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The purpose of this study was to assess the effect of pevonedistat, a neural precursor cell expressed, developmentally down-regulated protein 8 (NEDD8)-activating enzyme inhibitor, on the heart rate-corrected QT (QTc) interval in cancer patients. Patients were randomized 1:1 to receive pevonedistat 25 or 50 mg/m

ImportancePlatinum-based chemotherapy has been the standard of care for ovarian cancer for the past 3 decades. Although most patients respond to platinum-based treatment, emergence of platinum resistance in recurrent ovarian cancer is inevitable during the disease course. Outcomes for patients with platinum-resistant ovarian cancer are poor, and options remain limited, highlighting a substantial unmet need for new treatment options.ObservationsThis review summarizes the current and evolving treatment landscape for platinum-resistant ovarian cancer with a focus on the development of novel compounds. Biologic and targeted therapies such as bevacizumab and poly (ADP-ribose) polymerase (PARP) inhibitors—originally approved in the platinum-resistant setting but since withdrawn—are now used in the up-front or platinum-sensitive setting, prolonging the duration of platinum sensitivity and delaying the use of nonplatinum options. The greater use of maintenance therapy and the emphasis on using platinum beyond first-line treatment has most likely been associated with a greater number of lines of platinum therapy before a patient is designated as having platinum-resistant ovarian cancer. In this contemporary setting, recent trials in platinum-resistant ovarian cancer have mostly had negative outcomes, with none having a clinically significant effect on progression-free or overall survival since the approval of bevacizumab in combination with chemotherapy. Nonetheless, a multitude of new therapies are under evaluation; preliminary results are encouraging. A focus on biomarker-directed treatment and patient selection may provide greater success in identifying novel therapies for treating platinum-resistant ovarian cancer.Conclusions and RelevanceAlthough many clinical trials in platinum-resistant ovarian cancer have had negative outcomes, these failures provide insights into how clinical trial design, biomarker-directed therapy, and patient selection could facilitate future successes in platinum-resistant ovarian cancer treatment.

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To isolate circulating tumor cells (CTC) from women with advanced cervical cancer and estimate the impact of CTCs and treatment on overall survival and progression-free survival (PFS). A total of 7.5 mL of whole blood was drawn pre-cycle 1 and 36 days post-cycle 1 from patients enrolled on Gynecologic Oncology Group 0240, the phase III randomized trial that led directly to regulatory approval of the antiangiogenesis drug, bevacizumab, in women with recurrent/metastatic cervical cancer. CTCs (defined as anti-cytokeratin+/anti-CD45− cells) were isolated from the buffy coat layer using an anti-EpCAM antibody-conjugated ferrofluid and rare earth magnet, and counted using a semiautomated fluorescence microscope. The median pre-cycle 1 CTC count was 7 CTCs/7.5 mL whole blood (range, 0–18) and, at 36 days posttreatment, was 4 (range, 0–17). The greater the declination in CTCs between time points studied, the lower the risk of death [HR, 0.87; 95% confidence interval (CI), 0.79–0.95)]. Among patients with high (≥ median) pretreatment CTCs, bevacizumab treatment was associated with a reduction in the hazard of death (HR, 0.57; 95% CI, 0.32–1.03) and PFS (HR, 0.59; 95% CI, 0.36–0.96). This effect was not observed with low (< median) CTCs. CTCs can be isolated from women with advanced cervical cancer and may have prognostic significance. A survival benefit conferred by bevacizumab among patients with high pretreatment CTCs may reflect increased tumor neovascularization and concomitant vulnerability to VEGF inhibition. These data support studying CTC capture as a potential predictive biomarker.

