Manganese primed immunochemotherapy in platinum-resistant/refractory ovarian cancer: a randomized, single-blind, placebo-controlled, phase 2 trial

Manganese primed immunochemotherapy in platinum-resistant/refractory ovarian cancer: a randomized, single-blind, placebo-controlled, phase 2 trial | 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 Article Manganese primed immunochemotherapy in platinum-resistant/refractory ovarian cancer: a randomized, single-blind, placebo-controlled, phase 2 trial Weidong Han, Qian Mei, Yan Zhang, Jiejie Liu, Meixia Chen, Yandong Gong, and 10 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4434336/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Platinum-resistant or refractory ovarian cancer (PROC) remains without immunotherapy approval and dismal prognosis, emphasizing the urgent need for novel therapies. This phase 2, single-blind, placebo-controlled, randomized trial evaluated the safety and efficacy of manganese chloride or placebo plus sintilimab, nab-paclitaxel and cisplatin in these patients. 84 patients were randomized to the Mn 2+ (n=55) or placebo (n=29) arm. The primary endpoint of objective response rate (ORR) was met at 61.8% in the Mn 2+ and 13.8% in placebo group. The secondary endpoints of median PFS (9.8 vs. 3.9 months), OS (21.4 vs. 7.9 months) and DOR (14.9 vs. 1.8 months) were significantly prolonged in the Mn 2+ group. No significant differences in AEs and quality of life were document during the treatment period. The serum cytokines and scRNA-seq evidenced the cGAS-STING agonist function of Mn 2+ . Our study supported Mn 2+ -priming immunochemotherapy as a promising treatment regimen for PROC patients. ClinicalTrials.gov identifier: NCT03989336. Biological sciences/Cancer/Gynaecological cancer/Ovarian cancer Biological sciences/Cancer/Cancer therapy/Cancer immunotherapy Figures Figure 2 Figure 3 Figure 4 Introduction Epithelial ovarian cancer, the most lethal gynecologic malignancy, responds well to platinum-based chemotherapy, although a significant proportion of patients (85%) experience a relapse and acquire resistance 1 , 2 . Platinum-resistant ovarian cancer (PROC) is managed using chemotherapy alone or with bevacizumab 3 . Platinum sensitivity is not a dichotomous state but rather exists on a continuum. Therefore, platinum rechallenge may affect platinum-resistant ovarian cancer patients who are not primary refractory 3 , 4 . Moreover, Nab-paclitaxel is highly recommended for PROC patients due to its notable efficacy and favorable safety profile 5 . Nevertheless, subsequent chemotherapy regimens have shown declining efficacy, with response rates of 10–15% and substantial toxicities 6 . Despite of these limitations, the AURELIA research found that the addition of bevacizumab to chemotherapy improved outcomes for PROC patients and was approved by the FDA 7 . Regrettably, the majority of patients have received bevacizumab prior to platinum-resistant disease develops, causing inevitable progression 8 . In addition, mirvetuximab soravtansine (MIRV) was approved for ovarian cancer cased on the successful SORAYA trial, although only patients with FRα-positive PROC benefited 9 , 10 . Therefore, effective treatments for PROC remain elusive and urgently unmet need. OC stands out as a malignancy lacking FDA-approved immunotherapy options 11 . Thus far, trials involving either immune checkpoint blockade (ICB) monotherapy or in combination with chemotherapy demonstrated disappointing results in PROC, meeting neither outcome endpoints. However, these studies highlight the capability of ICB regimens to induce durable response in a small subset of patients with PROC 12 . OCs exhibit unique immunogenomic profile, including low-intermediate mutational load, aneuploidy and immunosuppressive tumor microenvironment (TME). Despite the presence of a high level of immune cells in the TME, the dominant innate immune cells prevent an effective response to ICB therapy 13 – 15 . Type-I interferon (IFN) stimulates intracellular pathways that regulate both innate and adaptive immune responses. Activation of type-I IFN is essential in rescuing a non-responsive tumor immune state 16 . An effective strategy to activating Type-I IFN is to exogenously inducing activation of innate immune sensing pathways. The cGAS-STING pathway is a crucial element of the innate immune system that triggers the production of type-I IFN, and its tumor immunomodulatory capability has received significant attention 16 , 17 . Preliminary research has indicated that activating the cGAS-STING pathway, along with treatments that induce immunogenic tumor cell death, can boost the sensitivity to ICB treatment and enhance its anti-tumor effects 18 , 19 . Novel immunomodulatory approaches focusing on interferon activation through cGAS-STING present as a promising avenue 20 , 21 . Manganese (Mn 2+ ) is an essential metal element in human body and acts as a potent natural agonist of cGAS-STING 1 , 21 . Mn 2+ enhances the sensitivity of cGAS to dsDNA and augments the binding affinity of STING to cGAMP, and it also triggers cGAS to synthesize cGAMP through a unique catalytic mechanism independent of dsDNA. cGAS-STING pathway plays a vital role in initiating both innate and adaptive immune responses via cross-presentation and priming, especially among immunosuppressive TME. The effect of Mn 2+ on systemic antitumor response and TME remodeling has been confirmed in multiple mouse models 21 – 23 . In the phase I trial conducted on patients with advanced metastatic solid tumors, the administration of Mn 2+ demonstrated promising efficacy, resulting in 45.5% objective response and 90.9% disease control. Furthermore, it successfully reinvigorated responses to immunotherapy in patients who had previously experienced treatment failure 22 . Notably, six of the 8 patients with recurrent OC showed positive response to the treatment as well as significant alleviation from frozen pelvic symptoms. This indicates the promising potential encouraging antitumor activity of Mn 2+ in ovarian cancer. Due to the ready accessibility and well-studied toxicity, Mn 2+ could be a compelling choice for innovative immunotherapy. Given this context, we hypothesized that the combination of cGAS-STING agonist Mn 2+ and genotoxic chemotherapy could boost the immune response and sensitize ovarian cancers to ICB therapy. This single-blinded randomized placebo-controlled trial was conducted to assess the efficacy and safety of immunochemotherapy (sintilimab plus nab-paclitaxel and platinum) with cGAS-STING agonist Mn 2+ or placebo, in patients with platinum-resistant/refractory ovarian cancer. Results Patients From December 23, 2020, to March 11, 2023, a total of 84 patients were randomized (Mn 2+ group, n=55; placebo group, n=29) and constitute the ITT population (Figure 1). A total of 83 patients were administered at least one dose of the assigned treatment (55 in Mn 2+ group and 28 in placebo group) and were included in the safety population. Table 1 shows the demographic and clinical characteristics of patients at baseline. The baseline characteristics were well balanced between the two arms. Out of the patients included in the study, 76 (90.5%) had high-grade serous epithelial OC, 47 (56.0%) had platinum-refractory disease, and all (100%) with microsatellite stable (MSS) genotype. Patients in both arms were heavily pretreated, with a median of 4 previous treatment lines. Out of the total, 66 (78.6%) patients had received three or more previous treatment lines. Out of all the participants, 47 (56.0%) had previous exposure to nab-paclitaxel, 44 (52.4%) to bevacizumab, and 30 (35.7%) to PARP inhibitor. As of the data cutoff on December 10, 2023, the median duration of follow-up was 20.3 months (95% CI, 18.7-32.5), with 23.9 months in Mn 2+ group and 18.7 months in placebo group. As of the data cutoff, the trial treatment was still ongoing for 8 (14.5%) patients in the Mn 2+ group, while no patients in the placebo group were receiving treatment (Figure 1). Efficacy The ORR was substantially improved in the Mn 2+ group (61.8%; 95% CI, 48.1-73.9) compared to the placebo group (13.8%; 95% CI, 5.1-32.5) (risk ratio,0.223; 95% CI, 0.088-0.567; P<0.0001) (Extended Data Table 1). In the Mn 2+ group, 3 (5.5%) patients had CRs and 31 (56.3%) had PRs, as compared to only 4 (13.8%) in the placebo group had PRs (Figure 2 and Extended Data Table 1). Extended Data Fig.1 and 2 display the course and response of treatment for each individual patient. The DCR was 92.7% (51/55; 95% CI, 81.8-97.3) in the Mn 2+ group and 82.8% (24/29; 95% CI, 63.7-92.9) in the placebo group. The CA-125 responses, as per GCIG criteria, were observed in 82.4% (42 out of 51) of patients in the Mn 2+ group, and 32.0% (8 out of 25) of patients in the placebo group (rate difference, 50.4%; 95% CI, 27.1-67.2; P<0.0001) (Extended Data Table 1). The subgroup analyses of objective response appeared to consistently favor Mn 2+ group over placebo group (Extended Data Fig. 3). These groups included patients with platinum-refractory disease (elevation in ORR, 39.0%), more than 4 prior lines of therapy (elevation, 49.6%), prior received bevacizumab, nab-paclitaxel and PARP inhibitor (elevation, 45.3%, 58.1% and 54.1%, respectively). PROC patients in the Mn 2+ group exhibited a substantially longer PFS (median, 9.8 months; 95% CI, 6.6-15.9) compared to the placebo group (median, 3.9 months; 95% CI, 3.0-4.7) (hazard ratio [HR], 0.34; 95% CI, 0.21-0.55; P<0.0001) (Figure 2 and Extended Data Table 1). The median OS was significantly prolonged in the Mn 2+ group (21.4 months; 95% CI, 16.1-29.9) than in the placebo group (7.9 months; 95% CI, 6.7-11.2) (HR, 0.32; 95% CI, 0.18-0.57; P<0.0001). Post hoc analyses demonstrated a consistent benefit in PFS and OS across multiple subgroups (Extended Data Fig. 4 and 5). The median DOR was 14.9 months (95% CI, 7.2-20.3) among 34 patients in the Mn 2+ group with CR and PR, as compared significantly with 1.8 months (95% CI, 0.6-NE) among 4 patients with PR in the placebo group (HR, 0.34; 95% CI, 0.11-0.998; P=0.0396) (Figure 2 and Extended Data Table 1). The PRO assessment comprised a total of 77 patients. The FACT-O status did not document a between-group difference during the first four cycles of treatment (Extended Data Fig. 6). Safety Adverse events (AEs) that occurred during the treatment period are summarized in Table 2. The safety profiles of both study arms were comparable, with 51 (92.7%) patients in the Mn 2+ group and 25 (89.3%) patients in the placebo group experiencing treatment-emergent AEs (TRAEs) of any grade. The most common AEs of any grade were nausea (37 [67.3%] patients in the Mn 2+ group vs 18 [64.3%] patients in the placebo group), vomiting (32 [58.2%] vs 14 [50.0%] patients), peripheral neuropathy (28 [50.9%] vs 12 [42.9%] patients) and anemia (21 [38.2%] vs 10 [35.7%] patients). Grade 3 AEs were observed in 8 (14.5%) patients in the Mn 2+ group and in 5 (17.9%) patients in the placebo group. No AEs were identified in grade 4-5. The majority AEs were associated with chemotherapy treatment. The treatment-related AEs of grade 1-2 were well-tolerated, and most AEs of grade 3 resolved with supportive care. AEs leading to treatment discontinuation occurred in 6 (10.9%) patients in the Mn 2+ groupand 3 (10.7%) patients in the placebo group. No death due to treatment-related AEs were reported. In the Mn 2+ group, neurologic evaluation and MRI/CT scan of the head were conducted at the prespecified timepoint during the Mn 2+ -based treatment. No extrapyramidal symptom as the Mn 2+ overdose-related toxicity was documented, and accumulation of Mn in the basal ganglia was also not observed. Liver-iron-overload-like MRI images were observed in 2 patients without any related clinical manifestation (Extended Data Fig. 7). Laboratory analysis The concentration of blood Mn 2+ was monitored using ICP-AES, with a normal range of 3.39 to 20.67 μg/L. The concentration of Mn 2+ in the blood augmented dramatically with the treatment cycle number in the Mn 2+ group, while it remained rather constant in the placebo group (Figure 3 and Extended Data Fig.8). In responders (patients with CR or PR) in the Mn 2+ group, there was a notable increase in blood Mn 2+ levels as the treatment cycles progressed. However, this increase was only noticed when compared to the baseline levels in patients with SD or PD (Figure 3 and Extended Data Fig.8). Notably, post-administration levels of blood Mn 2+ remained within the physiological range for most patients in the Mn 2+ group, with only a few individual patients slightly surpassing the upper limit over the post-treatment period (Figure 3 and Extended Data Fig.8). To confirm the activation of cGAS-STING signaling by Mn 2+ , we assessed serum cytokines and chemokines using multiplex immunoassay panels specifically designed for human antivirus response and proinflammatory chemokines. Significant correlations were recorded between the expression elevation of cytokines IFN-β, IFN-γ and IL-1β and the categorization based on clinical response in the Mn 2+ group. However, no differences in expression were observed in the placebo group (Figure 3 and Extended Data Fig. 8). Subsequently, an analysis was conducted to characterize the treatment-induced alterations in the transcriptional landscape of PBMCs using single-cell RNA sequencing (scRNA-seq). The identification of major PBMC subpopulations was straightforward using well-established gene markers (Figure 4A to C and Extended Data Fig. 9 A, B). The differences in cellular composition between the two groups were evident. The Mn 2+ group exhibited an increase in CD14 + , FCGR3a + , and CYBB hi monocytes, while also experiencing a decrease in exhausted T and NK cells