Randomized phase II trial of weekly ixabepilone ± biweekly bevacizumab for platinum- resistant or refractory ovarian / fallopian tube / primary peritoneal cancer (NCT03093155): updated survival and subgroup analyses

Randomized phase II trial of weekly ixabepilone ± biweekly bevacizumab for platinum- resistant or refractory ovarian / fallopian tube / primary peritoneal cancer (NCT03093155): updated survival and subgroup analyses | 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 Help Center Sign In Submit a Preprint Cite Share Download PDF Article Randomized phase II trial of weekly ixabepilone ± biweekly bevacizumab for platinum- resistant or refractory ovarian / fallopian tube / primary peritoneal cancer (NCT03093155): updated survival and subgroup analyses Dana M. Roque, Eric R. Siegel, Natalia Buza, Stefania Bellone, and 9 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4345163/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 20 Jun, 2024 Read the published version in BJC Reports → Version 1 posted 4 You are reading this latest preprint version Abstract Background: Ixabepilone may retain activity in paclitaxel-resistant disease. We previously reported improved response rates (ORR), progression-free (PFS) and overall survival (OS) conferred by ixabepilone+bevacizumab (IXA+BEV) compared to monotherapy (IXA) in heavily pre-treated ovarian cancers. We now describe a mature data set. Subset analyses were performed in patients with different taxane sensitivities and dose modifications. Methods Patients previously treated with paclitaxel were stratified by prior BEV and randomized to receive IXA 20 mg/m 2 days 1,8,15±BEV 10 mg/kg days 1,15 of a 28-day cycle in a multi-site prospective randomized phase 2 trial. Results: Thirty-seven patients were randomized to IXA and 39 patients to IXA+BEV. At the final data cutoff (05/27/2023), ORR was higher in the IXA+BEV arm (38.4% vs 8.1%,p=0.003). Dose reductions were necessary in most participants but did not diminish PFS/OS benefit. Most patients were paclitaxel-refractory/-resistant (51%,n=19/37;67%,n=26/39); the remainder were taxane-responsive. The addition of BEV to IXA conferred benefit in PFS (5.5 vs 2.2 mo; HR 0.31, 90%CI 0.20-0.49, p<0.001) and OS (10.3 vs 6.0mo; HR 0.56, 90%CI 0.38-0.84, p=0.02) that persisted after adjusting for prior taxane response. Conclusions: IXA+BEV has activity in heavily pre-treated ovarian cancers and offers significant improvement in ORR and PFS/OS compared to IXA, despite prior taxane response and dose reductions. Clinical Trial Registration: NCT03093155 Figures Figure 1 Figure 2 Figure 3 Figure 4 Introduction Platinum and taxane combination chemotherapy represents the backbone of ovarian cancer treatment in the upfront setting. 1 , 2 The combination of weekly paclitaxel with bevacizumab constitutes one of the most active regimens for platinum-resistant disease in patients treated with two or fewer prior lines of therapy. 3 , 4 Unfortunately, heavily pre-treated patients continue to suffer from a lack of effective treatment options. After 5 lines, response rates are as low as 10–16% 5 and median overall survival after 3 lines may be as low as 5–9 months. 6 Proposed mechanisms of taxane resistance include enhanced drug efflux from the cell, rapid drug metabolism, dysregulation of microtubule-stabilizing proteins, altered binding affinity, upregulation of mediators of cell cycle progression, blunted spindle cell assembly checkpoint signals, 7 and alterations in signal transduction pathways that affect autophagy, senescence and inflammation. 8 Though structurally distinct from taxanes, epothilones, such as ixabepilone (Ixempra® R-Pharm US, NJ), also hyperstabilize microtubules and may continue to exert effects in taxane-treated patients by overcoming these common resistance mechanisms. 9 , 10 We conducted a phase II prospective multi-site comparison of ixabepilone with bevacizumab (IXA + BEV) versus ixabepilone monotherapy (IXA). With an initial data analysis date of 11/2020, the previous publication 11 showed IXA + BEV to be an effective combination for heavily pre-treated (median of 4 prior lines) platinum-resistant and taxane-treated ovarian cancer patients. We found that the benefits of combination therapy on progression-free (PFS) and overall survival (OS) were not diminished by prior receipt of bevacizumab. IXA dose reductions were required by approximately 60% of participants in each arm most commonly due to peripheral neuropathy, neutropenia, and fatigue. The National Comprehensive Cancer Network (NCCN→) subsequently endorsed this combination as a category 2B treatment option for recurrent, platinum-resistant ovarian disease. 2 In the current manuscript, we present the final survival analyses of the matured clinical trial data and further characterize the performance of the regimen in patients previously treated with weekly paclitaxel and among those requiring dose reduction. Methods Study design and conduct. This was an investigator-initiated phase II randomized open-label trial (NCT3093155) conducted at Smilow Cancer Hospital at Yale University and the Greenebaum Comprehensive Cancer Center at the University of Maryland. As previously described, 11 study participants were stratified by study site and previous receipt of BEV with a 1:1 allocation using a dynamic randomization procedure to minimize stratification-factor imbalance between arms. IXA monotherapy at 20 mg/m 2 intravenously days 1, 8, and 15 of a 28-day cycle was administered alone or with BEV 10 mg/kg intravenously days 1 and 15 administered until disease progression, death, or prohibitive toxicity (Fig. 1 ).[1] There were no significant amendments made during its conduct, though enrollment was briefly suspended during the COVID-19 pandemic. Power calculations assumed a median PFS for IXA monotherapy to be 5 months, given observations from GOG 126M. 12 We required 80% power at 5% \(\alpha\) to detect a 2-fold increase in PFS via one-sided log-rank test while allowing for a single interim analysis for efficacy and futility. Calculations conducted in East v 6.4 (Cytel, Inc, Cambridge, MA) using the null variance estimator along with the O’Brien-Fleming spending functions for both alpha and beta required 28 PFS events in the interim and 56 PFS events in the final analysis. The first participant enrolled in March 2017. Because the COVID-19 pandemic slowed recruitment, we terminated enrollment after 78 participants and the occurrence of 61 PFS events. The present analyses represent a data cut-off of 05/27/2023. The full protocol is provided in the Supplemental Appendix. Similar to previously published definitions by others, 13 patients were considered taxane-resistant if they demonstrated disease progression within 6 months of paclitaxel/docetaxel administration. Patients were considered taxane-refractory if they progressed while receiving a taxane or demonstrated persistence of disease on end-of-treatment assessment that prompted initiation of a new line of therapy. By default, the remaining patients were considered taxane-responsive . This investigation was conducted in accordance with the Declaration of Helsinki and approved by local Institutional Review Board. All patients provided written informed consent. Eligibility. Participants must have received prior treatment with \(\ge\) 3 cycles paclitaxel, either 3-weekly or weekly. There was no limit on prior lines including BEV therapy. All participants were \(\ge\) 18 years and had platinum-resistant (i.e., platinum-free interval <6 months) or refractory (i.e., disease progression during or \(\le\) 4 weeks after last dose of platinum) histologically confirmed epithelial (non-mucinous) ovarian, fallopian tube, or primary peritoneal carcinoma. All participants had measurable disease per RECIST (Response Evaluation Criteria in Solid Tumors) v1.1. 14 Participants had to exhibit a performance status of 0-2. 15 Any prior debulking status was permitted. Study Drugs. IXA was provided by R-Pharm US LLC, Princeton, NJ. BEV was supplied commercially. Biosimilars were not permitted. Two 20% dose reductions were allowed for ixabepilone to 16 mg/m 2 then 12 mg/m. 2 Endpoints. Computed tomography was performed every 2 cycles. The primary endpoint was PFS, defined as time from randomization to progression or death. Secondary endpoints were OS, defined as time from randomization to death from any cause, and safety as defined by Common Terminology Criteria for Adverse Events (CTCAE) v.4. 