Antibody-drug conjugates (ADCs) represent a new class of drugs that combine a surface receptor-targeting antibody linked to a cytotoxic molecule delivering the potent cytotoxic payload directly to tumor cells. This review summarizes the current literature demonstrating their use in the treatment of gynecologic malignancies.Tisotumab vedotin is the first U.S. Food and Drug Administration (FDA) approved ADC for the treatment of gynecologic cancers. While in the phase 3 randomized controlled trial in platinum resistant ovarian cancer patients, FORWARD 1, mirvetuximab did not meet its primary endpoint of progression-free survival. But we await more recent data from the two ongoing phase 3 trials of mirvetuximab in recurrent ovarian cancer patients. HER2/neu, Napi2b, mesothelin, and human trophoblast cell-surface marker (Trop-2) overexpression have also been exploited as excellent targets by novel ADCs in multiple tumors including ovarian, endometrial, and cervical cancers.Current evidence strongly supports the use of ADCs and ongoing clinical trials will provide further information into the potential of making these drugs part of current standard practice allowing patients to be treated with a higher level of personalized cancer care.

Until recently, no data was available from randomized, controlled trials (RCT) to assess the role of secondary cytoreductive surgery (CRS) in the management of recurrent epithelial ovarian cancer. This review highlights results from the three completed RCTs, and other recent literature on this topic.Both the AGO and iMODEL criteria predict high rates of complete gross resection at the time of secondary CRS. Overall survival (OS) was improved in the surgical arms in both DESKTOP 3 and SOC-1. In contrast, surgery did not improve OS in GOG 213, but greater than 80% of patients received bevacizumab with chemotherapy in GOG 213.Secondary cytoreduction for recurrent ovarian cancer can be considered in patients who meet specific criteria. Available data supports improvement in OS for patients not receiving bevacizumab, who achieve complete gross resection. Surgery is harmful to patients with gross residual disease.

Novel biomarkers are needed to direct new treatments for ovarian cancer, a disease for which the standard of care remains heavily focused on platinum-based chemotherapy. Despite the success of PARP inhibitors, treatment options are limited, particularly in the platinum-resistant setting. NaPi2b is a cell surface sodium-dependent phosphate transporter that regulates phosphate homeostasis under normal physiological conditions and is a lineage marker that is expressed in select cancers, including ovarian, lung, thyroid, and breast cancers, with limited expression in normal tissues. Based on its increased expression in ovarian tumors, NaPi2b is a promising candidate to be studied as a biomarker for treatment and patient selection in ovarian cancer. In preclinical studies, the use of antibodies against NaPi2b showed that this protein can be exploited for tumor mapping and therapeutic targeting. Emerging data from phase 1 and 2 clinical trials in ovarian cancer have suggested that NaPi2b can be successfully detected in patient biopsy samples using immunohistochemistry, and the NaPi2b-targeting antibody-drug conjugate under evaluation appeared to elicit therapeutic responses. The aim of this review is to examine literature supporting NaPi2b as a novel biomarker for potential treatment and patient selection in ovarian cancer and to discuss the critical next steps and future analyses necessary to drive the study of this biomarker and therapeutic targeting forward.

Background Successfully combining targeted agents with chemotherapy is an important future goal for cancer therapy. However, an improvement in patient outcomes requires an enhanced understanding of the tumor biomarkers that predict for drug sensitivity. NRG Oncology/Gynecologic Oncology Group (GOG) Study GOG-86P was one of the first attempts to combine targeted agents (bevacizumab or temsirolimus) with chemotherapy in patients with advanced endometrial cancer. Herein we performed exploratory analyses to examine the relationship between mutations in TP53, the most commonly mutated gene in cancer, with outcomes on GOG-86P. Methods TP53 mutational status was determined and correlated with progression-free survival (PFS) and overall survival (OS) on GOG-86P. Results Mutations in TP53 were associated with improved PFS and OS for patients that received bevacizumab as compared to temsirolimus (PFS: HR 0.48, 95% CI 0.31, 0.75; OS: HR: 0.61, 95% CI 0.38, 0.98). By contrast, there was no statistically significant difference in PFS or OS between arms for cases with WT TP53. Conclusions This exploratory study suggests that combining chemotherapy with bevacizumab, but not temsirolimus, may enhance PFS and OS for patients whose tumors harbor mutant p53. These data set the stage for larger clinical studies evaluating the potential of TP53 mutational status as a biomarker to guide choice of treatment for endometrial cancer patients. Clintrials.gov : NCT00977574 .