following treatment, in contrast to the placebo group (Figure 4D, E and Extended Data Fig. 9C). The investigation identified three subsets of monocytes exhibiting an elevated pro-inflammatory signature and promoting pathways related to type-I interferon, antigen presentation, and lymphocyte activation (Figure 4F to H). Additionally, the activation and cytotoxicity signaling in pre-exhausted T, exhausted T and γδT cells from the Mn 2+ -treated sample were enhanced, despite the reduction in their numbers (Extended Data Fig. 9D-H). Discussion This randomized, single-blinded, placebo-controlled, phase II trial compared the safety and efficacy of immunochemotherapy with manganese or placebo in patients with platinum-resistant/refractory ovarian cancer (PROC). PROC has sparse treatment options and remains of dismal prognosis. The majority of patients with PROC was lack of response to immunotherapy attributed to the inadequate immune activation and suppressive TME 3 , 11 , 13 . Exogenously Type-I IFN activation presents as an attractive option to enhance antitumor immunity, and cGAS-STING agonists is emerging as a promising avenue 20 , 24 , 25 . However, the efficacy of cGAS-STING agonists is constrained by numerous obstacles related to drug delivery and pharmacology. Manganese, being an essential nutrient with simple and steady properties, could be a strong candidate and develop universal antitumor therapies 25 . To the best of our knowledge, this is the first randomized trial of systemic administration of STING agonists for ovarian cancer. This trial met the primary endpoint, showing of a significant benefit of both promotion (ORR, 61.8% v.s. 13.8%; RR, 0.223; 95% CI, 0.088–0.567) and persistence (median DOR, 14.9 M v.s. 1.8 M; HR, 0.336; 95% CI, 0.113–0.998) of efficacy with Mn 2+ priming immunochemotherapy in PROC. Mn 2+ priming immuno-chemotherapy demonstrated significant improvements in PFS and OS in the heavily pretreated population, including patients with platinum-refractory disease, more than 4 prior lines of therapy, prior received bevacizumab, nab-paclitaxel and PARP inhibitor. These subsets of patients have get a more negative outcome, and are often excluded or only a small proportion included in other randomized trials. The current trial has enrolled a broader population, and the encouraging outcomes support the potential of Mn 2+ priming immunochemotherapy to change the therapy landscape for PROC, a disease with a traditionally poor prognosis. cGAS-STING is an important pivot for cytosolic DNA sensation and Type-I IFN induction 21 , 24 . The activation effect of cGAS-STING agonists can be significantly enhanced by the immunogenic death induced by genotoxic agents 26 – 28 . This not only promotes the Type-I IFN immune response, but also increases the expression of PD-L1 in tumor cells, hence boosting the sensitivity to ICB therapy 27 , 29 . Manganese work as a powerful agonist of cGAS-STING via not only directly increasing the catalytic of cGAS, but also enhancing the affinity of cGAMP and STING to promote INF-I produce 21 , 25 . Mn 2+ has been documented to induce a superior antitumor effect in multiple murine tumor models, and markedly prolonged the survival of tumor-bearing mice 22 , 23 . Notably, our phase I trial involving multiple advanced metastatic solid tumors initially observed favorable clinical efficacy of Mn 2+ priming immunochemotherapy, and gave this strategy a broader antitumor spectrum and a durable antitumor immune response 22 . In the current trial focusing on the platinum-resistant/refractory ovarian cancer, the levels of serum Type-I IFN and inflammatory cytokines exhibited a substantial increase following the treatment, and this increase was strongly correlated with the clinical responses. Simultaneously, analysis of scRNA-seq data revealed significant stimulation of Type-I IFN signaling in monocytes, suggesting that Mn 2+ functions as a cGAS STING agonist in regulating the immune response, reinforcing the significant benefits of ORR, PFS and OS in this difficult-to-treat population. Mn 2+ was administrated via nebulized inhalation in the current trail, which is a safe way to deliver into the lung 30 . The selection of modalities and dosage regimens was informed by the results obtained from our previous phase I investigation and the application of a murine tumor model. Covid-19 vaccine studies have demonstrated that inhalation administration can effectively activate mucosal immune and simultaneously induce humoral and cellular immune responses 31 . Intranasal immunization of these vaccines has shown superior performance over traditional immunization modalities such as intramuscular immunization in inducing systemic and mucosal responses 32 . The pronounced changes of inflammatory cytokine and immune cell type have been detected in peripheral blood samples from enrolled patients. However, whether nebulized manganese chloride can play a similar role to inhaled vaccines remains to be confirmed. The AE profile of this trial was mostly consistent with the previously reported toxicities of ICB plus chemotherapy regimens in OC and other solid tumors 12 , 33 . Most AEs were grade 1 to 2 and relieved by symptomatic. The current trail did not document any clinical symptom of manganism, including MRI evidence of central nervous system impairment. Nevertheless, two patients exhibited liver-iron-overload-like MRI findings, requiring further long-term follow-up. Certain patients had symptoms resembling cytokine-release-syndrome in our previous phase I trial 22 , however, in this trial, no such suspicious reaction occurred due to the reduced frequency of the intermittent inhalation delivery modality. The assessment of quality of life using measuring scales remained relatively unchanged during the Mn 2+ -based treatment. Our trial has several limitations. Initially, we failed to collect biopsy tumor samples to validate the impact of Mn 2+ priming immunochemotherapy on the tumor microenvironment. Furthermore, the administration of Mn 2+ in this trial is limited to inhalation. The difference of effect and mechanism from traditional mode of administration should be established. In conclusion, the Mn 2+ priming immunochemotherapy demonstrated strongly favor superiority in terms of ORR, PFS, OS and DOR as compared with ICB plus chemotherapy in PROC. Platinum-refractory/resistant OC is a highly lethal disease with few efficacious treatments, thus there remains a pressing need to develop potent agents. Considering the essential role as nutrient and FDA approved usage of Mn 2+ , Mn 2+ priming immunochemotherapy appears to be a promising and attractive candidate for the treatment of PROC. Online Methods Study design This phase II, randomized, single-blind, placebo-controlled study (ClinicalTrials.gov identifier: NCT03989336) was conducted in accordance with the principles of the Declaration of Helsinki, the Good Clinical Practice guidelines of International Council for Harmonisation. The protocol was approved by the Institutional Review Board of the Chinese PLA General Hospital (Beijing, China, No. S2019-02-03). All enrolled patients provided written informed consent. All authors vouch that the study protocol was strictly followed and for the accuracy and completeness of the data. This study followed the Consolidated Standards of Reporting Trials (CONSORT) reporting guideline. The complete protocol was provided as supplementary information. Participants The study included adult female patients (≥ 18 years) with histologically confirmed epithelial ovarian, fallopian tube, or peritoneal cancer; experienced either platinum-resistant (defined as progression within 6 months following last dose of most recent platinum) or platinum-refractory (defined as lack of response or progression within 1 month since the last dose); at least one lesion measurable by Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1); a minimum of two previous lines of systemic therapy including at least one platinum-base regimen; Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2; and adequate organ function. The patients resistant to previous ICB or bevacizumab treatment were eligible. Patients were excluded if they had previous or concurrent other malignancies, autoimmune disease, active infections. Full eligibility criteria are listed in the protocol. Interventions Enrolled patients were allocated to treatment using minimization with a random element and stratified by platinum-free interval (PFI). The participants were assigned in a 2:1 ratio to receive manganese chloride or placebo plus immunochemotherapy. Patients were blinded to the treatment allocation. Manganese chloride (0.4mg/kg) or placebo was nebulized inhaled twice per week in the first 3-week cycle, and thereafter twice in the first week of each 3-week cycle. The immunochemotherapy consisted of nab-paclitaxel (200 mg/m 2 , administered intravenously on day 2 in a 3-week cycle), cisplatin (60 mg/m 2 , administered intravenously on day 2 in a 3-week cycle) and sintilimab (200 mg, administered intravenously on day 3 in a 3-week cycle). If patients with known hypersensitivity to cisplatin, carboplatin (area under the curve [AUC] 4 mg/mL per min) was used as alternative. Treatment continued until the second confirmed CR, progressive disease, development of unacceptable toxicity, or consent withdrawal. Outcomes and Assessments The primary endpoint was investigator-assessed ORR per RECIST v1.1, defined as the percentage of patients with at least one efficacy assessment who achieved a complete or partial response (CR/PR). The primary safety endpoint was the incidence of treatment-related AEs in patients who received at least one dose of study treatment. The key secondary endpoints included the progression-free survival (PFS, the time from the date of randomization until investigator-assessed progressive disease [PD] or death, whichever occurred first), overall survival (OS, the time from the date of randomization until the date of death or last known to be alive), and disease control rate (DCR, defined as the percentage of patients with at least 1 efficacy assessment achieved a CR, PR or stable disease [SD]). Further secondary endpoints included the duration of response (DOR, the time from initial response until investigator-assessed PD or death occurred for all participants who had a confirmed objective response), Gynecological Cancer interGroup CA-125 response rate and patient report outcome (PRO). Exploratory assessments included subgroup analyses, serum cytokines and chemokines, and blood Mn 2+ parameters. Responses were assessed by the same blinded radiologist per RECIST 1.1, using magnetic resonance imaging (MRI) or computed tomography (CT) at baseline, every 2 cycles during treatment, and 12 weeks after discontinuing treatment until PD, death, initiation of subsequent treatment, loss to follow-up, withdrawal of consent, or study closure. Post-progression follow-up was performed every 3 months for OS. PRO questionnaire FACT-O (Functional Assessment of Cancer Therapy-Ovarian Cancer) was administered at baseline, prior to each cycle of treatment, at the end of treatment, and at follow-up. All adverse events (AEs) were monitored and documented throughout the study and 3 months after the last dose according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 5.0. Neurologic evaluation and MRI/CT scan of the head were performed to monitor and exclude manganism symptoms. Laboratory parameters (including hematology parameters, blood biochemistry parameters, serum cytokine and chemokine parameters, blood Mn 2+ level, and CA-125) and vital signs were assessed during screening and on day 1 of each trial visit. Concentration of blood Mn 2+ was detected by the inductively coupled plasma-atomic emission spectroscopy (ICP-AES) recommended by ATSDR, and serum cytokines and chemokines were analyzed by LEGENDplex Bead-based Immunoassays (BioLegend) according to the manufacturer’s instructions. Serum cytokines and chemokines analyses All the blood samples were collected in nonheparinized tubes and allowed to clot at room temperature for 2 h and then centrifuged at 1,500 g for 10 min. The serum samples were absorbed from the coagulated blood and stored at -80℃. The serum cytokines and chemokines were analyzed by LEGENDplex bead-based immunoassays (BioLegend, San Diego, USA) according to the manufacturer’s instructions. The human anti-virus response (740349) and proinflammatory chemokine panel (740984) were used to simultaneous quantified of 25 serum cytokines/chemokines, including IL-1β/6/10, IFN-α/β/γ, CXCL-9/10/11 and CCL-2/4/5/20. Data acquisition was performed on a Beckman DxFLEX flow cytometer (Beckman COULTER) and analyzed with the LEGENDplex™ Data Analysis Software (BioLegend). Blood Mn 2+ concentration analysis The blood samples were collected before each cycle in heparinized tube. Inductively coupled plasma-atomic emission spectroscopy (ICP-AES) recommend by ATSDR was employed for detection of the concentration of blood Mn 2+ . The normal range of blood Mn 2+ was 3.39 ~ 20.67ug/L in Chinese population. Statistical Analysis A sample size of 78 patients (randomly assigned in a 2:1 ratio to the Mn 2+ group and placebo group) was required to achieve 90% power to detect an improvement in ORR from 14–50% at a two-sided α level of 0.05. The reference ORR of 14% was based on the JAVELIN 200 study with a 13.3% ORR in ICB plus chemotherapy group 33 . Efficacy was assessed in the intention-to-treat (ITT) population who underwent randomization regardless of whether assigned treatment received. The safety population included all participants who underwent randomization and received at least one dose of the assigned treatment. Objective response and CA-125 response were estimated