16 Best response was based on RECIST v1.1. OR consisted of complete response (CR) or partial response (PR), and it did not have a durability requirement. Durable Disease Control (DDC) was defined as CR, PR, or stable disease (SD) \(\ge\) 6 months from date of best response. Statistical Analyses. PFS and OS were analyzed using the Kaplan-Meier method with one-sided log-rank tests and Cox regression. Multi-variate analyses were performed with paclitaxel response as a co-variate (sensitive, resistant, refractory). Fisher’s exact tests were used to compare differences in best response between arms across subgroups. Individual patient responses were illustrated as a swimmer’s plot. The datasets generated and analyzed during the current study are available from the corresponding author on request. Results Treatment and disease characteristics. Eighty-one participants were screened, and 78 were randomized (Fig. 1 ). One withdrew consent and one was found ineligible, leaving 76 evaluable for efficacy. Patient and disease characteristics showed no evidence of imbalance. 11 Notably, 49% of participants had received > 3 prior lines of chemotherapy and 18% had platinum-refractory disease, with no statistical differences between the arms ( p = 0.82 and p = 0.14, respectively). Within the IXA arm ( N = 37), 9 (24%) of patients were taxane-resistant, 10 (27%) were taxane-refractory; within the IXA + BEV arm ( N = 39), 13 (33%) were taxane-resistant, 13 (33%) were taxane-refractory ( p = 0.44) (Table 1 ). Both arms contained patients previously treated with weekly paclitaxel, either in combination with carboplatin or in the platinum-resistant setting as part of an AURELIA 4 regimen: 35% ( N = 13; IXA) and 26% ( N = 10, IXA + BEV).[2] One additional patient in the IXA + BEV arm also received weekly nab-paclitaxel but was not included for purity of the analysis. Among all patients previously treated with weekly paclitaxel, two patients in each arm (5. % and 5.1%, respectively) had received weekly paclitaxel with bevacizumab and two patients in each arm had received weekly paclitaxel monotherapy. Of note, one patient received both weekly paclitaxel followed 16 months later by weekly paclitaxel with bevacizumab and is therefore counted towards both totals. Primary endpoint: PFS. At the data cutoff (05/27/2023), 75 PFS events and 70 deaths had occurred among 76 participants during 94.37 person-years of observation. Median PFS was 5.5 versus 2.2 months, HR 0.31, 90%CI 0.20–0.49, p < 0.001); this is unchanged from the previous estimates. Secondary endpoints: OS, OR rate (ORR), safety. Since the original report, there was one additional response. ORR increased and remained higher in the IXA + BEV arm (38.4% vs 8.1%, p = 0.003). Median OS was 10.3 versus 6.0 months (HR 0.56, 90%CI 0.38–0.84, p = 0.02); this is virtually unchanged from the previous estimates. There were no complete responses, but in the combination arm, 14 patients achieved a durable response (stable disease or partial response > 6 months) (Fig. 2 ). No new safety signals emerged since the original report. Among all participants, there were 30 patients who tolerated the initially prescribed dose, 25 patients who received at least one cycle at one dose reduction (16 mg/m 2 ) and 21 who received at least one cycle at a second dose reduction (12 mg/m 2 ). PFS benefit persisted in the combination arm despite dose reduction (HR 0.49, 95%CI 0.22–1.07, p = 0.074 [full dose]; HR 0.25, 95%CI 0.10–0.62, p = 0.003 [one dose reduction], HR 0.17, 95%CI 0.05–0.54, p = 0.002 [two dose reductions]) (Fig. 3 -upper ). OS was not affected (HR 0.7, 95%CI 0.33–1.49, p = 0.354 [full dose]; HR 0.6, 95%CI 0.26–1.36, p = 0.218 [one dose reduction]; HR 0.67, 95% CI 0.25–1.83, p = 0.438) [two dose reductions] (Fig. 3 -lower ). Subgroup analyses: prior taxane response and prior exposure to weekly paclitaxel. Among both arms, most patients were paclitaxel-refractory/-resistant (51% [n = 19/37] on IXA and 67% [n = 26/39] on IXA + BEV). The addition of BEV to IXA conferred benefit in PFS (HR 0.31, 90%CI 0.20–0.48, 2-tailed Wald p < 0.001) and OS (HR 0.59, 90%CI 0.39–0.88, 2-tailed Wald p = 0.03) even in a multivariate analysis with prior taxane response as a covariate. Among 10 taxane-refractory patients in the IXA arm, best responses included SD in 40% ( N = 4) and progressive disease (PD) in 50%( N = 5); one patient was not assessed due to rapid death. Among 13 taxane-refractory patients in the IXA + BEV arm, best responses included PR in 30.8% ( N = 4), SD in 30.8% ( N = 4) SD and PD in 38.5% ( N = 5). Although the likelihood of increased PR with BEV did not attain statistical significance within any one prior-taxane subgroup (lowest p = 0.06), a Cochran-Mantel-Haenszel analysis with strata defined by prior taxane response yielded a common odds ratio of 0.71 (95%CI: 1.77–28.8; p = 0.003) favoring PR with IXA + BEV. Among all 23 patients with prior weekly paclitaxel exposure (either in conjunction with carboplatin or as an AURELIA regimen in the recurrent setting), PFS was 6.0 (95%CI 2.9–13.0, IXA + BEV) versus 1.8 (95%CI 1.5–3.5, IXA) months (log-rank p = 0.005) (Fig. 4 -upper ; HR 0.26, 95%CI 0.10–0.71). OS estimates were 19.4 (95%CI 6.4 to not reached; IXA + BEV) versus 5.0 (95%CI 2.6–18.3, IXA) months (log-rank p = 0.10) (Fig. 4 -lower ; HR 0.46, 95%CI 0.18–1.18). In the subset of these patients who had received an AURELIA regimen (i.e., weekly paclitaxel with or without bevacizumab), PFS estimates were 2.9 (95%CI 2.0-6.9, IXA + BEV) and 1.7 (95%CI 0.9–2.2, IXA) months (p = 0.07). Following receipt of an AURELIA regimen of weekly paclitaxel with or without BEV, OS estimates were 20.2 (95%CI 2.2-not reached, IXA + BEV) and 4.5 (95%CI 0.9 to 18.3, IXA) months (p-0.17). Both patients treated with IXA + BEV following prior weekly paclitaxel and bevacizumab achieved a best response of SD, as did both patients treated with IXA + BEV following prior weekly paclitaxel monotherapy. One of two patients treated with IXA following prior weekly paclitaxel and bevacizumab achieved a best response of SD; one patient treated with IXA following prior weekly paclitaxel monotherapy experienced PD and one was not assessed due to death. The distribution of responses for all patients who received prior weekly paclitaxel are provided in Table 2 . Among these 23 patients, there were 3 PRs in the combination arm but no responses in the IXA arm ( p = 0.07). DDC was achieved in 4 patients in the combination arm but in none among the monotherapy arm (p = 0.02). Discussion We previously reported improved ORR, PFS, and OS conferred by weekly ixabepilone with biweekly bevacizumab (IXA + BEV) compared to monotherapy (IXA) in heavily pre-treated ovarian cancers. We suggested that prior BEV should not preclude re-treatment with the combination of IXA + BEV and highlighted pre-clinical observations that may explain the apparent synergy between these two agents. 11 The present report also illustrates encouraging activity of IXA + BEV in patients despite prior exposure to weekly paclitaxel and in the setting of dose reductions to further inform clinicians following endorsement of the combination by the NCCN (category 2B). 2 The mature data reveal an impressive ORR of the combination arm (38.4% vs 8.1%, p = 0.003), with durable response in 14 patients and respectable median PFS of 5.5 months and OS of 10 months. Unsurprisingly, in a heavily pre-treated population, dose reductions were common, but ancillary analyses suggest this did not damper response and allowed patients to continue therapy. Our data suggest that a starting dose of 16 mg/m 2 can be considered and may warrant further study. While favorable responses to weekly paclitaxel with 17 or without bevacizumab 18 , 19 after three-weekly paclitaxel are well-described, data quantifying the response to repeated treatment with weekly paclitaxel remain limited. Gunderson et al (2017) reported no attenuation of benefit for weekly paclitaxel despite prior exposure to weekly administration during primary therapy among 20 patients; compared to 79 patients previously exposed to three-weekly administration, the clinical benefit rate was actually improved (69% versus 36%, p = 0.05). 