To isolate circulating tumor cells (CTC) from women with advanced cervical cancer and estimate the impact of CTCs and treatment on overall survival and progression-free survival (PFS). A total of 7.5 mL of whole blood was drawn pre-cycle 1 and 36 days post-cycle 1 from patients enrolled on Gynecologic Oncology Group 0240, the phase III randomized trial that led directly to regulatory approval of the antiangiogenesis drug, bevacizumab, in women with recurrent/metastatic cervical cancer. CTCs (defined as anti-cytokeratin+/anti-CD45− cells) were isolated from the buffy coat layer using an anti-EpCAM antibody-conjugated ferrofluid and rare earth magnet, and counted using a semiautomated fluorescence microscope. The median pre-cycle 1 CTC count was 7 CTCs/7.5 mL whole blood (range, 0–18) and, at 36 days posttreatment, was 4 (range, 0–17). The greater the declination in CTCs between time points studied, the lower the risk of death [HR, 0.87; 95% confidence interval (CI), 0.79–0.95)]. Among patients with high (≥ median) pretreatment CTCs, bevacizumab treatment was associated with a reduction in the hazard of death (HR, 0.57; 95% CI, 0.32–1.03) and PFS (HR, 0.59; 95% CI, 0.36–0.96). This effect was not observed with low (< median) CTCs. CTCs can be isolated from women with advanced cervical cancer and may have prognostic significance. A survival benefit conferred by bevacizumab among patients with high pretreatment CTCs may reflect increased tumor neovascularization and concomitant vulnerability to VEGF inhibition. These data support studying CTC capture as a potential predictive biomarker.

To assess safety and efficacy of niraparib + bevacizumab as a first-line maintenance therapy for patients with newly diagnosed advanced ovarian cancer.This multicenter, phase II, single-arm, open-label study enrolled adult patients with stage IIIB to IV ovarian, fallopian tube, or primary peritoneal cancer (NCT03326193). Patients were required to have an attempt at debulking surgery and have a complete response, partial response, or no evidence of disease following first-line, platinum-based chemotherapy with ≥3 cycles of bevacizumab. The primary endpoint was the progression-free survival (PFS) rate at 18 months. Secondary endpoints included PFS, overall survival, and safety.Among the 105 evaluable patients, the PFS rate at 18 months was 62% (95% CI 52-71%) in the overall population and 76% (95% CI 61-87) in the homologous recombination deficient (HRd), 47% (95% CI 31-64%) in the HR proficient (HRp), and 56% (95% CI 31-79%) in the HR not determined (HRnd) subgroups (December 24, 2020, cutoff). After a median follow-up time of 28.7 months (IQR, 23.9-32.5 months), median PFS was 19.6 months (95% CI 16.5-25.1) in the overall population (N = 105) and 28.3 months (95% CI 19.9-NE), 14.2 months (95% CI 8.6-16.8), and 12.1 months (95% CI 8.0-NE) in the HRd, HRp, and HRnd subgroups, respectively (June 16, 2021, cutoff). The most common any-grade treatment-related adverse events (related to niraparib and/or bevacizumab) were thrombocytopenia (74/105), fatigue (60/105), and anemia (55/105; December 24, 2020, cutoff).Niraparib + bevacizumab first-line maintenance therapy displayed promising PFS results. Safety was consistent with the known safety profiles of niraparib and bevacizumab as monotherapy.