for each treatment group, along with two-sided 95% CIs using the Clopper-Pearson method. Comparison between the trial groups was performed using stratified Cochran-Mantel-Haenszel test. Time-to-event (PFS, OS and DOR) were estimated using the Kaplan-Meier method, with 95% CIs calculated with the Brookmeyer-Crowley method. The two trial groups were compared using the stratified log-rank test. The study utilized the stratified Cox proportional-hazards model to analyze hazard ratios and their corresponding CIs. Change in PRO was assessed in patients from baseline to the last safety follow-up visit for the FACT-O subscales. Paired t tests were performed to compare the blood Mn 2+ concentration and serum cytokines and chemokines between two groups. Unless otherwise specified, statistical tests were performed with a two-sided 5% significance. All statistical analyses were performed in StataMP 17. Abbreviations FIGO International Federation of Gynecology and Obstetrics ECOG Eastern Cooperative Oncology Group PFI platinum -free interval PARP poly (ADP-ribose) polymerase HRD HRD: homologous recombination deficiency MSS microsatellite stable TMB tumor mutational burden. Declarations Disclosure of Potential Conflicts of Interest No potential conflicts of interest were disclosed. Acknowlegment The authors thank the participants and their families, the investigators and trial teams for their support in executing the study. We are grateful to Prof. Rui-Ping Xiao (Peking University) for thorough discussion regarding to the design and results of this study. This study was funded by National Natural Science Foundation of China (82073183 to Q. Mei, 82150108, 82341208 and 31991171to W. Han, and 32100646 and 82370107 to Y. Gong). Data sharing The study protocol is accessible in the Supplementary information. The data substantiating the conclusions of this study can be obtained from the corresponding authors upon request via email. The request will undergo a thorough research evaluation process by the Institutional evaluation Board of the Chinese PLA General Hospital, focusing on the potential risks associated with patient reidentification. Sharing of raw data at the individual patient level, which includes personally identifying information, is not permitted. References Pujade-Lauraine, E., Banerjee, S. & Pignata, S. Management of Platinum-Resistant, Relapsed Epithelial Ovarian Cancer and New Drug Perspectives. J Clin Oncol 37 , 2437-2448 (2019). Richardson, D.L., Eskander, R.N. & O'Malley, D.M. Advances in Ovarian Cancer Care and Unmet Treatment Needs for Patients With Platinum Resistance: A Narrative Review. JAMA Oncol 9 , 851-859 (2023). St Laurent, J. & Liu, J.F. 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Respiratory mucosal delivery of next-generation COVID-19 vaccine provides robust protection against both ancestral and variant strains of SARS-CoV-2. Cell 185 , 896-915 e819 (2022). Pujade-Lauraine, E. , et al. Avelumab alone or in combination with chemotherapy versus chemotherapy alone in platinum-resistant or platinum-refractory ovarian cancer (JAVELIN Ovarian 200): an open-label, three-arm, randomised, phase 3 study. Lancet Oncol 22 , 1034-1046 (2021). Tables Table 1. Baseline Demographics and Disease Characteristics by Treat Arm Characteristic Mn+nPP+P (n=55) Placebo+nPP+P (n=29) Age, median (range), y 57 (30-71) 54 (42-73) FIGO stage II 2 (3.6) 1 (3.4) III 47 (85.5) 24 (82.8) IV 6 (10.9) 4 (13.8) ECOG 0 36 (65.5) 18 (62.1) 1 14 (25.4) 8 (27.6) 2 5 (9.1) 3 (10.3) Histology Epithelia 49 (89.1) 27 (93.1) Fallopian tube/primary peritoneal 6 (10.9) 2 (6.9) Primary PFI † < 6 M 35 (63.6) 17 (58.6) ≥ 6 to < 12 M 20 (36.4) 12 (41.4) Most recent PFI ‡ < 1 M (refractory) 30 (54.5) 17 (58.6) ≥ 1 to < 6 M (resistant) 25 (45.5) 12 (41.4) Previous treatment lines median 4 4 range 1-13 2-13 Prior exposure Bevacizumab 27 (49.1) 17 (58.6) Nab-Paclitaxel 31 (56.4) 16 (55.2) anti-PD-1 treatment 10 (18.2) 5 (17.2) PARP inhibitor 19 (34.5) 11 (37.9) BRCA mutated Yes 14 (25.5) 7 (24.1) No 36 (65.5) 18 (62.1) Unknown 5 (9.1) 4 (13.8) HRD Yes 16 (29.1) 7 (24.1) No 34 (61.8) 18 (62.1) Unknown 5 (9.1) 4 (13.8) MSS 55 (100) 29 (100) TMB median 6.1 5.9 range 1.56-14.35 3.04-11.34 Mn+nPP+P represents MnCl 2 , nab-paclitaxel, cisplatin (or carboplatin), plus sintilimab, and Placebo+nPP+P, placebo, nab-paclitaxel, cisplatin (or carboplatin), plus sintilimab. Abbreviations: FIGO, International Federation of Gynecology and Obstetrics; ECOG, Eastern Cooperative Oncology Group; PFI, platinum -free interval; PARP, poly (ADP-ribose) polymerase; HRD, HRD: homologous recombination deficiency; MSS, microsatellite stable; TMB, tumor mutational burden. † Primary PFI was defined as the time from last dose of first-line platinum therapy to the date of disease progression or relapse after first-line therapy. ‡ Most recent PFI was defined as the time from last dose of the latest line of platinum therapy to the date of disease progression or relapse after that line of therapy. Table 2. Treatment-related adverse events Event Mn+nPP+P (n=55) Placebo+nPP+P (n=28) Any Grade Grade1-2 Grade3 Any Grade Grade1-2 Grade3 no. % no. % no. % no. % no. % no. % Any treatment-related AEs 51 92.7 43 78.2 8 14.5 25 89.3 21 75 5 17.9 Mn treatment-related AEs Liver-iron-overload-like 2 3.6 2 3.6 0 0 0 0 0 0 0 0 Immunotherapy related AEs Hypothyroidism 11 20 11 20 0 0 5 17.9 5 17.9 0 0 Pruritus 5 9.1 5 9.1 0 0 1 3.6 1 3.6 0 0 Treatment-related AEs Nausea 37 67.3 31 56.4 6 10.9 18 64.3 15 53.6 3 10.7 Vomiting 32 58.2 27 49.1 5 9.1 14 50 12 42.9 2 7.1 Peripheral neuropathy 28 50.9 23 41.8 5 9.1 12 42.9 10 35.7 2 7.1 Anemia 21 38.2 15 27.3 6 10.9 10 35.7 8 28.6 2 7.1 Leucopenia 18 32.7 14 25.5 4 7.3 8 28.6 6 21.4 2 7.1 Rash 10 18.2 10 18.2 0 0 4 14.3 4 14.3 0 0 Neutropenia 12 21.8 9 16.4 3 5.5 6 21.4 4 14.3 2 7.1 Anorexia 8 14.5 8 14.5 0 0 5 17.9 5 17.9 0 0 Diarrhea 7 12.7 7 12.7 0 0 4 14.3 4 14.3 0 0 Constipation 7 12.7 7 12.7 0 0 3 10.7 3 10.7 0 0 Thrombocytopenia 8 14.5 5 9.1 3 5.5 4 14.3 3 10.7 1 3.6 Fatigue 4 7.3 4 7.3 0 0 3 10.7 3 10.7 0 0 Muscular soreness 4 7.3 4 7.3 0 0 2 7.1 2 7.1 0 0 Fever 4 7.3 4 7.3 0 0 2 7.1 2 7.1 0 0 Hyperthyroidism 4 7.3 4 7.3 0 0 3 10.7 3 10.7 0 0 Dizzy 4 7.3 4 7.3 0 0 0 0 0 0 0 0 Intestinal obstuction 0 0 0 0 0 0 3 10.7 3 10.7 0 0 Ascites 4 7.3 4 7.3 0 0 1 3.6 1 3.6 0 0 Additional Declarations There is NO Competing Interest. Supplementary Files Protocol0517.pdf SupplementaryAppendix0515.pdf FigureA1Swim.jpg FigureA2CR.jpg Extended Data Fig. 2 FigureA3ORRForest.jpg Extended Data Fig. 3 FigureA4PFSForest.jpg Extended Data Fig. 4 FigureA5OSForest.jpg FigureA6FACTO.jpg FigureA7XXXXXXXXX.jpg FigureA8SerumFigureSupplement.jpg FigureA9serumsuppl.jpg ExtendedDataFigureLegends.docx Cite Share Download PDF Status: Posted Version 1 posted 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 Advisory Board 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-4434336","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":306379764,"identity":"b05fa2c8-c4f5-4973-ab87-abf083f36d3c","order_by":0,"name":"Weidong 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2","display":"","copyAsset":false,"role":"figure","size":2852459,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eClinical Efficacy of the Mn\u003c/strong\u003e\u003csup\u003e\u003cstrong\u003e2+\u003c/strong\u003e\u003c/sup\u003e\u003cstrong\u003e Group as Compared with Placebo Group.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ea, b,\u003c/strong\u003e Waterfall plot of the best tumor percent change from baseline in the Mn\u003csup\u003e2+\u003c/sup\u003e arm (a) and placebo arm (b). Dashed lines indicate the thresholds regarding PD and PR per the RECIST v1.1. Two-side 95%CIs were estimated using the Clopper-Pearson method. \u003cstrong\u003ec to e,\u003c/strong\u003e Kaplan-Meier curves of investigator-assessed PFS, OS and DOR in the Mn\u003csup\u003e2+\u003c/sup\u003e and placebo group. HR, two-side 95%CIs and \u003cem\u003eP\u003c/em\u003e values were estimated using stratified Cox proportional-hazards model and stratified log-rank test, respectively. Analyses were performed in the intention-to-treat population (response, PFS and OS) and patients with objective response (DOR).\u003c/p\u003e","description":"","filename":"Figure2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4434336/v1/455a72653c3479370b6d2e67.jpg"},{"id":57379459,"identity":"9f9cb071-d9b4-4c92-b9bd-e5404314e50a","added_by":"auto","created_at":"2024-05-30 01:08:36","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":1577141,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eChanges of blood Mn\u003c/strong\u003e\u003csup\u003e\u003cstrong\u003e2+\u003c/strong\u003e\u003c/sup\u003e\u003cstrong\u003e levels and inflammatory cytokines following therapy.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ea, b, \u003c/strong\u003eBlood Mn\u003csup\u003e2+\u003c/sup\u003e levels as treatment progresses in patients divided by treatment group \u003cstrong\u003e(a)\u003c/strong\u003e or clinical response in the Mn\u003csup\u003e2+\u003c/sup\u003e group\u003cstrong\u003e (b)\u003c/strong\u003e. \u003cstrong\u003ec to h,\u003c/strong\u003e Concentration of serum cytokines IFN-β \u003cstrong\u003e(c, d)\u003c/strong\u003e, IFN-γ \u003cstrong\u003e(e, f)\u003c/strong\u003e and CXCL10 \u003cstrong\u003e(g, h)\u003c/strong\u003e following treatment in patients divided by treatment group \u003cstrong\u003e(c, e, g)\u003c/strong\u003e or clinical response in the Mn\u003csup\u003e2+\u003c/sup\u003e group\u003cstrong\u003e (d, f, h). \u003c/strong\u003eThe red horizontal lines in the box represent the median, the top and lower ends of the box represent the 75\u003csup\u003eth\u003c/sup\u003e and 25\u003csup\u003eth\u003c/sup\u003e percentiles; the whiskers extend to the minimum and maximum values. The blue dashed lines represent the median connecting line. The comparisons between pre- and post-treatment were performed with the pairing \u003cem\u003et\u003c/em\u003e test. \u003csup\u003e*\u003c/sup\u003e\u003cem\u003eP\u003c/em\u003e \u0026lt; 0.05; \u003csup\u003e**\u003c/sup\u003e\u003cem\u003eP\u003c/em\u003e \u0026lt;0.01; \u003csup\u003e***\u003c/sup\u003e\u003cem\u003eP\u003c/em\u003e \u0026lt;0.001; \u003csup\u003e****\u003c/sup\u003e\u003cem\u003eP\u003c/em\u003e \u0026lt;0.0001.\u003c/p\u003e","description":"","filename":"Figure3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4434336/v1/05734fe8aefc30b2cfcd2b2b.jpg"},{"id":57379458,"identity":"a28b83ec-a706-46b0-93af-67a30d2d3a2c","added_by":"auto","created_at":"2024-05-30 01:08:36","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":4386691,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eTreatment-induced cellular landscape of PBMCs by scRNA-seq.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ea, b,\u003c/strong\u003e Uniform manifold and approximation projection (UMAP) plot of all PBMCs, colored by the cluster \u003cstrong\u003e(a)\u003c/strong\u003e and treatment group\u003cstrong\u003e (b)\u003c/strong\u003e. \u003cstrong\u003ec,\u003c/strong\u003e dot plot of the marker gene expression of the 19 clusters. \u003cstrong\u003ed, e,\u003c/strong\u003e immune-cell-type fraction relative to the total PBMC count per treatment groups. \u003cstrong\u003ef, g,\u003c/strong\u003e the GO \u003cstrong\u003e(f)\u003c/strong\u003e and pathway \u003cstrong\u003e(g)\u003c/strong\u003e analysis of the upregulated genes for the three identified subsets of monocytes post Mn\u003csup\u003e2+\u003c/sup\u003e-based treatment. \u003cstrong\u003eh,\u003c/strong\u003e showed the elevated expression of interferon-stimulating genes (ISGs).\u003c/p\u003e","description":"","filename":"Figure4.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4434336/v1/06f4d3cd34d103f8c0b30223.jpg"},{"id":63665284,"identity":"2e510366-2820-41c4-8594-4e876a67f141","added_by":"auto","created_at":"2024-08-30 19:33:30","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":9818202,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4434336/v1/87ba3020-2739-4f95-9f7e-035b4f3930a9.pdf"},{"id":57379455,"identity":"89ea7cbf-0b34-474e-9d32-3e52cc9d6cd7","added_by":"auto","created_at":"2024-05-30 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01:08:37","extension":"jpg","order_by":11,"title":"","display":"","copyAsset":false,"role":"supplement","size":4784389,"visible":true,"origin":"","legend":"","description":"","filename":"FigureA9serumsuppl.