20 In another small series of 26 patients 21 re-challenge with weekly paclitaxel after prior weekly paclitaxel produced a radiologic response rate of 34.6% with a median PFS of 3.7 months (95%CI 2.3–6.7) and OS of 18.1 (95%CI 9.6–28.6). Three patients received weekly paclitaxel for a 3rd time and 2/3 achieved stable disease. It is therefore not unreasonable to expect a subset of patients to benefit from dose-dense treatment with another microtubule-stabilizing agent such as ixabepilone following prior weekly paclitaxel. Ixabepilone may overcome paclitaxel resistance in several ways. Firstly, epothilones tend not to be substrates of drug exportation pumps that shuttle paclitaxel from the cell. Secondly, epothilones also appear to retain affinity for the microtubule despite upregulation of class III β-tubulin over the constitutively expressed class I β-tubulin, which reduces paclitaxel binding by altering the sterics of the pocket. 9 , 10 Exploratory analyses employing whole exome sequencing among patients with a response to weekly paclitaxel for > 12 months suggested the importance of genes related to angiogenesis (VEGF, MMP9), tubulin superfamily (TSC2), apoptosis (BCL2L1, BAD) and interleukin pathways (CXCR1, CXCR2, IL1A, IL1B). Studies investigating predictors of response to weekly paclitaxel are surprisingly scant, and also lacking for epothilones, and should be the subject of future investigations. In summary, the regimen of weekly ixabepilone and biweekly bevacizumab achieves high response rates and respectable PFS and OS in heavily pre-treated ovarian cancer patients. Response rates appear to be higher than those reported in this setting for chemotherapy alone, as well as for non-taxane chemotherapies combined with bevacizumab. Use of the combination does not appear to be precluded by exposure to prior bevacizumab or previous treatment with weekly paclitaxel. Biomarkers to predict sustained response to treatment with weekly ixabepilone and bevacizumab are needed. Declarations ACKOWLEDGEMENTS: This study was accepted as a poster abstract to the 2024 Annual Meeting of the Society of Gynecologic Oncology. We would like to thank RPharm-US for their industry support and Lisa Baker, Martha Luther, Kay Debski, Amy Nicoletti, Kerry DeBenedictis, Michele Hill, Nancy Tait, Paige Smith, Jocelyn Reader, and Carolynn Harris for their invaluable technical support to the study. AUTHOR CONTRIBUTIONS: Collection and assembly of data: all authors Data analysis and interpretation: DMR, ES, ADS Manuscript writing: DMR, ES, ADS Final approval of manuscript for publication: all authors Accountable for all aspects of the work: all authors ETHICS APPROVAL AND CONSENT TO PARTICIPATE: All patients provided written informed consent to participate in this study. The study was approved by each participating institution’s Human Investigations Committee/Institutional Review Board. This study was performed in accordance with the Declaration of Helsinki. CONSENT FOR PUBLICATION: not applicable DATA AVAILABILITY: The datasets generated and/or analyzed during the current study are available from the corresponding author on reasonable request. COMPETING INTERESTS: The authors declare no conflicts of interest. FUNDING INFORMATION: Study drug was supplied by R-Pharm US, LLC (Princeton, NJ) References Ozols RF, Bundy BN, Greer BE, Fowler JM, Clarke-Pearson D, Burger RA, et al. Phase III trial of carboplatin and paclitaxel compared with cisplatin and paclitaxel in patients with optimally resected stage III ovarian cancer: a Gynecologic Oncology Group study. J. Clin. Oncol. 21(17), 3194–200 (2003). National Comprehensive Cancer Network. NCCN Clnical Practice Guidelines in Oncology: Ovarian, Fallopian Tube, Primary Peritoneal Cancer v2.2023 [Internet]. 2023. Available from: https://www.nccn.org/ Poveda AM, Selle F, Hilpert F, Reuss A, Savarese A, Vergote I, et al. 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Footnotes In the original publication, the CONSORT diagram listed the number of infusions as ‘cycles.’ This has been amended in the present work to reflect true cycles. A correction has been submitted to the original manuscript due to an error in Table 1 . We previously reported 27% ( N = 10) of patients in the IXA arm and 23% (of patients N = 9) in the IXA + BEV arm had been treated with weekly paclitaxel (either with carboplatin or as an AURELIA regimen with or without bevacizumab). Among these patients, we described 1 patient in the IXA arm and 4 patients in the IXA + BEV arm who had received weekly paclitaxel with bevacizumab and 1 patient in the IXA arm and 2 in the IXA + BEV arm who received weekly paclitaxel monotherapy. Tables Tables are available in the Supplementary Files section. Additional Declarations No competing interests reported. Supplementary Files TABLE1042124notracking.pdf TABLE2bestresponseafterpriorweeklypaclitaxel011524.pdf SUPPLEMENTALAPPENDIXprotocol.pdf Cite Share Download PDF Status: Published Journal Publication published 20 Jun, 2024 Read the published version in BJC Reports → Version 1 posted Editorial decision: Accepted 14 May, 2024 Editor assigned by journal 14 May, 2024 Submission checks completed at journal 09 May, 2024 First submitted to journal 29 Apr, 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. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4345163","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":302485817,"identity":"73cc8bd2-ccb1-45cb-bd9d-4cb3f5ad4716","order_by":0,"name":"Dana M. Roque","email":"","orcid":"","institution":"University of Maryland School of Medicine","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Dana","middleName":"M.","lastName":"Roque","suffix":""},{"id":302485822,"identity":"dc093835-5cfa-46aa-b91f-2f8604eaf5cf","order_by":1,"name":"Eric R. Siegel","email":"","orcid":"","institution":"University of Arkansas for Medical Sciences","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Eric","middleName":"R.","lastName":"Siegel","suffix":""},{"id":302485823,"identity":"09bd06ca-a3c5-49f1-b388-1277e5eb5c0a","order_by":2,"name":"Natalia Buza","email":"","orcid":"","institution":"Yale School of Medicine","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Natalia","middleName":"","lastName":"Buza","suffix":""},{"id":302485824,"identity":"4a7dfc83-55bc-4206-95a8-beac59b2f61f","order_by":3,"name":"Stefania Bellone","email":"","orcid":"","institution":"Yale School of Medicine","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Stefania","middleName":"","lastName":"Bellone","suffix":""},{"id":302485825,"identity":"8861e38e-a549-476c-a991-c43fc619f310","order_by":4,"name":"Gloria S. Huang","email":"","orcid":"","institution":"Yale School of Medicine","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Gloria","middleName":"S.","lastName":"Huang","suffix":""},{"id":302485826,"identity":"bfc889c1-391a-4939-b9a2-8dfb2134af02","order_by":5,"name":"Gary Altwerger","email":"","orcid":"","institution":"Yale School of Medicine","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Gary","middleName":"","lastName":"Altwerger","suffix":""},{"id":302485827,"identity":"254b45d1-7a02-4bfb-9988-8e2f3ebbe726","order_by":6,"name":"Vaagn Andikyan","email":"","orcid":"","institution":"Yale School of Medicine","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Vaagn","middleName":"","lastName":"Andikyan","suffix":""},{"id":302485828,"identity":"8909e845-d8b2-481c-b12c-1c9e1fa81be5","order_by":7,"name":"Mitchell Clark","email":"","orcid":"","institution":"Yale School of Medicine","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Mitchell","middleName":"","lastName":"Clark","suffix":""},{"id":302485829,"identity":"80fa1d1f-c53d-4f81-a44a-845a6484e6cc","order_by":8,"name":"Masoud Azodi","email":"","orcid":"","institution":"Yale School of Medicine","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Masoud","middleName":"","lastName":"Azodi","suffix":""},{"id":302485830,"identity":"a999b9b7-6833-4ab5-ad15-5646319a0c12","order_by":9,"name":"Peter