Background: PRO1184 is an antibody-drug conjugate (ADC) directed to folate receptor alpha (FRα), a cell surface antigen overexpressed in multiple cancers including ovarian, endometrial, lung, mesothelioma, and breast cancer. PRO1184 consists of a human monoclonal antibody that selectively binds FRα, a novel cleavable hydrophilic linker, and a topoisomerase 1 inhibitor payload, exatecan. Previous studies demonstrated that the hydrophilic linker confers excellent physicochemical properties and pharmacokinetic (PK) profiles across a range of payload mechanisms and is superior to conventional linkers on these critical parameters for ADCs. In addition, exatecan is broadly active in many tumor types, is membrane permeable, and is not a substrate of multidrug resistance efflux pumps. It may thus lend a robust bystander effect and induce deeper or more durable responses in refractory tumors. Preclinical studies further established that PRO1184 exerts potent antitumor activity in mouse xenograft models with high, moderate, and low FRα expression, consistent with the inherent potency and expected bystander activity of the exatecan payload. PRO1184 is stable in plasma and retains the excellent PK properties and bioactivity of the unconjugated parent antibody. The preliminary safety profile of PRO1184 was more favorable than a benchmarking deruxtecan-based ADC in cynomolgus monkeys. PRO1184 is thus a promising development candidate with a potentially large therapeutic index to benefit a broad population of patients with FRα-expressing solid tumors. Methods: PRO1184-001 is an ongoing, phase 1/2, open-label dose escalation and expansion study. Eligible patients are adults with metastatic or unresectable solid tumors, including ovarian, endometrial, non-small cell lung, breast cancer, or mesothelioma. Patients must have measurable disease per the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, or mRECIST 1.1 for pleural mesothelioma. Patients must also have previously received therapies known to confer clinical benefit unless considered ineligible, refused by the patient, or not available in the region. PRO1184 is given by intravenous infusion on Day 1 of a 21-day cycle and treatment may continue until disease progression, unacceptable toxicity, or other reason for discontinuation. The primary objectives are to evaluate the safety and tolerability of PRO1184 and to identify the maximum tolerated dose, if reached, and recommended phase 2 dose (RP2D). Part A of the study consists of a dose escalation phase and Part B consists of 4 FRα-expressing tumor-specific expansion cohorts treated at the RP2D. PK, immunogenicity, and antitumor activity will also be evaluated. The study is currently enrolling at sites in the US, with future enrollment in China planned (NCT05579366). Citation Format: Justin Call, Douglas Orr, Ian Anderson, Debra L. Richardson, Zhu Chen, Sharon Ma, Naomi N. Hunder, Erika Hamilton. Phase 1/2 study of PRO1184, a novel folate receptor alpha-directed antibody-drug conjugate, in patients with locally advanced and/or metastatic solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT244.

The Bromodomain and Extra-Terminal (BET) Domain proteins facilitate the development of many human cancers via epigenetic regulation. BET inhibitors may be effective in reversing platinum resistance in ovarian cancer (OC) and may generate synthetic lethality with ARID1A loss. PLX2853 is an orally active, small molecule inhibitor of BET bromodomain-mediated interactions that exhibits low nanomolar potency in blocking all 4 BET family members (BRD2, BRD3, BRD4, and BRDT). PLX2853 development is continuing at Opna Bio as OPN-2853. Clinical experience with PLX2853 monotherapy in subjects with heavily pretreated solid tumors and lymphoma showed signs of activity. The current study (NCT04493619) was designed as a multicenter, open-label trial with two parallel arms: (1) a phase 2a study of PLX2853 monotherapy in advanced gynecological malignancies with a known ARID1A mutation and (2) a phase Ib/2a combination study of PLX2853 plus carboplatin in platinum resistant OC. The primary objective of the Ib portion of the study was safety and tolerability, with the primary objective of both phase 2a portions being efficacy. In the monotherapy arm, up to 6 patients were treated at 80 mg PLX2853 daily in a safety lead-in, with progression to phase 2a using a Simon 2-stage design if dose limiting toxicities (DLTs) were observed in fewer than 33% subjects. In Stage 1, 6 additional subjects (N=12 total) were planned, with progression to stage 2 if two or more patients responded in stage 1. The combination arm included an escalation phase Ib. Three to six evaluable subjects were planned for each group, with dose escalation pending less than 33% DLT rate. The combination arm defined by the phase 1b portion of the study continued to a planned phase 2a Simon 2 stage design similar to that described for the monotherapy arm. 34 of 37 enrolled patients were evaluable with data from at least 1 post-baseline response (14 monotherapy, 20 combination therapy). Of the 14 evaluable patients on the monotherapy arm, 1 (7.1%) achieved a partial response (PR) with progression-free survival of 278 days, 5 (35.7%) had stable disease (SD) and 8 (57.1%) had progressive disease (PD). Of the 20 evaluable OC patients on the PLX2843 + carboplatin combination, 1 (5.0%) had PR, 9 (45.0%) had SD, and 10 (50%) had PD. This study in a larger cohort of gynecologic cancer patients confirmed the safety profile of the agent and demonstrated the feasibility of combination with carboplatin. While these results did not meet the pre-specified response criteria, evidence of clinical activity nevertheless highlights the rationale for further exploration of BRD4 inhibitors in patients with ARID1A-mutated gynecologic malignancies, possibly in combination with agents targeting potential feedback mechanisms such as the PI3K pathway, frequently activated in these cancers. Citation Format: Elizabeth M. Swisher, Linda R. Duska, Erika P. Hamilton, Amit M. Oza, Gini Fleming, Oladapo O. Yeku, Alexander I. Spira, Debra L. Richardson, Robin Guo, Jackie Walling, Kerry Inokuchi, Dmitriy Zamarin. Phase 1b/2a clinical trial of the oral BET inhibitor PLX2853 as monotherapy for ARID1A mutated gynecologic cancers and in combination with carboplatin for platinum resistant ovarian cance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT160.