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4434336/v1/82e2afbe9b6dcc34008eeac6.jpg"},{"id":57379466,"identity":"0d30c10a-25e0-460b-acc2-cd3dd25a9560","added_by":"auto","created_at":"2024-05-30 01:08:37","extension":"docx","order_by":12,"title":"","display":"","copyAsset":false,"role":"supplement","size":20432,"visible":true,"origin":"","legend":"","description":"","filename":"ExtendedDataFigureLegends.docx","url":"https://assets-eu.researchsquare.com/files/rs-4434336/v1/3d42bfb471ea7d11a2d9752b.docx"}],"financialInterests":"There is \u003cb\u003eNO\u003c/b\u003e Competing Interest.","formattedTitle":"Manganese primed immunochemotherapy in platinum-resistant/refractory ovarian cancer: a randomized, single-blind, placebo-controlled, phase 2 trial","fulltext":[{"header":"Introduction","content":"\u003cp\u003eEpithelial ovarian cancer, the most lethal gynecologic malignancy, responds well to platinum-based chemotherapy, although a significant proportion of patients (85%) experience a relapse and acquire resistance\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e,\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e. Platinum-resistant ovarian cancer (PROC) is managed using chemotherapy alone or with bevacizumab\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e. Platinum sensitivity is not a dichotomous state but rather exists on a continuum. Therefore, platinum rechallenge may affect platinum-resistant ovarian cancer patients who are not primary refractory\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e,\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e. Moreover, Nab-paclitaxel is highly recommended for PROC patients due to its notable efficacy and favorable safety profile\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e. Nevertheless, subsequent chemotherapy regimens have shown declining efficacy, with response rates of 10\u0026ndash;15% and substantial toxicities\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e. Despite of these limitations, the AURELIA research found that the addition of bevacizumab to chemotherapy improved outcomes for PROC patients and was approved by the FDA\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e. Regrettably, the majority of patients have received bevacizumab prior to platinum-resistant disease develops, causing inevitable progression\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e. In addition, mirvetuximab soravtansine (MIRV) was approved for ovarian cancer cased on the successful SORAYA trial, although only patients with FRα-positive PROC benefited\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e,\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e. Therefore, effective treatments for PROC remain elusive and urgently unmet need.\u003c/p\u003e \u003cp\u003eOC stands out as a malignancy lacking FDA-approved immunotherapy options\u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e. Thus far, trials involving either immune checkpoint blockade (ICB) monotherapy or in combination with chemotherapy demonstrated disappointing results in PROC, meeting neither outcome endpoints. However, these studies highlight the capability of ICB regimens to induce durable response in a small subset of patients with PROC\u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e. OCs exhibit unique immunogenomic profile, including low-intermediate mutational load, aneuploidy and immunosuppressive tumor microenvironment (TME). Despite the presence of a high level of immune cells in the TME, the dominant innate immune cells prevent an effective response to ICB therapy\u003csup\u003e\u003cspan additionalcitationids=\"CR14\" citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e. Type-I interferon (IFN) stimulates intracellular pathways that regulate both innate and adaptive immune responses. Activation of type-I IFN is essential in rescuing a non-responsive tumor immune state\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e. An effective strategy to activating Type-I IFN is to exogenously inducing activation of innate immune sensing pathways. The cGAS-STING pathway is a crucial element of the innate immune system that triggers the production of type-I IFN, and its tumor immunomodulatory capability has received significant attention\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e,\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e. Preliminary research has indicated that activating the cGAS-STING pathway, along with treatments that induce immunogenic tumor cell death, can boost the sensitivity to ICB treatment and enhance its anti-tumor effects\u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e,\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e. Novel immunomodulatory approaches focusing on interferon activation through cGAS-STING present as a promising avenue\u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e,\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eManganese (Mn\u003csup\u003e2+\u003c/sup\u003e) is an essential metal element in human body and acts as a potent natural agonist of cGAS-STING\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e,\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e. Mn\u003csup\u003e2+\u003c/sup\u003e enhances the sensitivity of cGAS to dsDNA and augments the binding affinity of STING to cGAMP, and it also triggers cGAS to synthesize cGAMP through a unique catalytic mechanism independent of dsDNA. cGAS-STING pathway plays a vital role in initiating both innate and adaptive immune responses via cross-presentation and priming, especially among immunosuppressive TME. The effect of Mn\u003csup\u003e2+\u003c/sup\u003e on systemic antitumor response and TME remodeling has been confirmed in multiple mouse models\u003csup\u003e\u003cspan additionalcitationids=\"CR22\" citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u003c/sup\u003e. In the phase I trial conducted on patients with advanced metastatic solid tumors, the administration of Mn\u003csup\u003e2+\u003c/sup\u003e demonstrated promising efficacy, resulting in 45.5% objective response and 90.9% disease control. Furthermore, it successfully reinvigorated responses to immunotherapy in patients who had previously experienced treatment failure\u003csup\u003e\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e. Notably, six of the 8 patients with recurrent OC showed positive response to the treatment as well as significant alleviation from frozen pelvic symptoms. This indicates the promising potential encouraging antitumor activity of Mn\u003csup\u003e2+\u003c/sup\u003e in ovarian cancer. Due to the ready accessibility and well-studied toxicity, Mn\u003csup\u003e2+\u003c/sup\u003e could be a compelling choice for innovative immunotherapy.\u003c/p\u003e \u003cp\u003eGiven this context, we hypothesized that the combination of cGAS-STING agonist Mn\u003csup\u003e2+\u003c/sup\u003e and genotoxic chemotherapy could boost the immune response and sensitize ovarian cancers to ICB therapy. This single-blinded randomized placebo-controlled trial was conducted to assess the efficacy and safety of immunochemotherapy (sintilimab plus nab-paclitaxel and platinum) with cGAS-STING agonist Mn\u003csup\u003e2+\u003c/sup\u003e or placebo, in patients with platinum-resistant/refractory ovarian cancer.\u003c/p\u003e"},{"header":"Results","content":"\u003ch2\u003e\u003cstrong\u003ePatients\u003c/strong\u003e\u003c/h2\u003e\n\u003cp\u003eFrom December 23, 2020, to March 11, 2023, a total of 84 patients were randomized (Mn\u003csup\u003e2+\u003c/sup\u003e group, n=55; placebo group, n=29) and constitute the ITT population (Figure 1). A total of 83 patients were administered at least one dose of the assigned treatment (55 in Mn\u003csup\u003e2+\u003c/sup\u003e group and 28 in placebo group) and were included in the safety population.\u003c/p\u003e\n\u003cp\u003eTable 1 shows the demographic and clinical characteristics of patients at baseline. The baseline characteristics were well balanced between the two arms. Out of the patients included in the study, 76 (90.5%) had high-grade serous epithelial OC, 47 (56.0%) had platinum-refractory disease, and all (100%) with microsatellite stable (MSS) genotype. Patients in both arms were heavily pretreated, with a median of 4 previous treatment lines. Out of the total, 66 (78.6%) patients had received three or more previous treatment lines. Out of all the participants, 47 (56.0%) had previous exposure to nab-paclitaxel, 44 (52.4%) to bevacizumab, and 30 (35.7%) to PARP inhibitor.\u003c/p\u003e\n\u003cp\u003eAs of the data cutoff on December 10, 2023, the median duration of follow-up was 20.3 months (95% CI, 18.7-32.5), with 23.9 months in Mn\u003csup\u003e2+\u003c/sup\u003e group and 18.7 months in placebo group. As of the data cutoff, the trial treatment was still ongoing for 8 (14.5%) patients in the Mn\u003csup\u003e2+\u003c/sup\u003e group, while no patients in the placebo group were receiving treatment (Figure 1).\u003c/p\u003e\n\u003ch2\u003e\u003cstrong\u003eEfficacy\u003c/strong\u003e\u003c/h2\u003e\n\u003cp\u003eThe ORR was substantially improved in the Mn\u003csup\u003e2+\u003c/sup\u003e group (61.8%; 95% CI, 48.1-73.9) compared to the placebo group (13.8%; 95% CI, 5.1-32.5) (risk ratio,0.223; 95% CI, 0.088-0.567; P\u0026lt;0.0001) (Extended Data Table 1). In the Mn\u003csup\u003e2+\u003c/sup\u003e group, 3 (5.5%) patients had CRs and 31 (56.3%) had PRs, as compared to only 4 (13.8%) in the placebo group had PRs (Figure 2 and Extended Data Table 1). Extended Data Fig.1 and 2 display the course and response of treatment for each individual patient. The DCR was 92.7% (51/55; 95% CI, 81.8-97.3) in the Mn\u003csup\u003e2+\u003c/sup\u003e group and 82.8% (24/29; 95% CI, 63.7-92.9) in the placebo group. The CA-125 responses, as per GCIG criteria, were observed in 82.4% (42 out of 51) of patients in the Mn\u003csup\u003e2+\u003c/sup\u003e group, and 32.0% (8 out of 25) of patients in the placebo group (rate difference, 50.4%; 95% CI, 27.1-67.2; P\u0026lt;0.0001) (Extended Data Table 1). The subgroup analyses of objective response appeared to consistently favor Mn\u003csup\u003e2+\u003c/sup\u003e group over placebo group (Extended Data Fig. 3). These groups included patients with platinum-refractory disease (elevation in ORR, 39.0%), more than 4 prior lines of therapy (elevation, 49.6%), prior received bevacizumab, nab-paclitaxel and PARP inhibitor (elevation, 45.3%, 58.1% and 54.1%, respectively).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003ePROC patients in the Mn\u003csup\u003e2+\u003c/sup\u003e group exhibited a substantially longer PFS (median, 9.8 months; 95% CI, 6.6-15.9) compared to the placebo group (median, 3.9 months; 95% CI, 3.0-4.7) (hazard ratio [HR], 0.34; 95% CI, 0.21-0.55; P\u0026lt;0.0001) (Figure 2 and Extended Data Table 1). The median OS was significantly prolonged in the Mn\u003csup\u003e2+\u003c/sup\u003e group (21.4 months; 95% CI, 16.1-29.9) than in the placebo group (7.9 months; 95% CI, 6.7-11.2) (HR, 0.32; 95% CI, 0.18-0.57; P\u0026lt;0.0001). Post hoc analyses demonstrated a consistent benefit in PFS and OS across multiple subgroups (Extended Data Fig. 4 and 5). The median DOR was 14.9 months (95% CI, 7.2-20.3) among 34 patients in the Mn\u003csup\u003e2+\u003c/sup\u003e group with CR and PR, as compared significantly with 1.8 months (95% CI, 0.6-NE) among 4 patients with PR in the placebo group (HR, 0.34; 95% CI, 0.11-0.998; P=0.0396) (Figure 2 and Extended Data Table 1).\u003c/p\u003e\n\u003cp\u003eThe PRO assessment comprised a total of 77 patients. The FACT-O status did not document a between-group difference during the first four cycles of treatment (Extended Data Fig. 6).\u003c/p\u003e\n\u003ch2\u003e\u003cstrong\u003eSafety\u003c/strong\u003e\u003c/h2\u003e\n\u003cp\u003eAdverse events (AEs) that occurred during the treatment period are summarized in Table 2. The safety profiles of both study arms were comparable, with 51 (92.7%) patients in the Mn\u003csup\u003e2+\u003c/sup\u003e group and 25 (89.3%) patients in the placebo group experiencing treatment-emergent AEs (TRAEs) of any grade. The most common AEs of any grade were nausea (37 [67.3%] patients in the Mn\u003csup\u003e2+\u003c/sup\u003e group \u003cem\u003evs\u003c/em\u003e 18 [64.3%] patients in the placebo group), vomiting (32 [58.2%] \u003cem\u003evs\u003c/em\u003e 14 [50.0%] patients), peripheral neuropathy (28 [50.9%] \u003cem\u003evs\u003c/em\u003e 12 [42.9%] patients) and anemia (21 [38.2%] \u003cem\u003evs\u003c/em\u003e 10 [35.7%] patients). Grade 3 AEs were observed in 8 (14.5%) patients in the Mn\u003csup\u003e2+\u003c/sup\u003e group and in 5 (17.9%) patients in the placebo group. No AEs were identified in grade 4-5. The majority AEs were associated with chemotherapy treatment. The treatment-related AEs of grade 1-2 were well-tolerated, and most AEs of grade 3 resolved with supportive care. AEs leading to treatment discontinuation occurred in 6 (10.9%) patients in the Mn\u003csup\u003e2+\u003c/sup\u003e groupand 3 (10.7%) patients in the placebo group. No death due to treatment-related AEs were reported.\u003c/p\u003e\n\u003cp\u003eIn the Mn\u003csup\u003e2+\u003c/sup\u003e group, neurologic evaluation and MRI/CT scan of the head were conducted at the prespecified timepoint during the Mn\u003csup\u003e2+\u003c/sup\u003e-based treatment. No extrapyramidal symptom as the Mn\u003csup\u003e2+\u003c/sup\u003e overdose-related toxicity was documented, and accumulation of Mn in the basal ganglia was also not observed. Liver-iron-overload-like MRI images were observed in 2 patients without any related clinical manifestation (Extended Data Fig. 7).\u003c/p\u003e\n\u003ch2\u003e\u003cstrong\u003eLaboratory analysis\u003c/strong\u003e\u003c/h2\u003e\n\u003cp\u003eThe concentration of blood Mn\u003csup\u003e2+\u003c/sup\u003e was monitored using ICP-AES, with a normal range of 3.39 to 20.67 μg/L. The concentration of Mn\u003csup\u003e2+\u003c/sup\u003e in the blood augmented dramatically with the treatment cycle number in the Mn\u003csup\u003e2+\u003c/sup\u003e group, while it remained rather constant in the placebo group (Figure 3 and Extended Data Fig.8). In responders (patients with CR or PR) in the Mn\u003csup\u003e2+\u003c/sup\u003e group, there was a notable increase in blood Mn\u003csup\u003e2+\u003c/sup\u003e levels as the treatment cycles progressed. However, this increase was only noticed when compared to the baseline levels in patients with SD or PD (Figure 3 and Extended Data Fig.8). Notably, post-administration levels of blood Mn\u003csup\u003e2+\u003c/sup\u003e remained within the physiological range for most patients in the Mn\u003csup\u003e2+\u003c/sup\u003e group, with only a few individual patients slightly surpassing the upper limit over the post-treatment period (Figure 3 and Extended Data Fig.8).