E. Schwartz","email":"","orcid":"","institution":"Yale School of Medicine","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Peter","middleName":"E.","lastName":"Schwartz","suffix":""},{"id":302485831,"identity":"168c83a8-d0bb-46bd-9b88-28fedfca6fc7","order_by":10,"name":"Gautam G. Rao","email":"","orcid":"","institution":"University of Maryland School of Medicine","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Gautam","middleName":"G.","lastName":"Rao","suffix":""},{"id":302485832,"identity":"f73ff013-2c96-48e5-97ee-59166c00deaf","order_by":11,"name":"Elena Ratner","email":"","orcid":"","institution":"Yale School of Medicine","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Elena","middleName":"","lastName":"Ratner","suffix":""},{"id":302485833,"identity":"32cccd5c-1a7e-411a-a067-bde43dc0214f","order_by":12,"name":"Alessandro D. Santin","email":"data:image/png;base64,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","orcid":"","institution":"Yale School of Medicine","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Alessandro","middleName":"D.","lastName":"Santin","suffix":""}],"badges":[],"createdAt":"2024-04-29 22:09:59","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4345163/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4345163/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1038/s44276-024-00067-5","type":"published","date":"2024-06-20T16:04:27+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":56887149,"identity":"deaf4063-7e72-4e38-b0ef-9d47d8965980","added_by":"auto","created_at":"2024-05-21 18:57:01","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":92808,"visible":true,"origin":"","legend":"\u003cp\u003eCONSORT (Consolidated Standards of Reporting Trials) diagram.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-4345163/v1/8ad1259c058ab7c6b74c247e.png"},{"id":56887152,"identity":"2dc078ef-cdc5-4e0e-aacf-1c7ab25dc36c","added_by":"auto","created_at":"2024-05-21 18:57:01","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":874708,"visible":true,"origin":"","legend":"\u003cp\u003eSwimmer’s plot of responses among 39 patients who received ixabepilone and bevacizumab.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-4345163/v1/e57bf1ddbc1deb1bb9d1ff23.png"},{"id":56887154,"identity":"710aaed5-af20-4e25-b075-ceede28cee50","added_by":"auto","created_at":"2024-05-21 18:57:01","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":771598,"visible":true,"origin":"","legend":"\u003cp\u003eProgression-free (top) and overall (bottom) survival among patients in the setting of ixabepilone dose reductions (left, none; middle, one dose reduction, right, two dose reductions).\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-4345163/v1/e4c6272a9c911c22133b0d0a.png"},{"id":56887153,"identity":"729ad23b-ca03-42d6-940e-1f16d73a0eec","added_by":"auto","created_at":"2024-05-21 18:57:01","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":359329,"visible":true,"origin":"","legend":"\u003cp\u003eProgression-free (top) and overall (bottom) survival among patients in 23 patients who received prior weekly paclitaxel.\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-4345163/v1/c8685b4bdfb08d5685f9f370.png"},{"id":58823901,"identity":"1f18e72b-b5c2-49fc-92b8-f302a0f61c10","added_by":"auto","created_at":"2024-06-21 17:09:56","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":3017376,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4345163/v1/44daf150-042b-46d8-9121-4cb54cb485d6.pdf"},{"id":56887150,"identity":"9f831d09-378b-4a18-b6d0-36537bed1419","added_by":"auto","created_at":"2024-05-21 18:57:01","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":63886,"visible":true,"origin":"","legend":"","description":"","filename":"TABLE1042124notracking.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4345163/v1/443e6caa477384cdf9fe7fa6.pdf"},{"id":56887151,"identity":"032a2371-e304-48eb-8dcc-a05cba4da739","added_by":"auto","created_at":"2024-05-21 18:57:01","extension":"pdf","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":72661,"visible":true,"origin":"","legend":"","description":"","filename":"TABLE2bestresponseafterpriorweeklypaclitaxel011524.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4345163/v1/19544992ff9c740c29d703ca.pdf"},{"id":56887155,"identity":"d6ef8665-2b33-4a78-8726-352db0538e29","added_by":"auto","created_at":"2024-05-21 18:57:02","extension":"pdf","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":856691,"visible":true,"origin":"","legend":"","description":"","filename":"SUPPLEMENTALAPPENDIXprotocol.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4345163/v1/98470172f830d98870863e59.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Randomized phase II trial of weekly ixabepilone ± biweekly bevacizumab for platinum- resistant or refractory ovarian / fallopian tube / primary peritoneal cancer (NCT03093155): updated survival and subgroup analyses","fulltext":[{"header":"Introduction","content":"\u003cp\u003ePlatinum and taxane combination chemotherapy represents the backbone of ovarian cancer treatment in the upfront setting.\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e,\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e The combination of weekly paclitaxel with bevacizumab constitutes one of the most active regimens for platinum-resistant disease in patients treated with two or fewer prior lines of therapy.\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e,\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e Unfortunately, heavily pre-treated patients continue to suffer from a lack of effective treatment options. After 5 lines, response rates are as low as 10\u0026ndash;16%\u003csup\u003e5\u003c/sup\u003e and median overall survival after 3 lines may be as low as 5\u0026ndash;9 months.\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eProposed mechanisms of taxane resistance include enhanced drug efflux from the cell, rapid drug metabolism, dysregulation of microtubule-stabilizing proteins, altered binding affinity, upregulation of mediators of cell cycle progression, blunted spindle cell assembly checkpoint signals,\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e and alterations in signal transduction pathways that affect autophagy, senescence and inflammation.\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e Though structurally distinct from taxanes, epothilones, such as ixabepilone (Ixempra\u0026reg; R-Pharm US, NJ), also hyperstabilize microtubules and may continue to exert effects in taxane-treated patients by overcoming these common resistance mechanisms.\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e,\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eWe conducted a phase II prospective multi-site comparison of ixabepilone with bevacizumab (IXA\u0026thinsp;+\u0026thinsp;BEV) versus ixabepilone monotherapy (IXA). With an initial data analysis date of 11/2020, the previous publication\u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e showed IXA\u0026thinsp;+\u0026thinsp;BEV to be an effective combination for heavily pre-treated (median of 4 prior lines) platinum-resistant and taxane-treated ovarian cancer patients. We found that the benefits of combination therapy on progression-free (PFS) and overall survival (OS) were not diminished by prior receipt of bevacizumab. IXA dose reductions were required by approximately 60% of participants in each arm most commonly due to peripheral neuropathy, neutropenia, and fatigue. The National Comprehensive Cancer Network (NCCN\u0026rarr;) subsequently endorsed this combination as a category 2B treatment option for recurrent, platinum-resistant ovarian disease.\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eIn the current manuscript, we present the final survival analyses of the matured clinical trial data and further characterize the performance of the regimen in patients previously treated with weekly paclitaxel and among those requiring dose reduction.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003e\u003cb\u003eStudy design and conduct.