5517 Background: LIO-1 is assessing the oral antiangiogenic, multikinase inhibitor lucitanib in combination with the programmed cell death receptor 1 (PD-1) inhibitor nivolumab. Individualized lucitanib dose titration is being explored to maximize lucitanib exposure and potential clinical benefit of the combination. Here, we present data from stage 1 of a Simon 2-stage design across 4 different types of advanced gynecologic cancers from the phase 2 part of LIO-1. Methods: Patients (pts) with advanced, recurrent, or metastatic endometrial cancer (EC, who received ≥1 prior platinum-based chemotherapy); cervical cancer (CC, who received ≥1 prior platinum-based chemotherapy ± bevacizumab); high-grade ovarian cancer (OC, who received ≥2 prior chemotherapies); or EC/OC with clear-cell histology (EOCC, who received ≥1 prior platinum-based chemotherapy + taxane) were enrolled. Prior PD-1 or programmed cell death ligand 1 (PD-L1) inhibitor treatment was excluded, except for up to 10 pts in the EC cohort. Pts received lucitanib at a starting dose of 6 mg once daily (QD), escalating to 8 mg QD and then 10 mg QD if safety-based titration criteria were met, plus intravenous nivolumab 480 mg every 28 days. The data cutoff was Jan 10, 2022. Results: Across cohorts, 100 pts were enrolled to stage 1; 27 (27%) remain on treatment. To date, 28 (28%) have escalated to lucitanib 8 mg, and 17 (17%) have escalated to the maximum dose of 10 mg. Confirmed responses per RECIST v1.1 have been reported in 5/22 (22.7%; 5 partial responses [PRs]) EC pts, 7/22 (31.8%; 2 complete responses [CRs], 5 PRs) CC pts, 4/33 (12.1%; 4 PRs) OC pts, and 5/23 (21.7%; 1 CR, 4 PRs) EOCC pts. Response duration ranges from 1.9+ to 13.1+ months. Of 5 pts with EC who received prior PD-1 inhibitor, there were 2 PRs, and 1 pt with ongoing stable disease of 7+ months. Grade ≥3 treatment-emergent adverse events (TEAEs) considered related to study treatment were reported in 43 (43%) pts, with hypertension the most frequent (n = 25 [25%]). Forty-six (46%) pts had a lucitanib-related TEAE that led to lucitanib interruption and 12 (12%) had one that led to lucitanib dose reduction. Eleven (11%) and 8 (8%) pts discontinued lucitanib and nivolumab, respectively, due to a treatment-related TEAE. Safety results were generally consistent across tumor cohorts. Conclusions: The combination of lucitanib + nivolumab is active in the treatment of advanced gynecological malignancies and has a manageable safety profile through effective dose titration. Stage 2 enrollment has continued in the CC cohort. Biomarker analysis is ongoing, and more mature efficacy and safety data will be presented at the meeting. Clinical trial information: NCT04042116.