\u003c/p\u003e\n\u003cp\u003eTo confirm the activation of cGAS-STING signaling by Mn\u003csup\u003e2+\u003c/sup\u003e, we assessed serum cytokines and chemokines using multiplex immunoassay panels specifically designed for human antivirus response and proinflammatory chemokines. Significant correlations were recorded between the expression elevation of cytokines IFN-β, IFN-γ and IL-1β and the categorization based on clinical response in the Mn\u003csup\u003e2+\u003c/sup\u003e group. However, no differences in expression were observed in the placebo group (Figure 3 and Extended Data Fig. 8).\u003c/p\u003e\n\u003cp\u003eSubsequently, an analysis was conducted to characterize the treatment-induced alterations in the transcriptional landscape of PBMCs using single-cell RNA sequencing (scRNA-seq). The identification of major PBMC subpopulations was straightforward using well-established gene markers (Figure 4A to C and Extended Data Fig. 9 A, B). The differences in cellular composition between the two groups were evident. The Mn\u003csup\u003e2+\u003c/sup\u003e group exhibited an increase in CD14\u003csup\u003e+\u003c/sup\u003e, FCGR3a\u003csup\u003e+\u003c/sup\u003e, and CYBB\u003csup\u003ehi\u003c/sup\u003e monocytes, while also experiencing a decrease in exhausted T and NK cells following treatment, in contrast to the placebo group (Figure 4D, E and Extended Data Fig. 9C). The investigation identified three subsets of monocytes exhibiting an elevated pro-inflammatory signature and promoting pathways related to type-I interferon, antigen presentation, and lymphocyte activation (Figure 4F to H). Additionally, the activation and cytotoxicity signaling in pre-exhausted T, exhausted T and γδT cells from the Mn\u003csup\u003e2+\u003c/sup\u003e-treated sample were enhanced, despite the reduction in their numbers (Extended Data Fig. 9D-H).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis randomized, single-blinded, placebo-controlled, phase II trial compared the safety and efficacy of immunochemotherapy with manganese or placebo in patients with platinum-resistant/refractory ovarian cancer (PROC). PROC has sparse treatment options and remains of dismal prognosis. The majority of patients with PROC was lack of response to immunotherapy attributed to the inadequate immune activation and suppressive TME\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e,\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e,\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e. Exogenously Type-I IFN activation presents as an attractive option to enhance antitumor immunity, and cGAS-STING agonists is emerging as a promising avenue\u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e,\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e,\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u003c/sup\u003e. However, the efficacy of cGAS-STING agonists is constrained by numerous obstacles related to drug delivery and pharmacology. Manganese, being an essential nutrient with simple and steady properties, could be a strong candidate and develop universal antitumor therapies\u003csup\u003e\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u003c/sup\u003e. To the best of our knowledge, this is the first randomized trial of systemic administration of STING agonists for ovarian cancer.\u003c/p\u003e \u003cp\u003eThis trial met the primary endpoint, showing of a significant benefit of both promotion (ORR, 61.8% \u003cem\u003ev.s.\u003c/em\u003e 13.8%; RR, 0.223; 95% CI, 0.088\u0026ndash;0.567) and persistence (median DOR, 14.9 M \u003cem\u003ev.s.\u003c/em\u003e 1.8 M; HR, 0.336; 95% CI, 0.113\u0026ndash;0.998) of efficacy with Mn\u003csup\u003e2+\u003c/sup\u003e priming immunochemotherapy in PROC. Mn\u003csup\u003e2+\u003c/sup\u003e priming immuno-chemotherapy demonstrated significant improvements in PFS and OS in the heavily pretreated population, including patients with platinum-refractory disease, more than 4 prior lines of therapy, prior received bevacizumab, nab-paclitaxel and PARP inhibitor. These subsets of patients have get a more negative outcome, and are often excluded or only a small proportion included in other randomized trials. The current trial has enrolled a broader population, and the encouraging outcomes support the potential of Mn\u003csup\u003e2+\u003c/sup\u003e priming immunochemotherapy to change the therapy landscape for PROC, a disease with a traditionally poor prognosis.\u003c/p\u003e \u003cp\u003ecGAS-STING is an important pivot for cytosolic DNA sensation and Type-I IFN induction\u003csup\u003e\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e,\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u003c/sup\u003e. The activation effect of cGAS-STING agonists can be significantly enhanced by the immunogenic death induced by genotoxic agents\u003csup\u003e\u003cspan additionalcitationids=\"CR27\" citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u003c/sup\u003e. This not only promotes the Type-I IFN immune response, but also increases the expression of PD-L1 in tumor cells, hence boosting the sensitivity to ICB therapy\u003csup\u003e\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e,\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u003c/sup\u003e. Manganese work as a powerful agonist of cGAS-STING via not only directly increasing the catalytic of cGAS, but also enhancing the affinity of cGAMP and STING to promote INF-I produce\u003csup\u003e\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e,\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u003c/sup\u003e. Mn\u003csup\u003e2+\u003c/sup\u003e has been documented to induce a superior antitumor effect in multiple murine tumor models, and markedly prolonged the survival of tumor-bearing mice\u003csup\u003e\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e,\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u003c/sup\u003e. Notably, our phase I trial involving multiple advanced metastatic solid tumors initially observed favorable clinical efficacy of Mn\u003csup\u003e2+\u003c/sup\u003e priming immunochemotherapy, and gave this strategy a broader antitumor spectrum and a durable antitumor immune response\u003csup\u003e\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e. In the current trial focusing on the platinum-resistant/refractory ovarian cancer, the levels of serum Type-I IFN and inflammatory cytokines exhibited a substantial increase following the treatment, and this increase was strongly correlated with the clinical responses. Simultaneously, analysis of scRNA-seq data revealed significant stimulation of Type-I IFN signaling in monocytes, suggesting that Mn\u003csup\u003e2+\u003c/sup\u003e functions as a cGAS STING agonist in regulating the immune response, reinforcing the significant benefits of ORR, PFS and OS in this difficult-to-treat population.\u003c/p\u003e \u003cp\u003eMn\u003csup\u003e2+\u003c/sup\u003e was administrated via nebulized inhalation in the current trail, which is a safe way to deliver into the lung\u003csup\u003e\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e\u003c/sup\u003e. The selection of modalities and dosage regimens was informed by the results obtained from our previous phase I investigation and the application of a murine tumor model. Covid-19 vaccine studies have demonstrated that inhalation administration can effectively activate mucosal immune and simultaneously induce humoral and cellular immune responses\u003csup\u003e\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e\u003c/sup\u003e. Intranasal immunization of these vaccines has shown superior performance over traditional immunization modalities such as intramuscular immunization in inducing systemic and mucosal responses\u003csup\u003e\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e\u003c/sup\u003e. The pronounced changes of inflammatory cytokine and immune cell type have been detected in peripheral blood samples from enrolled patients. However, whether nebulized manganese chloride can play a similar role to inhaled vaccines remains to be confirmed.\u003c/p\u003e \u003cp\u003eThe AE profile of this trial was mostly consistent with the previously reported toxicities of ICB plus chemotherapy regimens in OC and other solid tumors\u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e,\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e\u003c/sup\u003e. Most AEs were grade 1 to 2 and relieved by symptomatic. The current trail did not document any clinical symptom of manganism, including MRI evidence of central nervous system impairment. Nevertheless, two patients exhibited liver-iron-overload-like MRI findings, requiring further long-term follow-up. Certain patients had symptoms resembling cytokine-release-syndrome in our previous phase I trial\u003csup\u003e\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e, however, in this trial, no such suspicious reaction occurred due to the reduced frequency of the intermittent inhalation delivery modality. The assessment of quality of life using measuring scales remained relatively unchanged during the Mn\u003csup\u003e2+\u003c/sup\u003e-based treatment.\u003c/p\u003e \u003cp\u003eOur trial has several limitations. Initially, we failed to collect biopsy tumor samples to validate the impact of Mn\u003csup\u003e2+\u003c/sup\u003e priming immunochemotherapy on the tumor microenvironment. Furthermore, the administration of Mn\u003csup\u003e2+\u003c/sup\u003e in this trial is limited to inhalation. The difference of effect and mechanism from traditional mode of administration should be established.\u003c/p\u003e \u003cp\u003eIn conclusion, the Mn\u003csup\u003e2+\u003c/sup\u003e priming immunochemotherapy demonstrated strongly favor superiority in terms of ORR, PFS, OS and DOR as compared with ICB plus chemotherapy in PROC. Platinum-refractory/resistant OC is a highly lethal disease with few efficacious treatments, thus there remains a pressing need to develop potent agents. Considering the essential role as nutrient and FDA approved usage of Mn\u003csup\u003e2+\u003c/sup\u003e, Mn\u003csup\u003e2+\u003c/sup\u003e priming immunochemotherapy appears to be a promising and attractive candidate for the treatment of PROC.\u003c/p\u003e"},{"header":"Online Methods","content":"\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003eStudy design\u003c/h2\u003e \u003cp\u003e This phase II, randomized, single-blind, placebo-controlled study (ClinicalTrials.gov identifier: NCT03989336) was conducted in accordance with the principles of the Declaration of Helsinki, the Good Clinical Practice guidelines of International Council for Harmonisation. The protocol was approved by the Institutional Review Board of the Chinese PLA General Hospital (Beijing, China, No. S2019-02-03). All enrolled patients provided written informed consent. All authors vouch that the study protocol was strictly followed and for the accuracy and completeness of the data. This study followed the Consolidated Standards of Reporting Trials (CONSORT) reporting guideline. The complete protocol was provided as supplementary information.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003eParticipants\u003c/h2\u003e \u003cp\u003eThe study included adult female patients (\u0026ge;\u0026thinsp;18 years) with histologically confirmed epithelial ovarian, fallopian tube, or peritoneal cancer; experienced either platinum-resistant (defined as progression within 6 months following last dose of most recent platinum) or platinum-refractory (defined as lack of response or progression within 1 month since the last dose); at least one lesion measurable by Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1); a minimum of two previous lines of systemic therapy including at least one platinum-base regimen; Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2; and adequate organ function. The patients resistant to previous ICB or bevacizumab treatment were eligible. Patients were excluded if they had previous or concurrent other malignancies, autoimmune disease, active infections. Full eligibility criteria are listed in the protocol.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eInterventions\u003c/h2\u003e \u003cp\u003eEnrolled patients were allocated to treatment using minimization with a random element and stratified by platinum-free interval (PFI). The participants were assigned in a 2:1 ratio to receive manganese chloride or placebo plus immunochemotherapy. Patients were blinded to the treatment allocation. Manganese chloride (0.4mg/kg) or placebo was nebulized inhaled twice per week in the first 3-week cycle, and thereafter twice in the first week of each 3-week cycle. The immunochemotherapy consisted of nab-paclitaxel (200 mg/m\u003csup\u003e2\u003c/sup\u003e, administered intravenously on day 2 in a 3-week cycle), cisplatin (60 mg/m\u003csup\u003e2\u003c/sup\u003e, administered intravenously on day 2 in a 3-week cycle) and sintilimab (200 mg, administered intravenously on day 3 in a 3-week cycle). If patients with known hypersensitivity to cisplatin, carboplatin (area under the curve [AUC] 4 mg/mL per min) was used as alternative. Treatment continued until the second confirmed CR, progressive disease, development of unacceptable toxicity, or consent withdrawal.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eOutcomes and Assessments\u003c/h2\u003e \u003cp\u003eThe primary endpoint was investigator-assessed ORR per RECIST v1.1, defined as the percentage of patients with at least one efficacy assessment who achieved a complete or partial response (CR/PR). The primary safety endpoint was the incidence of treatment-related AEs in patients who received at least one dose of study treatment. The key secondary endpoints included the progression-free survival (PFS, the time from the date of randomization until investigator-assessed progressive disease [PD] or death, whichever occurred first), overall survival (OS, the time from the date of randomization until the date of death or last known to be alive), and disease control rate (DCR, defined as the percentage of patients with at least 1 efficacy assessment achieved a CR, PR or stable disease [SD]). Further secondary endpoints included the duration of response (DOR, the time from initial response until investigator-assessed PD or death occurred for all participants who had a confirmed objective response), Gynecological Cancer interGroup CA-125 response rate and patient report outcome (PRO). Exploratory assessments included subgroup analyses, serum cytokines and chemokines, and blood Mn\u003csup\u003e2+\u003c/sup\u003e parameters.