\u003c/b\u003e This was an investigator-initiated phase II randomized open-label trial (NCT3093155) conducted at Smilow Cancer Hospital at Yale University and the Greenebaum Comprehensive Cancer Center at the University of Maryland. As previously described,\u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e study participants were stratified by study site and previous receipt of BEV with a 1:1 allocation using a dynamic randomization procedure to minimize stratification-factor imbalance between arms. IXA monotherapy at 20 mg/m\u003csup\u003e2\u003c/sup\u003e intravenously days 1, 8, and 15 of a 28-day cycle was administered alone or with BEV 10 mg/kg intravenously days 1 and 15 administered until disease progression, death, or prohibitive toxicity (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).[1]\u003ca class=\"FNLink\" href=\"#Fn1\" id=\"#FNLinkFn1\"\u003e\u003c/a\u003e There were no significant amendments made during its conduct, though enrollment was briefly suspended during the COVID-19 pandemic. Power calculations assumed a median PFS for IXA monotherapy to be 5 months, given observations from GOG 126M.\u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e We required 80% power at 5% \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(\\alpha\\)\u003c/span\u003e\u003c/span\u003e to detect a 2-fold increase in PFS via one-sided log-rank test while allowing for a single interim analysis for efficacy and futility. Calculations conducted in East v 6.4 (Cytel, Inc, Cambridge, MA) using the null variance estimator along with the O\u0026rsquo;Brien-Fleming spending functions for both alpha and beta required 28 PFS events in the interim and 56 PFS events in the final analysis. The first participant enrolled in March 2017. Because the COVID-19 pandemic slowed recruitment, we terminated enrollment after 78 participants and the occurrence of 61 PFS events. The present analyses represent a data cut-off of 05/27/2023. The full protocol is provided in the \u003cb\u003eSupplemental Appendix.\u003c/b\u003e Similar to previously published definitions by others,\u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e patients were considered \u003cem\u003etaxane-resistant\u003c/em\u003e if they demonstrated disease progression within 6 months of paclitaxel/docetaxel administration. Patients were considered \u003cem\u003etaxane-refractory\u003c/em\u003e if they progressed while receiving a taxane or demonstrated persistence of disease on end-of-treatment assessment that prompted initiation of a new line of therapy. By default, the remaining patients were considered \u003cem\u003etaxane-responsive\u003c/em\u003e. This investigation was conducted in accordance with the Declaration of Helsinki and approved by local Institutional Review Board. All patients provided written informed consent.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cb\u003eEligibility.\u003c/b\u003e Participants must have received prior treatment with \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(\\ge\\)\u003c/span\u003e\u003c/span\u003e3 cycles paclitaxel, either 3-weekly or weekly. There was no limit on prior lines including BEV therapy. All participants were \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(\\ge\\)\u003c/span\u003e\u003c/span\u003e18 years and had platinum-resistant (i.e., platinum-free interval \u0026lt;6 months) or refractory (i.e., disease progression during or \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(\\le\\)\u003c/span\u003e\u003c/span\u003e4 weeks after last dose of platinum) histologically confirmed epithelial (non-mucinous) ovarian, fallopian tube, or primary peritoneal carcinoma. All participants had measurable disease per RECIST (Response Evaluation Criteria in Solid Tumors) v1.1.\u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e Participants had to exhibit a performance status of 0-2.\u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e Any prior debulking status was permitted.\u003c/p\u003e \u003cp\u003e \u003cb\u003eStudy Drugs.\u003c/b\u003e IXA was provided by R-Pharm US LLC, Princeton, NJ. BEV was supplied commercially. Biosimilars were not permitted. Two 20% dose reductions were allowed for ixabepilone to 16 mg/m\u003csup\u003e2\u003c/sup\u003e then 12 mg/m.\u003csup\u003e2\u003c/sup\u003e\u003c/p\u003e \u003cp\u003e \u003cb\u003eEndpoints.\u003c/b\u003e Computed tomography was performed every 2 cycles. The primary endpoint was PFS, defined as time from randomization to progression or death. Secondary endpoints were OS, defined as time from randomization to death from any cause, and safety as defined by Common Terminology Criteria for Adverse Events (CTCAE) v.4.\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e Best response was based on RECIST v1.1. OR consisted of complete response (CR) or partial response (PR), and it did not have a durability requirement. Durable Disease Control (DDC) was defined as CR, PR, or stable disease (SD) \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(\\ge\\)\u003c/span\u003e\u003c/span\u003e6 months from date of best response.\u003c/p\u003e \u003cp\u003e \u003cb\u003eStatistical Analyses.\u003c/b\u003e PFS and OS were analyzed using the Kaplan-Meier method with one-sided log-rank tests and Cox regression. Multi-variate analyses were performed with paclitaxel response as a co-variate (sensitive, resistant, refractory). Fisher\u0026rsquo;s exact tests were used to compare differences in best response between arms across subgroups. Individual patient responses were illustrated as a swimmer\u0026rsquo;s plot. The datasets generated and analyzed during the current study are available from the corresponding author on request.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cstrong\u003eTreatment and disease characteristics.\u003c/strong\u003e Eighty-one participants were screened, and 78 were randomized (Fig. \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e). One withdrew consent and one was found ineligible, leaving 76 evaluable for efficacy. Patient and disease characteristics showed no evidence of imbalance.\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e Notably, 49% of participants had received\u0026thinsp;\u0026gt;\u0026thinsp;3 prior lines of chemotherapy and 18% had platinum-refractory disease, with no statistical differences between the arms (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.82 and \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.14, respectively). Within the IXA arm (\u003cem\u003eN\u003c/em\u003e\u0026thinsp;=\u0026thinsp;37), 9 (24%) of patients were taxane-resistant, 10 (27%) were taxane-refractory; within the IXA\u0026thinsp;+\u0026thinsp;BEV arm (\u003cem\u003eN\u003c/em\u003e\u0026thinsp;=\u0026thinsp;39), 13 (33%) were taxane-resistant, 13 (33%) were taxane-refractory (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.44) (Table \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e). Both arms contained patients previously treated with weekly paclitaxel, either in combination with carboplatin or in the platinum-resistant setting as part of an AURELIA\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e regimen: 35% (\u003cem\u003eN\u003c/em\u003e\u0026thinsp;=\u0026thinsp;13; IXA) and 26% (\u003cem\u003eN\u003c/em\u003e\u0026thinsp;=\u0026thinsp;10, IXA\u0026thinsp;+\u0026thinsp;BEV).[2]\u003ca class=\"FNLink\" href=\"#Fn2\" id=\"#FNLinkFn2\"\u003e\u003c/a\u003e One additional patient in the IXA\u0026thinsp;+\u0026thinsp;BEV arm also received weekly nab-paclitaxel but was not included for purity of the analysis. Among all patients previously treated with weekly paclitaxel, two patients in each arm (5. % and 5.1%, respectively) had received weekly paclitaxel with bevacizumab and two patients in each arm had received weekly paclitaxel monotherapy. Of note, one patient received both weekly paclitaxel followed 16 months later by weekly paclitaxel with bevacizumab and is therefore counted towards both totals.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePrimary endpoint: PFS.\u003c/strong\u003e At the data cutoff (05/27/2023), 75 PFS events and 70 deaths had occurred among 76 participants during 94.37 person-years of observation. Median PFS was 5.5 versus 2.2 months, HR 0.31, 90%CI 0.20\u0026ndash;0.49, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001); this is unchanged from the previous estimates.