2517 Background: Treatment options are limited for patients with recurrent or metastatic human papillomavirus 16 positive (HPV16+) cancers. Generation and maintenance of HPV16+ cancers requires stable expression of HPV16-specific E7 and E6 oncoproteins, which are also a source of tumor-specific immunogenic neoantigens. HB-201 and HB-202 are replicating live-attenuated vectors based on lymphocytic choriomeningitis virus and Pichinde virus, respectively, which express the same non-oncogenic HPV16 E7E6 fusion protein and infect antigen presenting cells to induce tumor-specific T cell responses. The Phase 1 part of this study of HB-200 therapy (HB-201 single-vector therapy and HB-202/HB-201 two-vector alternating therapy) was conducted to determine RP2D for further exploration alone or in combination with pembrolizumab. Methods: The Phase 1 part used a 3+3 dose escalation design with up to 3 dose levels (DLs) of HB-201 and 4 DLs of HB-202/HB-201 explored. Patients with HPV16+ head and neck squamous cell carcinoma (HNSCC) or with other HPV16+ cancers were evaluated. Safety, tolerability, immunogenicity, and preliminary antitumor activity by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 or immune RECIST were assessed to determine RP2D. Results: As of January 2022, 65 patients with a median of 3 prior anticancer treatments have been enrolled in the Phase 1 part of the study. All had HPV16+ confirmed genotype; the most common primary site was oropharynx, followed by anal and cervix. Adverse events were generally mild or moderate. For HB-201, 3 DLs, 2 dosing schedules and 2 administration routes were assessed across 40 patients. At DL3 of HB-201 administered intravenously (IV), dose-limiting toxicity (DLT) occurred in 1/6 patients in the HNSCC group (Grade 4 encephalopathy, fully recovered) and 1/2 patients in the non-HNSCC group (Grade 3 rash, fully recovered). Preliminary safety, efficacy, and immunogenicity data support IV injection of DL3 (5 × 107 units) every 3 weeks (Q3W) as the RP2D for HB-201 single-vector therapy. For HB-202/HB-201, 4 DLs and 2 administration routes were assessed across 25 patients. At DL4 of HB-202/HB-201 IV, 1/5 subjects in the HNSCC group reported a DLT (Grade 4 hepatitis, recovering at time of discontinuation). RP2D for HB-202/HB-201 will be determined in the very near future. Tumor control, including partial response, have been observed in subjects treated with either HB-201 or HB-202/HB-201 as monotherapy. Conclusions: HB-201 and HB-202/HB-201 were generally well tolerated and showed preliminary antitumor activity in heavily pre-treated patients with HPV16+ solid tumors. DL3 was selected as RP2D for HB-201 monotherapy. In the Phase 2 part of the study a combination of HB-201 at 5 × 106 units IV Q3W with pembrolizumab is being tested in HPV16+ HNSCC patients. Clinical trial information: NCT04180215.

Objectives: In women with recurrent ovarian cancer (OC), advanced care planning (ACP) such as advanced directives (AD), code status, and timely hospice referral should be addressed. In a high-volume, clinical trial focused cancer center, treatment with novel potentially life-prolonging therapies may alter timing of discussions. Our study compares patterns of ACP between trial and non-trial recurrent OC patients. Methods: All patients ≥18 years who were treated at a single institution for the diagnosis of OC during the year of 2015 and had ever recurred were reviewed. Patients who ever (n=84) versus never (n=41) participated in a therapeutic clinical trial (CT) were compared. Chi-square or Fisher's exact tests and 2 sided t-tests or Wilcoxon Rank-Sum tests compared demographic data and ACP variables of interest using an α = 0.05. Multivariable logistic regression estimated adjusted odds ratios (aOR) adjusted by CT participation, age, and Charlson comorbidity index. Results: A total of 125 patients were identified, and 84 (67%) participated in CTs. Cohorts were similar in age, BMI, insurance status, and histopathologic characteristics. Median time to follow up after first recurrence was 856 days in trial patients vs 308 days in non-trial patients (p Download : Download high-res image (331KB) Download : Download full-size image Conclusions: The time between the recurrence and code status discussions was significantly longer in CT participants, and ACP discussions occurred typically during or after a trial. ACP occurred more frequently when patients were referred to palliative or supportive care referral, independent of participation in either late phase or phase 1 CT. Prioritizing ACP and supportive care referral, especially in CT participants, may improve these rates and optimize end of life care.

