://doi.org/10.1038/leu.2014.326 \u003c/li\u003e\n\u003cli\u003eIvanova ES, Tatarskiy VV, Yastrebova MA et al (2019) PF‑114, a novel selective inhibitor of BCR‑ABL tyrosine kinase, is a potent inducer of apoptosis in chronic myelogenous leukemia cells. Int J Oncol 55(1):289-297. https://doi.org/10.3892/ijo.2019.4801 \u003c/li\u003e\n\u003cli\u003eNational Cancer Institute Common Terminology Criteria for Adverse Events 4.03, 14 June 2010. https://www.eortc.be/services/doc/ctc/ctcae_4.03_2010-06-14_quickreference_5x7.pdf \u003c/li\u003e\n\u003cli\u003eBaccarani M, Deininger MW, Rosti G et al (2013) European LeukemiaNet recommendations for the management of chronic myeloid leukemia: 2013. Blood 122(6):872\u0026ndash;884. https://doi.org/10.1182/blood-2013-05-501569 \u003c/li\u003e\n\u003cli\u003eMcDermott MM, Liu K, Criqui MH et al (2005) Ankle-Brachial Index and Subclinical Cardiac and Carotid Disease The Multi-Ethnic Study of Atherosclerosis, Am J Epidemiol 162:33\u0026ndash;41. https://doi.org/10.1093/aje/kwi167 \u003c/li\u003e\n\u003cli\u003eCopland M (2022) Treatment of blast phase chronic myeloid leukaemia: A rare and challenging entity. Br J Haematol 199(5):665-678. https://doi.org/10.1111/bjh.18370 \u003c/li\u003e\n\u003cli\u003eJain P, Kantarjian HM, Ghorab A et al (2017) Prognostic factors and survival outcomes in patients with chronic myeloid leukemia in blast phase in the tyrosine kinase inhibitor era: Cohort study of 477 patients. Cancer 123(22):4391-4402. https://doi.org/10.1002/cncr.30864 \u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"annals-of-hematology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"aohe","sideBox":"Learn more about [Annals of Hematology](http://link.springer.com/journal/277)","snPcode":"277","submissionUrl":"https://submission.nature.com/new-submission/277/3","title":"Annals of Hematology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Chronic myeloid leukaemia, tyrosine kinase inhibitor, PF-114, vamotinib","lastPublishedDoi":"10.21203/rs.3.rs-5341421/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5341421/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eVamotinib (PF-114) is a 3\u003csup\u003erd\u003c/sup\u003e-generation, ATP-competitive oral tyrosine kinase inhibitor (TKI) active against wild-type and mutated \u003cem\u003eBCR::ABL1\u003c/em\u003e isoforms including \u003cem\u003eBCR::ABL1\u003c/em\u003e\u003csup\u003eT315I\u003c/sup\u003e. \u0026nbsp;We present final results of a phase-1 vamotinib dose-escalation study to identify maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) followed by expansion cohorts. \u0026nbsp;51 subjects with chronic myeloid leukaemia (CML) failing ≥ 1 \u0026nbsp;2\u003csup\u003end\u003c/sup\u003e generation TKI or with \u003cem\u003eBCR::ABL1\u003c/em\u003e\u003csup\u003eT315I\u003c/sup\u003e were enrolled.\u0026nbsp; Subjects received vamotinib, 50-750 mg/d, continuously. Median exposure was 6 months (range, \u0026lt;1 - 52 months). \u0026nbsp;Median CML duration pre-study was 10 years (range, \u0026lt;1 - 23\u0026nbsp;years). \u0026nbsp;36 subjects received ≥ 3 prior TKIs and 16 had \u003cem\u003eBCR::ABL1\u003c/em\u003e\u003csup\u003eT315I\u003c/sup\u003e. \u0026nbsp;The MTD was 600\u0026nbsp;mg with the Grade-3 psoriasis-like skin toxicity as the DLT. There were no vascular occlusive events nor deviations of ankle-brachial index. \u0026nbsp;Complete haematologic response (CHR) was achieved in 14 of 30 subjects, major cytogenetic response (MCyR) in 14 of 44 subjects, complete cytogenetic response (CCyR) in 10 of 50 and major molecular response (MMR) in 7 of 51 subjects who did not have a CHR, MCyR, CCyR or MMR at enrollment. \u0026nbsp;The best safety/efficacy dose was 300 mg with MCyR achieved in 6 of 7 subjects, CCyR in 5 of 9 and MMR in 4 of 9 subjects who did not have a MCyR, CCyR or MMR at enrollment. \u0026nbsp;5 of 16 subjects with \u003cem\u003eBCR::ABL1\u003c/em\u003e\u003csup\u003eT315I\u003c/sup\u003e responded including 3 achieving a CHR, 1, \u0026nbsp;a MCyR, and 1,a CCyR. \u0026nbsp;\u0026nbsp;2 of 5 subjects failing ponatinib achieved a CHR. Vamotinib dose for further phase-3 study is 300 mg/d.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCTR:\u003c/strong\u003e NCT02885766, August 26, 2016\u003c/p\u003e","manuscriptTitle":"Phase-1 study of vamotinib (PF-114), a 3rd generation BCR::ABL1 tyrosine kinase-inhibitor, in chronic myeloid leukaemia","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-11-21 06:16:40","doi":"10.21203/rs.3.rs-5341421/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-11-25T18:20:02+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-11-24T16:28:30+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-11-20T12:27:47+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-11-17T18:10:37+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"287220080555635829195491223997851425970","date":"2024-11-13T11:30:41+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"291975602544388453101311177363326991940","date":"2024-11-13T09:53:57+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"75885423263060170323405451010523820679","date":"2024-11-11T10:30:41+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-11-11T08:21:39+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-11-06T11:10:11+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-11-06T11:08:39+00:00","index":"","fulltext":""},{"type":"submitted","content":"Annals of Hematology","date":"2024-10-27T13:09:14+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"annals-of-hematology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"aohe","sideBox":"Learn more about [Annals of Hematology](http://link.springer.com/journal/277)","snPcode":"277","submissionUrl":"https://submission.nature.com/new-submission/277/3","title":"Annals of Hematology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"7c148fd4-bd02-4661-a2e8-b66ed3ad16d3","owner":[],"postedDate":"November 21st, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-05-05T16:06:19+00:00","versionOfRecord":{"articleIdentity":"rs-5341421","link":"https://doi.org/10.1007/s00277-025-06239-8","journal":{"identity":"annals-of-hematology","isVorOnly":false,"title":"Annals of Hematology"},"publishedOn":"2025-04-29 15:57:44","publishedOnDateReadable":"April 29th, 2025"},"versionCreatedAt":"2024-11-21 06:16:40","video":"","vorDoi":"10.1007/s00277-025-06239-8","vorDoiUrl":"https://doi.org/10.1007/s00277-025-06239-8","workflowStages":[]},"version":"v1","identity":"rs-5341421","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5341421","identity":"rs-5341421","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}