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSecondary endpoints: OS, OR rate (ORR), safety.\u003c/strong\u003e Since the original report, there was one additional response. ORR increased and remained higher in the IXA\u0026thinsp;+\u0026thinsp;BEV arm (38.4% vs 8.1%, p\u0026thinsp;=\u0026thinsp;0.003). Median OS was 10.3 versus 6.0 months (HR 0.56, 90%CI 0.38\u0026ndash;0.84, p\u0026thinsp;=\u0026thinsp;0.02); this is virtually unchanged from the previous estimates. There were no complete responses, but in the combination arm, 14 patients achieved a durable response (stable disease or partial response\u0026thinsp;\u0026gt;\u0026thinsp;6 months) (Fig. \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e\n\u003cp\u003eNo new safety signals emerged since the original report. Among all participants, there were 30 patients who tolerated the initially prescribed dose, 25 patients who received at least one cycle at one dose reduction (16 mg/m\u003csup\u003e2\u003c/sup\u003e) and 21 who received at least one cycle at a second dose reduction (12 mg/m\u003csup\u003e2\u003c/sup\u003e). PFS benefit persisted in the combination arm despite dose reduction (HR 0.49, 95%CI 0.22\u0026ndash;1.07, p\u0026thinsp;=\u0026thinsp;0.074 [full dose]; HR 0.25, 95%CI 0.10\u0026ndash;0.62, p\u0026thinsp;=\u0026thinsp;0.003 [one dose reduction], HR 0.17, 95%CI 0.05\u0026ndash;0.54, p\u0026thinsp;=\u0026thinsp;0.002 [two dose reductions]) (Fig. \u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e\u003cstrong\u003e-upper\u003c/strong\u003e). OS was not affected (HR 0.7, 95%CI 0.33\u0026ndash;1.49, p\u0026thinsp;=\u0026thinsp;0.354 [full dose]; HR 0.6, 95%CI 0.26\u0026ndash;1.36, p\u0026thinsp;=\u0026thinsp;0.218 [one dose reduction]; HR 0.67, 95% CI 0.25\u0026ndash;1.83, p\u0026thinsp;=\u0026thinsp;0.438) [two dose reductions] (Fig. \u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e\u003cstrong\u003e-lower\u003c/strong\u003e).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSubgroup analyses: prior taxane response and prior exposure to weekly paclitaxel.\u003c/strong\u003e Among both arms, most patients were paclitaxel-refractory/-resistant (51% [n\u0026thinsp;=\u0026thinsp;19/37] on IXA and 67% [n\u0026thinsp;=\u0026thinsp;26/39] on IXA\u0026thinsp;+\u0026thinsp;BEV). The addition of BEV to IXA conferred benefit in PFS (HR 0.31, 90%CI 0.20\u0026ndash;0.48, 2-tailed Wald p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) and OS (HR 0.59, 90%CI 0.39\u0026ndash;0.88, 2-tailed Wald p\u0026thinsp;=\u0026thinsp;0.03) even in a multivariate analysis with prior taxane response as a covariate. Among 10 taxane-refractory patients in the IXA arm, best responses included SD in 40% (\u003cem\u003eN\u003c/em\u003e\u0026thinsp;=\u0026thinsp;4) and progressive disease (PD) in 50%(\u003cem\u003eN\u003c/em\u003e\u0026thinsp;=\u0026thinsp;5); one patient was not assessed due to rapid death. Among 13 taxane-refractory patients in the IXA\u0026thinsp;+\u0026thinsp;BEV arm, best responses included PR in 30.8% (\u003cem\u003eN\u003c/em\u003e\u0026thinsp;=\u0026thinsp;4), SD in 30.8% (\u003cem\u003eN\u003c/em\u003e\u0026thinsp;=\u0026thinsp;4) SD and PD in 38.5% (\u003cem\u003eN\u003c/em\u003e\u0026thinsp;=\u0026thinsp;5). Although the likelihood of increased PR with BEV did not attain statistical significance within any one prior-taxane subgroup (lowest p\u0026thinsp;=\u0026thinsp;0.06), a Cochran-Mantel-Haenszel analysis with strata defined by prior taxane response yielded a common odds ratio of 0.71 (95%CI: 1.77\u0026ndash;28.8; p\u0026thinsp;=\u0026thinsp;0.003) favoring PR with IXA\u0026thinsp;+\u0026thinsp;BEV.\u003c/p\u003e\n\u003cp\u003eAmong all 23 patients with prior weekly paclitaxel exposure (either in conjunction with carboplatin or as an AURELIA regimen in the recurrent setting), PFS was 6.0 (95%CI 2.9\u0026ndash;13.0, IXA\u0026thinsp;+\u0026thinsp;BEV) versus 1.8 (95%CI 1.5\u0026ndash;3.5, IXA) months (log-rank \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.005) (Fig. \u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003e\u003cstrong\u003e-upper\u003c/strong\u003e; HR 0.26, 95%CI 0.10\u0026ndash;0.71). OS estimates were 19.4 (95%CI 6.4 to not reached; IXA\u0026thinsp;+\u0026thinsp;BEV) versus 5.0 (95%CI 2.6\u0026ndash;18.3, IXA) months (log-rank \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.10) (Fig. \u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003e\u003cstrong\u003e-lower\u003c/strong\u003e; HR 0.46, 95%CI 0.18\u0026ndash;1.18). In the subset of these patients who had received an AURELIA regimen (i.e., weekly paclitaxel with or without bevacizumab), PFS estimates were 2.9 (95%CI 2.0-6.9, IXA\u0026thinsp;+\u0026thinsp;BEV) and 1.7 (95%CI 0.9\u0026ndash;2.2, IXA) months (p\u0026thinsp;=\u0026thinsp;0.07). Following receipt of an AURELIA regimen of weekly paclitaxel with or without BEV, OS estimates were 20.2 (95%CI 2.2-not reached, IXA\u0026thinsp;+\u0026thinsp;BEV) and 4.5 (95%CI 0.9 to 18.3, IXA) months (p-0.17). Both patients treated with IXA\u0026thinsp;+\u0026thinsp;BEV following prior weekly paclitaxel and bevacizumab achieved a best response of SD, as did both patients treated with IXA\u0026thinsp;+\u0026thinsp;BEV following prior weekly paclitaxel monotherapy. One of two patients treated with IXA following prior weekly paclitaxel and bevacizumab achieved a best response of SD; one patient treated with IXA following prior weekly paclitaxel monotherapy experienced PD and one was not assessed due to death. The distribution of responses for all patients who received prior weekly paclitaxel are provided in Table \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e. Among these 23 patients, there were 3 PRs in the combination arm but no responses in the IXA arm (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.07). DDC was achieved in 4 patients in the combination arm but in none among the monotherapy arm (p\u0026thinsp;=\u0026thinsp;0.02).\u003c/p\u003e\n\n"},{"header":"Discussion","content":"\u003cp\u003eWe previously reported improved ORR, PFS, and OS conferred by weekly ixabepilone with biweekly bevacizumab (IXA\u0026thinsp;+\u0026thinsp;BEV) compared to monotherapy (IXA) in heavily pre-treated ovarian cancers. We suggested that prior BEV should not preclude re-treatment with the combination of IXA\u0026thinsp;+\u0026thinsp;BEV and highlighted pre-clinical observations that may explain the apparent synergy between these two agents.\u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e The present report also illustrates encouraging activity of IXA\u0026thinsp;+\u0026thinsp;BEV in patients despite prior exposure to weekly paclitaxel and in the setting of dose reductions to further inform clinicians following endorsement of the combination by the NCCN (category 2B).\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eThe mature data reveal an impressive ORR of the combination arm (38.4% vs 8.1%, p\u0026thinsp;=\u0026thinsp;0.003), with durable response in 14 patients and respectable median PFS of 5.5 months and OS of 10 months. Unsurprisingly, in a heavily pre-treated population, dose reductions were common, but ancillary analyses suggest this did not damper response and allowed patients to continue therapy. Our data suggest that a starting dose of 16 mg/m\u003csup\u003e2\u003c/sup\u003e can be considered and may warrant further study.\u003c/p\u003e \u003cp\u003eWhile favorable responses to weekly paclitaxel with\u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e or without bevacizumab\u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e,\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e after three-weekly paclitaxel are well-described, data quantifying the response to repeated treatment with weekly paclitaxel remain limited. Gunderson et al (2017) reported no attenuation of benefit for weekly paclitaxel despite prior exposure to weekly administration during primary therapy among 20 patients; compared to 79 patients previously exposed to three-weekly administration, the clinical benefit rate was actually improved (69% versus 36%, p\u0026thinsp;=\u0026thinsp;0.05).