Chemotherapy resistance is a common occurrence in women who have undergone treatment for epithelial ovarian cancer. Combination chemotherapy, while helpful in delaying the development of resistance, carries increased toxicity and a poorer safety profile. As a result, numerous studies are investigating additional pharmacological targets, combination therapies, and repurposed agents for ovarian cancer treatment. This chapter summarizes clinical studies investigating novel combination therapies and targeted treatments that may hold promise in future clinical applications.

Highlights • Social services utilization may highlight patients at risk of prolonged time to completion of chemoradiation. • With support from the treating institution, more patients may be able to complete therapy in an appropriate time. • Time to completion of chemoradiation >56 days remains a predictor of shorter PFS and OS., We aimed to evaluate how the need for social services programs is associated with outcomes amongst patients with cervical cancer undergoing chemoradiation with a single institution, retrospective analysis of patients from January 1, 2015-July 31, 2018. Demographic, clinical, and social services utilization data were collected. Descriptive statistics and Chi-squared tests were performed. Kaplan-Meier curves estimated progression free (PFS) and overall survival (OS). Among 117 eligible patients, median household income was $45,782 ($19,771 – $96,222). There was no difference in stage among income cohorts. Uninsured/publically insured patients had a higher stage at diagnosis than those privately insured (p = 0.003). Patients used 0–5 assistance programs during treatment. 77.6% of low income versus 54.2% of high income patients utilized ≥1 program. Assistance with lodging was utilized more often in low than high income patients. (36.2% vs 15.7%, p = 0.013). 58.3% of patients completed therapy in less than 56 days. Patients who completed therapy in >56 days utilized 1.44 social services while patients completing in ≤56 days used 1.06 (p = 0.102). Social security disability utilization trended towards completion times >56 days (p = 0.064). There was no difference in PFS or OS based on income or social services utilized. Financial toxicities associated with therapy are not limited to uninsured/publically insured or low income patients as over 50% of high income patients utilized at least one service. Additionally, the trend towards significance between enrollment in disability and completion of chemoradiation >56 days may highlight a group of at risk patients who need additional support.

BackgroundAdjuvant therapy in early-stage endometrial cancer has not shown a clear overall survival benefit, and hence, patient selection remains crucial.ObjectiveTo determine whether women with high-intermediate risk, early-stage endometrial cancer with lymphovascular space invasion particularly benefit from adjuvant treatment in improving oncologic outcomes.MethodsA multi-center retrospective study was conducted in women with stage IA, IB, and II endometrial cancer with lymphovascular space invasion who met criteria for high-intermediate risk by Gynecologic Oncology Group (GOG) 99. Patients were stratified by the type of adjuvant treatment received. Clinical and pathologic features were abstracted. Progression-free and overall survival were evaluated using multivariable analysis.Results405 patients were included with the median age of 67 years (range 27–92, IQR 59–73). 75.0% of the patients had full staging with lymphadenectomy, and 8.6% had sentinel lymph node biopsy (total 83.6%). After surgery, 24.9% of the patients underwent observation and 75.1% received adjuvant therapy, which included external beam radiation therapy (15.1%), vaginal brachytherapy (45.4%), and combined brachytherapy + chemotherapy (19.1%). Overall, adjuvant treatment resulted in improved oncologic outcomes for both 5-year progression-free survival (77.2% vs 69.6%, HR 0.55, p=0.01) and overall survival (81.5% vs 60.2%, HR 0.42, pConclusionAdjuvant therapy improves both progression-free survival and overall survival in women with early-stage endometrial cancer meeting high-intermediate risk criteria with lymphovascular space invasion. External beam radiation or adding chemotherapy did not confer additional survival advantage compared with vaginal brachytherapy alone.