\u003c/p\u003e \u003cp\u003eResponses were assessed by the same blinded radiologist per RECIST 1.1, using magnetic resonance imaging (MRI) or computed tomography (CT) at baseline, every 2 cycles during treatment, and 12 weeks after discontinuing treatment until PD, death, initiation of subsequent treatment, loss to follow-up, withdrawal of consent, or study closure. Post-progression follow-up was performed every 3 months for OS. PRO questionnaire FACT-O (Functional Assessment of Cancer Therapy-Ovarian Cancer) was administered at baseline, prior to each cycle of treatment, at the end of treatment, and at follow-up.\u003c/p\u003e \u003cp\u003eAll adverse events (AEs) were monitored and documented throughout the study and 3 months after the last dose according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 5.0. Neurologic evaluation and MRI/CT scan of the head were performed to monitor and exclude manganism symptoms. Laboratory parameters (including hematology parameters, blood biochemistry parameters, serum cytokine and chemokine parameters, blood Mn\u003csup\u003e2+\u003c/sup\u003e level, and CA-125) and vital signs were assessed during screening and on day 1 of each trial visit. Concentration of blood Mn\u003csup\u003e2+\u003c/sup\u003e was detected by the inductively coupled plasma-atomic emission spectroscopy (ICP-AES) recommended by ATSDR, and serum cytokines and chemokines were analyzed by LEGENDplex Bead-based Immunoassays (BioLegend) according to the manufacturer\u0026rsquo;s instructions.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eSerum cytokines and chemokines analyses\u003c/h2\u003e \u003cp\u003eAll the blood samples were collected in nonheparinized tubes and allowed to clot at room temperature for 2 h and then centrifuged at 1,500 g for 10 min. The serum samples were absorbed from the coagulated blood and stored at -80℃. The serum cytokines and chemokines were analyzed by LEGENDplex bead-based immunoassays (BioLegend, San Diego, USA) according to the manufacturer\u0026rsquo;s instructions. The human anti-virus response (740349) and proinflammatory chemokine panel (740984) were used to simultaneous quantified of 25 serum cytokines/chemokines, including IL-1β/6/10, IFN-α/β/γ, CXCL-9/10/11 and CCL-2/4/5/20. Data acquisition was performed on a Beckman DxFLEX flow cytometer (Beckman COULTER) and analyzed with the LEGENDplex\u0026trade; Data Analysis Software (BioLegend).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003eBlood Mn\u003csup\u003e2+\u003c/sup\u003e concentration analysis\u003c/h2\u003e \u003cp\u003eThe blood samples were collected before each cycle in heparinized tube. Inductively coupled plasma-atomic emission spectroscopy (ICP-AES) recommend by ATSDR was employed for detection of the concentration of blood Mn\u003csup\u003e2+\u003c/sup\u003e. The normal range of blood Mn\u003csup\u003e2+\u003c/sup\u003e was 3.39\u0026thinsp;~\u0026thinsp;20.67ug/L in Chinese population.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec15\" class=\"Section2\"\u003e \u003ch2\u003eStatistical Analysis\u003c/h2\u003e \u003cp\u003eA sample size of 78 patients (randomly assigned in a 2:1 ratio to the Mn\u003csup\u003e2+\u003c/sup\u003e group and placebo group) was required to achieve 90% power to detect an improvement in ORR from 14\u0026ndash;50% at a two-sided α level of 0.05. The reference ORR of 14% was based on the JAVELIN 200 study with a 13.3% ORR in ICB plus chemotherapy group\u003csup\u003e\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eEfficacy was assessed in the intention-to-treat (ITT) population who underwent randomization regardless of whether assigned treatment received. The safety population included all participants who underwent randomization and received at least one dose of the assigned treatment. Objective response and CA-125 response were estimated for each treatment group, along with two-sided 95% CIs using the Clopper-Pearson method. Comparison between the trial groups was performed using stratified Cochran-Mantel-Haenszel test.\u003c/p\u003e \u003cp\u003eTime-to-event (PFS, OS and DOR) were estimated using the Kaplan-Meier method, with 95% CIs calculated with the Brookmeyer-Crowley method. The two trial groups were compared using the stratified log-rank test. The study utilized the stratified Cox proportional-hazards model to analyze hazard ratios and their corresponding CIs. Change in PRO was assessed in patients from baseline to the last safety follow-up visit for the FACT-O subscales. Paired t tests were performed to compare the blood Mn\u003csup\u003e2+\u003c/sup\u003e concentration and serum cytokines and chemokines between two groups.\u003c/p\u003e \u003cp\u003eUnless otherwise specified, statistical tests were performed with a two-sided 5% significance. All statistical analyses were performed in StataMP 17.\u003c/p\u003e \u003c/div\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eFIGO\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eInternational Federation of Gynecology and Obstetrics\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eECOG\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eEastern Cooperative Oncology Group\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ePFI\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eplatinum -free interval\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ePARP\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003epoly (ADP-ribose) polymerase\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eHRD\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eHRD: homologous recombination deficiency\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eMSS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003emicrosatellite stable\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eTMB\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003etumor mutational burden.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003ch2\u003e\u003cstrong\u003eDisclosure of Potential Conflicts of Interest\u003c/strong\u003e\u003c/h2\u003e\n\u003cp\u003eNo potential conflicts of interest were disclosed.\u003c/p\u003e\n\u003ch2\u003e\u003cstrong\u003eAcknowlegment\u003c/strong\u003e\u003c/h2\u003e\n\u003cp\u003eThe authors thank the participants and their families, the investigators and trial teams for their support in executing the study. We are grateful to Prof. Rui-Ping Xiao (Peking University) for\u0026nbsp;thorough discussion regarding to the design and results of this study.\u0026nbsp;This study was funded by National Natural Science Foundation of China (82073183 to Q. Mei, 82150108, 82341208 and 31991171to W. Han, and 32100646 and 82370107 to Y. Gong).\u003c/p\u003e\n\u003ch2\u003e\u003cstrong\u003eData sharing\u003c/strong\u003e\u003c/h2\u003e\n\u003cp\u003eThe study protocol is accessible in the Supplementary information. The data substantiating the conclusions of this study can be obtained from the corresponding authors upon request via email. The request will undergo a thorough research evaluation process by the Institutional evaluation Board of the Chinese PLA General Hospital, focusing on the potential risks associated with patient reidentification. Sharing of raw data at the individual patient level, which includes personally identifying information, is not permitted.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003ePujade-Lauraine, E., Banerjee, S. \u0026amp; Pignata, S. Management of Platinum-Resistant, Relapsed Epithelial Ovarian Cancer and New Drug Perspectives. \u003cem\u003eJ Clin Oncol\u003c/em\u003e \u003cstrong\u003e37\u003c/strong\u003e, 2437-2448 (2019).\u003c/li\u003e\n \u003cli\u003eRichardson, D.L., Eskander, R.N. \u0026amp; O\u0026apos;Malley, D.M. Advances in Ovarian Cancer Care and Unmet Treatment Needs for Patients With Platinum Resistance: A Narrative Review. \u003cem\u003eJAMA Oncol\u003c/em\u003e \u003cstrong\u003e9\u003c/strong\u003e, 851-859 (2023).\u003c/li\u003e\n \u003cli\u003eSt Laurent, J. \u0026amp; Liu, J.F. 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The Cytosolic DNA-Sensing cGAS-STING Pathway in Cancer. \u003cem\u003eCancer Discov\u003c/em\u003e \u003cstrong\u003e10\u003c/strong\u003e, 26-39 (2020).\u003c/li\u003e\n \u003cli\u003eBerger, G., Marloye, M. \u0026amp; Lawler, S.E. Pharmacological Modulation of the STING Pathway for Cancer Immunotherapy. \u003cem\u003eTrends Mol Med\u003c/em\u003e \u003cstrong\u003e25\u003c/strong\u003e, 412-427 (2019).\u003c/li\u003e\n \u003cli\u003eDeng, L.\u003cem\u003e, et al.\u003c/em\u003e STING-Dependent Cytosolic DNA Sensing Promotes Radiation-Induced Type I Interferon-Dependent Antitumor Immunity in Immunogenic Tumors. \u003cem\u003eImmunity\u003c/em\u003e \u003cstrong\u003e41\u003c/strong\u003e, 843-852 (2014).\u003c/li\u003e\n \u003cli\u003eGalluzzi, L., Humeau, J., Buque, A., Zitvogel, L. \u0026amp; Kroemer, G. Immunostimulation with chemotherapy in the era of immune checkpoint inhibitors. \u003cem\u003eNat Rev Clin Oncol\u003c/em\u003e \u003cstrong\u003e17\u003c/strong\u003e, 725-741 (2020).\u003c/li\u003e\n \u003cli\u003eShakfa, N., Li, D., Nersesian, S., Wilson-Sanchez, J. \u0026amp; Koti, M. The STING pathway: Therapeutic vulnerabilities in ovarian cancer. \u003cem\u003eBr J Cancer\u003c/em\u003e \u003cstrong\u003e127\u003c/strong\u003e, 603-611 (2022).\u003c/li\u003e\n \u003cli\u003eYu, X., Zhao, Z. \u0026amp; Jiang, Z. Recent progress on the activation of the cGAS-STING pathway and its regulation by biomolecular condensation. \u003cem\u003eJ Mol Cell Biol\u003c/em\u003e \u003cstrong\u003e14\u003c/strong\u003e(2022).\u003c/li\u003e\n \u003cli\u003eLv, M.\u003cem\u003e, et al.\u003c/em\u003e Manganese is critical for antitumor immune responses via cGAS-STING and improves the efficacy of clinical immunotherapy. \u003cem\u003eCell Res\u003c/em\u003e \u003cstrong\u003e30\u003c/strong\u003e, 966-979 (2020).\u003c/li\u003e\n \u003cli\u003eSun, X.\u003cem\u003e, et al.\u003c/em\u003e Amplifying STING activation by cyclic dinucleotide-manganese particles for local and systemic cancer metalloimmunotherapy. \u003cem\u003eNat Nanotechnol\u003c/em\u003e \u003cstrong\u003e16\u003c/strong\u003e, 1260-1270 (2021).\u003c/li\u003e\n \u003cli\u003eZhang, Z.\u003cem\u003e, et al.\u003c/em\u003e Multifaceted functions of STING in human health and disease: from molecular mechanism to targeted strategy. \u003cem\u003eSignal Transduct Target Ther\u003c/em\u003e \u003cstrong\u003e7\u003c/strong\u003e, 394 (2022).\u003c/li\u003e\n \u003cli\u003eZhang, K., Qi, C. \u0026amp; Cai, K. Manganese-Based Tumor Immunotherapy. \u003cem\u003eAdv Mater\u003c/em\u003e \u003cstrong\u003e35\u003c/strong\u003e, e2205409 (2023).\u003c/li\u003e\n \u003cli\u003ePetroni, G., Buque, A., Zitvogel, L., Kroemer, G. \u0026amp; Galluzzi, L. Immunomodulation by targeted anticancer agents. \u003cem\u003eCancer Cell\u003c/em\u003e \u003cstrong\u003e39\u003c/strong\u003e, 310-345 (2021).\u003c/li\u003e\n \u003cli\u003eReislander, T., Groelly, F.J. \u0026amp; Tarsounas, M. DNA Damage and Cancer Immunotherapy: A STING in the Tale. \u003cem\u003eMol Cell\u003c/em\u003e \u003cstrong\u003e80\u003c/strong\u003e, 21-28 (2020).\u003c/li\u003e\n \u003cli\u003eRottenberg, S., Disler, C. \u0026amp; Perego, P. The rediscovery of platinum-based cancer therapy. \u003cem\u003eNat Rev Cancer\u003c/em\u003e \u003cstrong\u003e21\u003c/strong\u003e, 37-50 (2021).\u003c/li\u003e\n \u003cli\u003eGrabosch, S.\u003cem\u003e, et al.\u003c/em\u003e Cisplatin-induced immune modulation in ovarian cancer mouse models with distinct inflammation profiles. \u003cem\u003eOncogene\u003c/em\u003e \u003cstrong\u003e38\u003c/strong\u003e, 2380-2393 (2019).\u003c/li\u003e\n \u003cli\u003eXu, J.\u003cem\u003e, et al.\u003c/em\u003e Systematic evaluation of membrane-camouflaged nanoparticles in neutralizing Clostridium perfringens epsilon-toxin. \u003cem\u003eJ Nanobiotechnology\u003c/em\u003e \u003cstrong\u003e21\u003c/strong\u003e, 95 (2023).\u003c/li\u003e\n \u003cli\u003eYe, T.\u003cem\u003e, et al.\u003c/em\u003e Inhaled SARS-CoV-2 vaccine for single-dose dry powder aerosol immunization. \u003cem\u003eNature\u003c/em\u003e \u003cstrong\u003e624\u003c/strong\u003e, 630-638 (2023).\u003c/li\u003e\n \u003cli\u003eAfkhami, S.\u003cem\u003e, et al.\u003c/em\u003e Respiratory mucosal delivery of next-generation COVID-19 vaccine provides robust protection against both ancestral and variant strains of SARS-CoV-2. \u003cem\u003eCell\u003c/em\u003e \u003cstrong\u003e185\u003c/strong\u003e, 896-915 e819 (2022).\u003c/li\u003e\n \u003cli\u003ePujade-Lauraine, E.\u003cem\u003e, et al.\u003c/em\u003e Avelumab alone or in combination with chemotherapy versus chemotherapy alone in platinum-resistant or platinum-refractory ovarian cancer (JAVELIN Ovarian 200): an open-label, three-arm, randomised, phase 3 study. \u003cem\u003eLancet Oncol\u003c/em\u003e \u003cstrong\u003e22\u003c/strong\u003e, 1034-1046 (2021).