\u003csup\u003e20\u003c/sup\u003e In another small series of 26 patients\u003csup\u003e\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e re-challenge with weekly paclitaxel after prior weekly paclitaxel produced a radiologic response rate of 34.6% with a median PFS of 3.7 months (95%CI 2.3\u0026ndash;6.7) and OS of 18.1 (95%CI 9.6\u0026ndash;28.6). Three patients received weekly paclitaxel for a 3rd time and 2/3 achieved stable disease. It is therefore not unreasonable to expect a subset of patients to benefit from dose-dense treatment with another microtubule-stabilizing agent such as ixabepilone following prior weekly paclitaxel. Ixabepilone may overcome paclitaxel resistance in several ways. Firstly, epothilones tend not to be substrates of drug exportation pumps that shuttle paclitaxel from the cell. Secondly, epothilones also appear to retain affinity for the microtubule despite upregulation of class III β-tubulin over the constitutively expressed class I β-tubulin, which reduces paclitaxel binding by altering the sterics of the pocket. \u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e,\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e Exploratory analyses employing whole exome sequencing among patients with a response to weekly paclitaxel for \u0026gt;\u0026thinsp;12 months suggested the importance of genes related to angiogenesis (VEGF, MMP9), tubulin superfamily (TSC2), apoptosis (BCL2L1, BAD) and interleukin pathways (CXCR1, CXCR2, IL1A, IL1B). Studies investigating predictors of response to weekly paclitaxel are surprisingly scant, and also lacking for epothilones, and should be the subject of future investigations.\u003c/p\u003e \u003cp\u003eIn summary, the regimen of weekly ixabepilone and biweekly bevacizumab achieves high response rates and respectable PFS and OS in heavily pre-treated ovarian cancer patients. Response rates appear to be higher than those reported in this setting for chemotherapy alone, as well as for non-taxane chemotherapies combined with bevacizumab. Use of the combination does not appear to be precluded by exposure to prior bevacizumab or previous treatment with weekly paclitaxel. Biomarkers to predict sustained response to treatment with weekly ixabepilone and bevacizumab are needed.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eACKOWLEDGEMENTS:\u003c/strong\u003e\u0026nbsp; This study was accepted as a poster abstract to the 2024 Annual Meeting of the Society of Gynecologic Oncology. We would like to thank RPharm-US for their industry support and Lisa Baker, Martha Luther, Kay Debski, Amy Nicoletti, Kerry DeBenedictis, Michele Hill, Nancy Tait, Paige Smith, Jocelyn Reader, and Carolynn Harris for their invaluable technical support to the study.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAUTHOR CONTRIBUTIONS:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eCollection and assembly of data: \u0026nbsp;all authors\u003c/p\u003e\n\u003cp\u003eData analysis and interpretation: DMR, ES, ADS\u003c/p\u003e\n\u003cp\u003eManuscript writing: \u0026nbsp;DMR, ES, ADS\u003c/p\u003e\n\u003cp\u003eFinal approval of manuscript for publication: all authors\u003c/p\u003e\n\u003cp\u003eAccountable for all aspects of the work: all authors\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eETHICS APPROVAL AND CONSENT TO PARTICIPATE: \u0026nbsp;\u003c/strong\u003eAll patients provided written informed consent to participate in this study. The study was approved by each participating institution\u0026rsquo;s Human Investigations Committee/Institutional Review Board. This study was performed in accordance with the Declaration of Helsinki. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCONSENT FOR PUBLICATION:\u0026nbsp;\u003c/strong\u003enot applicable\u003cstrong\u003e\u0026nbsp;\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDATA AVAILABILITY:\u0026nbsp;\u003c/strong\u003eThe datasets generated and/or analyzed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCOMPETING INTERESTS:\u0026nbsp;\u003c/strong\u003eThe authors declare no conflicts of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFUNDING INFORMATION:\u0026nbsp;\u003c/strong\u003eStudy drug was supplied by R-Pharm US, LLC (Princeton, NJ)\u003c/p\u003e\n"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eOzols RF, Bundy BN, Greer BE, Fowler JM, Clarke-Pearson D, Burger RA, et al. Phase III trial of carboplatin and paclitaxel compared with cisplatin and paclitaxel in patients with optimally resected stage III ovarian cancer: a Gynecologic Oncology Group study. J. Clin. Oncol. \u003cstrong\u003e21(17),\u003c/strong\u003e 3194\u0026ndash;200 (2003).\u003c/li\u003e\n\u003cli\u003eNational Comprehensive Cancer Network. NCCN Clnical Practice Guidelines in Oncology: Ovarian, Fallopian Tube, Primary Peritoneal Cancer v2.2023 [Internet]. 2023. Available from: https://www.nccn.org/\u003c/li\u003e\n\u003cli\u003ePoveda AM, Selle F, Hilpert F, Reuss A, Savarese A, Vergote I, et al. Bevacizumab Combined With Weekly Paclitaxel, Pegylated Liposomal Doxorubicin, or Topotecan in Platinum-Resistant Recurrent Ovarian Cancer: Analysis by Chemotherapy Cohort of the Randomized Phase III AURELIA Trial. J. Clin. Oncol. \u003cstrong\u003e33(32)\u003c/strong\u003e, 3836\u0026ndash;8, (2015).\u003c/li\u003e\n\u003cli\u003ePujade-Lauraine E, Hilpert F, Weber B, Reuss A, Poveda A, Kristensen G, et al. Bevacizumab combined with chemotherapy for platinum-resistant recurrent ovarian cancer: The AURELIA open-label randomized phase III trial. J, Clin. Oncol. \u003cstrong\u003e32(13)\u003c/strong\u003e,1302\u0026ndash;8 (2014).\u003c/li\u003e\n\u003cli\u003eKessous R, Wissing MD, Laskov I, Abitbol J, Bitharas J, Agnihotram VR, et al. Multiple lines of chemotherapy for patients with high-grade ovarian cancer: Predictors for response and effect on survival. Int. J. Cancer \u003cstrong\u003e148(9),\u003c/strong\u003e 2304\u0026ndash;12 (2021).\u003c/li\u003e\n\u003cli\u003eMoore KN, Secord AA, Geller MA, Miller DS, Cloven N, Fleming GF, et al. Niraparib monotherapy for late-line treatment of ovarian cancer (QUADRA): a multicentre, open-label, single-arm, phase 2 trial. Lancet Oncol. \u003cstrong\u003e20(5)\u003c/strong\u003e,636\u0026ndash;48 (2019).\u003c/li\u003e\n\u003cli\u003eMaloney SM, Hoover CA, Morejon-Lasso LV, Prosperi JR. Mechanisms of Taxane Resistance. Cancers (Basel) \u003cstrong\u003e12(11)\u003c/strong\u003e, 3323 (2020).\u003c/li\u003e\n\u003cli\u003eSazonova EV, Kopeina GS, Imyanitov EN, Zhivotovsky B. Platinum drugs and taxanes: can we overcome resistance? Cell Death Discov. \u003cstrong\u003e7(1)\u003c/strong\u003e, 155 (2021).\u003c/li\u003e\n\u003cli\u003eLee FYF, Borzilleri R, Fairchild CR, Kamath A, Smykla R, Kramer R, et al. Preclinical discovery of ixabepilone, a highly active antineoplastic agent. Cancer Chemother. Pharmacol. \u003cstrong\u003e63(1)\u003c/strong\u003e, 157\u0026ndash;66 (2008).\u003c/li\u003e\n\u003cli\u003eMozzetti S, Ferlini C, Concolino P, Filippetti F, Raspaglio G, Prislei S, et al. Class III beta-tubulin overexpression is a prominent mechanism of paclitaxel resistance in ovarian cancer patients. Clin Cancer Res. \u003cstrong\u003e11(1)\u003c/strong\u003e, 298\u0026ndash;305 (2005). \u003c/li\u003e\n\u003cli\u003eRoque DM, Siegel ER, Buza N, Bellone S, Silasi DA, Huang GS, et al. Randomised phase II trial of weekly ixabepilone\u0026thinsp;\u0026plusmn;\u0026thinsp;biweekly bevacizumab for platinum-resistant or refractory ovarian/fallopian tube/primary peritoneal cancer. Br. J. Cancer \u003cstrong\u003e126(12)\u003c/strong\u003e, 1695\u0026ndash;703 (2022). \u003c/li\u003e\n\u003cli\u003eDe Geest K, Blessing JA, Morris RT, Yamada SD, Monk BJ, Zweizig SL, et al. Phase II clinical trial of ixabepilone in patients with recurrent or persistent platinum- and taxane-resistant ovarian or primary peritoneal cancer: a gynecologic oncology group study. J. Clin. Oncol. \u003cstrong\u003e28(1)\u003c/strong\u003e, 149\u0026ndash;53 (2010). \u003c/li\u003e\n\u003cli\u003eVerschraegen CF, Sittisomwong T, Kudelka AP, Guedes E d, Steger M, Nelson-Taylor T, et al. Docetaxel for patients with paclitaxel-resistant M\u0026uuml;llerian