\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003e\u003cstrong\u003eTable 1. Baseline Demographics and Disease Characteristics by Treat Arm\u003c/strong\u003e\u003c/p\u003e\n\u003cdiv align=\"Left\"\u003e\n \u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"548\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"39.5985401459854%\"\u003e\n \u003cp\u003e\u003cstrong\u003eCharacteristic\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"32.846715328467155%\"\u003e\n \u003cp\u003e\u003cstrong\u003eMn+nPP+P (n=55)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.554744525547445%\"\u003e\n \u003cp\u003e\u003cstrong\u003ePlacebo+nPP+P (n=29)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"39.5985401459854%\"\u003e\n \u003cp\u003e\u003cstrong\u003eAge, median (range), y\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"32.846715328467155%\"\u003e\n \u003cp\u003e57 (30-71)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.554744525547445%\"\u003e\n \u003cp\u003e54 (42-73)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"39.5985401459854%\"\u003e\n \u003cp\u003e\u003cstrong\u003eFIGO stage\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"32.846715328467155%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"27.554744525547445%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"39.5985401459854%\"\u003e\n \u003cp\u003eII\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"32.846715328467155%\"\u003e\n \u003cp\u003e2 (3.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.554744525547445%\"\u003e\n \u003cp\u003e1 (3.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"39.5985401459854%\"\u003e\n \u003cp\u003eIII\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"32.846715328467155%\"\u003e\n \u003cp\u003e47 (85.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.554744525547445%\"\u003e\n \u003cp\u003e24 (82.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"39.5985401459854%\"\u003e\n \u003cp\u003eIV\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"32.846715328467155%\"\u003e\n \u003cp\u003e6 (10.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.554744525547445%\"\u003e\n \u003cp\u003e4 (13.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"39.5985401459854%\"\u003e\n \u003cp\u003e\u003cstrong\u003eECOG\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"32.846715328467155%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"27.554744525547445%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"39.5985401459854%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"32.846715328467155%\"\u003e\n \u003cp\u003e36 (65.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.554744525547445%\"\u003e\n \u003cp\u003e18 (62.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"39.5985401459854%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"32.846715328467155%\"\u003e\n \u003cp\u003e14 (25.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.554744525547445%\"\u003e\n \u003cp\u003e8 (27.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"39.5985401459854%\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"32.846715328467155%\"\u003e\n \u003cp\u003e5 (9.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.554744525547445%\"\u003e\n \u003cp\u003e3 (10.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"39.5985401459854%\"\u003e\n \u003cp\u003e\u003cstrong\u003eHistology\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"32.846715328467155%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"27.554744525547445%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"39.5985401459854%\"\u003e\n \u003cp\u003eEpithelia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"32.846715328467155%\"\u003e\n \u003cp\u003e49 (89.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.554744525547445%\"\u003e\n \u003cp\u003e27 (93.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"39.5985401459854%\"\u003e\n \u003cp\u003eFallopian tube/primary peritoneal\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"32.846715328467155%\"\u003e\n \u003cp\u003e6 (10.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.554744525547445%\"\u003e\n \u003cp\u003e2 (6.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"39.5985401459854%\"\u003e\n \u003cp\u003e\u003cstrong\u003ePrimary PFI\u003csup\u003e\u0026dagger;\u003c/sup\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"32.846715328467155%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"27.554744525547445%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"39.5985401459854%\"\u003e\n \u003cp\u003e\u0026lt; 6 M\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"32.846715328467155%\"\u003e\n \u003cp\u003e35 (63.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.554744525547445%\"\u003e\n \u003cp\u003e17 (58.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"39.5985401459854%\"\u003e\n \u003cp\u003e\u0026ge; 6 to \u0026lt; 12 M\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"32.846715328467155%\"\u003e\n \u003cp\u003e20 (36.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.554744525547445%\"\u003e\n \u003cp\u003e12 (41.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"39.5985401459854%\"\u003e\n \u003cp\u003e\u003cstrong\u003eMost recent PFI\u003csup\u003e\u0026Dagger;\u003c/sup\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"32.846715328467155%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"27.554744525547445%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"39.5985401459854%\"\u003e\n \u003cp\u003e\u0026lt; 1 M (refractory)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"32.846715328467155%\"\u003e\n \u003cp\u003e30 (54.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.554744525547445%\"\u003e\n \u003cp\u003e17 (58.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"39.5985401459854%\"\u003e\n \u003cp\u003e\u0026ge; 1 to \u0026lt; 6 M (resistant)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"32.846715328467155%\"\u003e\n \u003cp\u003e25 (45.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.554744525547445%\"\u003e\n \u003cp\u003e12 (41.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"39.5985401459854%\"\u003e\n \u003cp\u003e\u003cstrong\u003ePrevious treatment lines\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"32.846715328467155%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"27.554744525547445%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"39.5985401459854%\"\u003e\n \u003cp\u003emedian\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"32.846715328467155%\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.554744525547445%\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"39.5985401459854%\"\u003e\n \u003cp\u003erange\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"32.846715328467155%\"\u003e\n \u003cp\u003e1-13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.554744525547445%\"\u003e\n \u003cp\u003e2-13\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"39.5985401459854%\"\u003e\n \u003cp\u003e\u003cstrong\u003ePrior exposure\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"32.846715328467155%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"27.554744525547445%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"39.5985401459854%\"\u003e\n \u003cp\u003eBevacizumab\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"32.846715328467155%\"\u003e\n \u003cp\u003e27 (49.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.554744525547445%\"\u003e\n \u003cp\u003e17 (58.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"39.5985401459854%\"\u003e\n \u003cp\u003eNab-Paclitaxel\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"32.846715328467155%\"\u003e\n \u003cp\u003e31 (56.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.554744525547445%\"\u003e\n \u003cp\u003e16 (55.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"39.5985401459854%\"\u003e\n \u003cp\u003eanti-PD-1 treatment\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"32.846715328467155%\"\u003e\n \u003cp\u003e10 (18.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.554744525547445%\"\u003e\n \u003cp\u003e5 (17.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"39.5985401459854%\"\u003e\n \u003cp\u003ePARP inhibitor\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"32.846715328467155%\"\u003e\n \u003cp\u003e19 (34.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.554744525547445%\"\u003e\n \u003cp\u003e11 (37.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"39.5985401459854%\"\u003e\n \u003cp\u003e\u003cstrong\u003eBRCA mutated\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"32.846715328467155%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"27.554744525547445%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"39.5985401459854%\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"32.846715328467155%\"\u003e\n \u003cp\u003e14 (25.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.554744525547445%\"\u003e\n \u003cp\u003e7 (24.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"39.5985401459854%\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"32.846715328467155%\"\u003e\n \u003cp\u003e36 (65.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.554744525547445%\"\u003e\n \u003cp\u003e18 (62.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"39.5985401459854%\"\u003e\n \u003cp\u003eUnknown\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"32.846715328467155%\"\u003e\n \u003cp\u003e5 (9.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.554744525547445%\"\u003e\n \u003cp\u003e4 (13.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"39.5985401459854%\"\u003e\n \u003cp\u003e\u003cstrong\u003eHRD\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"32.846715328467155%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"27.554744525547445%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"39.5985401459854%\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"32.846715328467155%\"\u003e\n \u003cp\u003e16 (29.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.554744525547445%\"\u003e\n \u003cp\u003e7 (24.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"39.5985401459854%\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"32.846715328467155%\"\u003e\n \u003cp\u003e34 (61.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.554744525547445%\"\u003e\n \u003cp\u003e18 (62.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"39.5985401459854%\"\u003e\n \u003cp\u003eUnknown\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"32.846715328467155%\"\u003e\n \u003cp\u003e5 (9.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.554744525547445%\"\u003e\n \u003cp\u003e4 (13.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"39.5985401459854%\"\u003e\n \u003cp\u003e\u003cstrong\u003eMSS\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"32.846715328467155%\"\u003e\n \u003cp\u003e55 (100)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.554744525547445%\"\u003e\n \u003cp\u003e29 (100)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"39.5985401459854%\"\u003e\n \u003cp\u003e\u003cstrong\u003eTMB\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"32.846715328467155%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"27.554744525547445%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"39.5985401459854%\"\u003e\n \u003cp\u003emedian\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"32.846715328467155%\"\u003e\n \u003cp\u003e6.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.554744525547445%\"\u003e\n \u003cp\u003e5.9\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"39.5985401459854%\"\u003e\n \u003cp\u003erange\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"32.846715328467155%\"\u003e\n \u003cp\u003e1.56-14.35\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.554744525547445%\"\u003e\n \u003cp\u003e3.04-11.34\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003eMn+nPP+P represents MnCl\u003csub\u003e2\u003c/sub\u003e, nab-paclitaxel,\u0026nbsp;cisplatin (or carboplatin), plus sintilimab, and Placebo+nPP+P, placebo,\u0026nbsp;nab-paclitaxel,\u0026nbsp;cisplatin (or carboplatin), plus sintilimab.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAbbreviations:\u003c/strong\u003e FIGO, International Federation of Gynecology and Obstetrics; ECOG, Eastern Cooperative Oncology Group; PFI, platinum -free interval; PARP, poly (ADP-ribose) polymerase; HRD, HRD: homologous recombination deficiency; MSS, microsatellite stable; TMB, tumor mutational burden.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003csup\u003e\u0026dagger;\u003c/sup\u003e\u003c/strong\u003ePrimary PFI was defined as the time from last dose of first-line platinum therapy to the date of disease progression or relapse after first-line therapy.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003csup\u003e\u0026Dagger;\u003c/sup\u003e\u003c/strong\u003eMost recent PFI was defined as the time from last dose of the latest line of platinum therapy to the date of disease progression or relapse after that line of therapy.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2. Treatment-related adverse events\u003c/strong\u003e\u003c/p\u003e\n\u003cdiv align=\"center\"\u003e\n \u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"718\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"23.537604456824514%\" rowspan=\"3\"\u003e\n \u003cp\u003e\u003cstrong\u003eEvent\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"40.94707520891365%\" colspan=\"7\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eMn+nPP+P (n=55)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"35.51532033426184%\" colspan=\"6\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003ePlacebo+nPP+P (n=28)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"16.545454545454547%\" colspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eAny Grade\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.727272727272727%\" colspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;Grade1-2\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.727272727272727%\" colspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003eGrade3\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.545454545454547%\" colspan=\"3\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eAny Grade\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.727272727272727%\" colspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;Grade1-2\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.727272727272727%\" colspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003eGrade3\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"8.333333333333334%\"\u003e\n \u003cp\u003e\u003cstrong\u003eno.