carcinoma. J. Clin. Oncol. \u003cstrong\u003e18(14)\u003c/strong\u003e, 2733\u0026ndash;9 (2000). \u003c/li\u003e\n\u003cli\u003eEisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur. J. Cancer \u003cstrong\u003e45(2)\u003c/strong\u003e, 228\u0026ndash;47 (2009). \u003c/li\u003e\n\u003cli\u003eOken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am. J. Clin. Oncol. \u003cstrong\u003e5(6)\u003c/strong\u003e, 649\u0026ndash;55 (1982). \u003c/li\u003e\n\u003cli\u003eCommon Terminology Criteria for Adverse Events (CTCAE) | Protocol Development | CTEP [Internet]. [cited 2020 Nov 6]. Available from: https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm\u003c/li\u003e\n\u003cli\u003eO\u0026rsquo;Malley DM, Richardson DL, Rheaume PS, Salani R, Eisenhauer EL, McCann GA, et al. Addition of bevacizumab to weekly paclitaxel significantly improves progression-free survival in heavily pretreated recurrent epithelial ovarian cancer. Gynecol. Oncol. \u003cstrong\u003e121(2)\u003c/strong\u003e, 269\u0026ndash;72 (2011). \u003c/li\u003e\n\u003cli\u003eBaird RD, Tan DSP, Kaye SB. Weekly paclitaxel in the treatment of recurrent ovarian cancer. Nat. Rev. Clin. Oncol. \u003cstrong\u003e7(10)\u003c/strong\u003e, 575\u0026ndash;82 (2010). \u003c/li\u003e\n\u003cli\u003eGynecologic Oncology Group, Markman M, Blessing J, Rubin SC, Connor J, Hanjani P, et al. Phase II trial of weekly paclitaxel (80 mg/m2) in platinum and paclitaxel-resistant ovarian and primary peritoneal cancers: a Gynecologic Oncology Group study. Gynecol. Oncol.\u003cstrong\u003e 101(3)\u003c/strong\u003e, 436\u0026ndash;40 (2006). \u003c/li\u003e\n\u003cli\u003eGunderson C, Papaila A, Ding K, Jernigan A, Bedell S, Miller D, et al. Weekly paclitaxe for recurrent ovarian cancer: does weekly administration during primary therapy impact efficacy and toxicity at recurrence? [Internet]. 2017 [cited 2023 Jan 14]. Available from: doi:10.1016/j.ygyno.2017.03.359\u003c/li\u003e\n\u003cli\u003eAlicia O, Bodla, Shankar, Gore, Marin, Kaye, Stan, Banerjee, Susana. B59: Re-challenge with weekly paclitaxel in patients with advanced epithelial ovarian cancer, fallopian tube and primary peritoneal cancer. [Internet]. National Cancer Research Institute Cancer Conference; 2015 Nov 3 [cited 2023 Dec 17]. Available from: https://abstracts.ncri.org.uk/abstract/re-challenge-with-weekly-paclitaxel-in-patients-with-advanced-epithelial-ovarian-cancer-fallopian-tube-and-primary-peritoneal-cancer-ppc-2/\u003c/li\u003e\n\u003cli\u003eMadariaga A, Garg S, Bruce JP, Thiryayi S, Mandilaras V, Rath P, et al. Biomarkers of outcome to weekly paclitaxel in epithelial ovarian cancer. Gynecol. Oncol. 159(2), 539\u0026ndash;45 (2020).\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Footnotes","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003e In the original publication, the CONSORT diagram listed the number of infusions as \u0026lsquo;cycles.\u0026rsquo; This has been amended in the present work to reflect true cycles.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003e A correction has been submitted to the original manuscript due to an error in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. We previously reported 27% (\u003cem\u003eN\u003c/em\u003e\u0026thinsp;=\u0026thinsp;10) of patients in the IXA arm and 23% (of patients \u003cem\u003eN\u003c/em\u003e\u0026thinsp;=\u0026thinsp;9) in the IXA\u0026thinsp;+\u0026thinsp;BEV arm had been treated with weekly paclitaxel (either with carboplatin or as an AURELIA regimen with or without bevacizumab). Among these patients, we described 1 patient in the IXA arm and 4 patients in the IXA\u0026thinsp;+\u0026thinsp;BEV arm who had received weekly paclitaxel with bevacizumab and 1 patient in the IXA arm and 2 in the IXA\u0026thinsp;+\u0026thinsp;BEV arm who received weekly paclitaxel monotherapy.\u003c/span\u003e \u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables are available in the Supplementary Files section.\u003c/p\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":"bjc-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"","sideBox":"Learn more about [BJC Reports](https://www.springer.com/journal/44276) ","snPcode":"44276","submissionUrl":"https://submission.springernature.com/new-submission/44276/3","title":"BJC Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Nature","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-4345163/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4345163/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground:\u003c/strong\u003e Ixabepilone may retain activity in paclitaxel-resistant disease. We previously reported improved response rates (ORR), progression-free (PFS) and overall survival (OS) conferred by ixabepilone+bevacizumab (IXA+BEV) compared to monotherapy (IXA) in heavily pre-treated ovarian cancers. We now describe a mature data set. Subset analyses were performed in patients with different taxane sensitivities and dose modifications.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e Patients previously treated with paclitaxel were stratified by prior BEV and randomized to receive IXA 20 mg/m\u003csup\u003e2\u003c/sup\u003e days 1,8,15±BEV 10 mg/kg days 1,15 of a 28-day cycle in a multi-site prospective randomized phase 2 trial.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults:\u003c/strong\u003e Thirty-seven patients were randomized to IXA and 39 patients to IXA+BEV. At the final data cutoff (05/27/2023), ORR was higher in the IXA+BEV arm (38.4% vs 8.1%,p=0.003). Dose reductions were necessary in most participants but did not diminish PFS/OS benefit. Most patients were paclitaxel-refractory/-resistant (51%,n=19/37;67%,n=26/39); the remainder were taxane-responsive. The addition of BEV to IXA conferred benefit in PFS (5.5 vs 2.2 mo; HR 0.31, 90%CI 0.20-0.49, p\u0026lt;0.001) and OS (10.3 vs 6.0mo; HR 0.56, 90%CI 0.38-0.84, p=0.02) that persisted after adjusting for prior taxane response.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions:\u003c/strong\u003e IXA+BEV has activity in heavily pre-treated ovarian cancers and offers significant improvement in ORR and PFS/OS compared to IXA, despite prior taxane response and dose reductions.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eClinical Trial Registration: \u003c/strong\u003eNCT03093155\u003c/p\u003e","manuscriptTitle":"Randomized phase II trial of weekly ixabepilone ± biweekly bevacizumab for platinum- resistant or refractory ovarian / fallopian tube / primary peritoneal cancer (NCT03093155): updated survival and subgroup analyses","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-05-21 18:56:56","doi":"10.21203/rs.3.rs-4345163/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Accepted","date":"2024-05-14T18:57:04+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-05-14T18:48:52+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-05-09T10:31:27+00:00","index":"","fulltext":""},{"type":"submitted","content":"BJC Reports","date":"2024-04-29T22:00:28+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bjc-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"","sideBox":"Learn more about [BJC Reports](https://www.springer.com/journal/44276) ","snPcode":"44276","submissionUrl":"https://submission.springernature.com/new-submission/44276/3","title":"BJC Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Nature","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"349d61ce-afa1-4a49-ab83-d066699ea57f","owner":[],"postedDate":"May 21st, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2024-06-21T16:04:27+00:00","versionOfRecord":{"articleIdentity":"rs-4345163","link":"https://doi.org/10.1038/s44276-024-00067-5","journal":{"identity":"bjc-reports","isVorOnly":false,"title":"BJC Reports"},"publishedOn":"2024-06-20 16:04:27","publishedOnDateReadable":"June 20th, 2024"},"versionCreatedAt":"2024-05-21 18:56:56","video":"","vorDoi":"10.1038/s44276-024-00067-5","vorDoiUrl":"https://doi.org/10.1038/s44276-024-00067-5","workflowStages":[]},"version":"v1","identity":"rs-4345163","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4345163","identity":"rs-4345163","version":["v1"]},"buildId":"cTy_lsJlmDsVRNrSptgXS","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}