\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.333333333333334%\"\u003e\n \u003cp\u003e\u003cstrong\u003e%\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.333333333333334%\"\u003e\n \u003cp\u003e\u003cstrong\u003eno.\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.333333333333334%\"\u003e\n \u003cp\u003e\u003cstrong\u003e%\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.333333333333334%\"\u003e\n \u003cp\u003e\u003cstrong\u003eno.\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.333333333333334%\"\u003e\n \u003cp\u003e\u003cstrong\u003e%\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.333333333333334%\" colspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003eno.\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.333333333333334%\"\u003e\n \u003cp\u003e\u003cstrong\u003e%\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.333333333333334%\"\u003e\n \u003cp\u003e\u003cstrong\u003eno.\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.333333333333334%\"\u003e\n \u003cp\u003e\u003cstrong\u003e%\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.333333333333334%\"\u003e\n \u003cp\u003e\u003cstrong\u003eno.\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.333333333333334%\"\u003e\n \u003cp\u003e\u003cstrong\u003e%\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"23.439667128987516%\"\u003e\n \u003cp\u003e\u003cstrong\u003eAny treatment-related AEs\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e51\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e92.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e43\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e78.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e14.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\" colspan=\"2\"\u003e\n \u003cp\u003e25\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e89.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e21\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e75\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e17.9\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"100%\" colspan=\"14\"\u003e\n \u003cp\u003e\u003cstrong\u003eMn treatment-related AEs\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"23.439667128987516%\"\u003e\n \u003cp\u003eLiver-iron-overload-like\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e3.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e3.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\" colspan=\"2\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"100%\" colspan=\"14\"\u003e\n \u003cp\u003e\u003cstrong\u003eImmunotherapy related AEs\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"23.439667128987516%\"\u003e\n \u003cp\u003eHypothyroidism\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\" colspan=\"2\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e17.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e17.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"23.439667128987516%\"\u003e\n \u003cp\u003ePruritus\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e9.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e9.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\" colspan=\"2\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e3.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e3.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"100%\" colspan=\"14\"\u003e\n \u003cp\u003e\u003cstrong\u003eTreatment-related AEs\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"23.439667128987516%\"\u003e\n \u003cp\u003eNausea\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e37\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e67.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e31\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e56.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e10.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\" colspan=\"2\"\u003e\n \u003cp\u003e18\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e64.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e53.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e10.7\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"23.439667128987516%\"\u003e\n \u003cp\u003eVomiting\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e32\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e58.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e27\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e49.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e9.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\" colspan=\"2\"\u003e\n \u003cp\u003e14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e50\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e42.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e7.1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"23.439667128987516%\"\u003e\n \u003cp\u003ePeripheral neuropathy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e28\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e50.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e23\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e41.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e9.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\" colspan=\"2\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e42.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e35.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e7.1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"23.439667128987516%\"\u003e\n \u003cp\u003eAnemia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e21\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e38.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e27.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e10.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\" colspan=\"2\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e35.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e28.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e7.1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"23.439667128987516%\"\u003e\n \u003cp\u003eLeucopenia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e18\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e32.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e25.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e7.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\" colspan=\"2\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e28.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e21.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e7.1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"23.439667128987516%\"\u003e\n \u003cp\u003eRash\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e18.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e18.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\" colspan=\"2\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e14.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e14.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"23.439667128987516%\"\u003e\n \u003cp\u003eNeutropenia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e21.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e16.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e5.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\" colspan=\"2\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e21.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e14.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e7.1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"23.439667128987516%\"\u003e\n \u003cp\u003eAnorexia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e14.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e14.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\" colspan=\"2\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e17.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e17.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"23.439667128987516%\"\u003e\n \u003cp\u003eDiarrhea\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e12.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e12.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\" colspan=\"2\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e14.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e14.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"23.439667128987516%\"\u003e\n \u003cp\u003eConstipation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e12.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e12.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\" colspan=\"2\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e10.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e10.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"23.439667128987516%\"\u003e\n \u003cp\u003eThrombocytopenia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e14.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e9.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e5.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\" colspan=\"2\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e14.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e10.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e3.6\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"23.439667128987516%\"\u003e\n \u003cp\u003eFatigue\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e7.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e7.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\" colspan=\"2\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e10.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e10.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"23.439667128987516%\"\u003e\n \u003cp\u003eMuscular soreness\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e7.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e7.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\" colspan=\"2\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e7.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e7.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"23.439667128987516%\"\u003e\n \u003cp\u003eFever\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e7.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e7.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\" colspan=\"2\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e7.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e7.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"23.439667128987516%\"\u003e\n \u003cp\u003eHyperthyroidism\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e7.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e7.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\" colspan=\"2\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e10.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e10.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.38002773925104%\"\u003e\n 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\u003c/table\u003e\n\u003c/div\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-4434336/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4434336/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003ePlatinum-resistant or refractory ovarian cancer (PROC) remains without immunotherapy approval and dismal prognosis, emphasizing the urgent need for novel therapies. This phase 2, single-blind, placebo-controlled, randomized trial evaluated the safety and efficacy of manganese chloride or placebo plus sintilimab, nab-paclitaxel and cisplatin in these patients. 84 patients were randomized to the Mn\u003csup\u003e2+\u003c/sup\u003e (n=55) or placebo (n=29) arm. The primary endpoint of objective response rate (ORR) was met at 61.8% in the Mn\u003csup\u003e2+\u003c/sup\u003e and 13.8% in placebo group. The secondary endpoints of median PFS (9.8 vs. 3.9 months), OS (21.4 vs. 7.9 months) and DOR (14.9 vs. 1.8 months) were significantly prolonged in the Mn\u003csup\u003e2+\u003c/sup\u003e group. No significant differences in AEs and quality of life were document during the treatment period. The serum cytokines and scRNA-seq evidenced the cGAS-STING agonist function of Mn\u003csup\u003e2+\u003c/sup\u003e. Our study supported Mn\u003csup\u003e2+\u003c/sup\u003e-priming immunochemotherapy as a promising treatment regimen for PROC patients. ClinicalTrials.gov identifier: NCT03989336.\u003c/p\u003e","manuscriptTitle":"Manganese primed immunochemotherapy in platinum-resistant/refractory ovarian cancer: a randomized, single-blind, placebo-controlled, phase 2 trial","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-05-30 01:08:31","doi":"10.21203/rs.3.rs-4434336/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"9b85bb5e-d834-4b07-8bfd-92102bbdcf9e","owner":[],"postedDate":"May 30th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":32363081,"name":"Biological sciences/Cancer/Gynaecological cancer/Ovarian cancer"},{"id":32363082,"name":"Biological sciences/Cancer/Cancer therapy/Cancer immunotherapy"}],"tags":[],"updatedAt":"2024-08-30T19:25:20+00:00","versionOfRecord":[],"versionCreatedAt":"2024-05-30 01:08:31","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4434336","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4434336","identity":"rs-4434336","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}