IntroductionTo describe patient-reported outcomes and toxicities at time of treatment discontinuation secondary to progression or toxicities in advanced/recurrent cervical cancer patients receiving chemotherapy with bevacizumab.MethodsSummarize toxicity, grade, and health-related quality of life within 1 month of treatment discontinuation for women receiving chemotherapy with bevacizumab in GOG240.ResultsOf the 227 patients who received chemotherapy with bevacizumab, 148 discontinued study protocol treatment (90 for disease progression and 58 for toxicity). The median survival time from treatment discontinuation to death was 7.9 months (95% CI 5.0 to 9.0) for those who progressed versus 12.1 months (95% CI 8.9 to 23.2) for those who discontinued therapy due to toxicities. The most common grade 3 or higher toxicities included hematologic, gastrointestinal, and pain. Some 57% (84/148) of patients completed quality of life assessment within 1 month of treatment discontinuation. Those patients who discontinued treatment due to progression had a mean decline in the FACT-Cx TOI of 3.2 points versus 2.2 in patients who discontinued therapy due to toxicity. This was a 9.9 point greater decline in the FACT-Cx TOI scores than those who discontinued treatment due to progression (95% CI 2.8 to 17.0, p=0.007). The decline in quality of life was due to worsening physical and functional well-being. Those who discontinued treatment due to toxicities had worse neurotoxicity and pain.DiscussionPatients who discontinued chemotherapy with bevacizumab for toxicity experienced longer post-protocol survival but significantly greater declination in quality of life than those with progression. Future trial design should include supportive care interventions that optimize physiologic function and performance status for salvage therapies.

Background Metastatic and recurrent cervical cancer is rarely a curable disease. Systemic chemotherapy is typically recommended for treatment based on clinical trials in the first-line or second-line setting. Rare patients who progress through 2 salvage regimens will have the performance status, medical ability, and desire to continue cytotoxic therapy. For these patients, there are no data to provide effective counseling regarding expected response rates (RRs) and toxicities. We sought to review our experience with this patient population. Methods A single institution review was performed of all patients treated for cervical cancer between January 1, 2000 and June 30, 2013. Eligible patients were those who received at least 3 unique salvage chemotherapy regimens following primary surgery or radiation. RRs, survival statistics and toxicities were evaluated. Results Twenty-three of 710 (3.2%) patients treated for cervical cancer met eligibility criteria. Nineteen received 2 or more cycles of a third-line regimen and were assessed for response and progression-free survival. The remainder were included in analysis of overall survival and toxicity. The RR to third-line chemotherapy was 10% (1 complete, 1 partial). An additional 27% achieved stable disease. In total, 57% suffered a grade 3 or 4 toxicity. The progression-free survival from the beginning of third-line therapy was 3.8 months, and the overall survival was 7.4 months. Conclusions Patients eligible to receive third-line chemotherapy for metastatic and recurrent cervical cancer can expect minimal benefit at the cost of significant toxicity. Quality of life considerations should be of paramount importance when counseling regarding the risks and benefits of further cytotoxic therapy.

Adherence to treatment regimen and schedule is recommended to improve control of disease and overall survival (OS) in locally advanced cervical cancer. However, treatment-related toxicities and patient and physician factors all impact timely completion of treatment. We sought to correlate adherence to treatment plan with survival and toxicities of patients treated for locally advanced cervical cancer. A retrospective review of patients treated for advanced cervical cancer at our institution between 2003 and 2011 was performed. Demographics, clinicopathologic variables, treatment, and disease outcomes were collected. Endpoints of disease outcome were disease-free survival and OS. Statistical analyses were performed using the Kaplan-Meier method, log-rank test, and Cox regression analysis. A total of 162 patients met the inclusion criteria and were included in study analysis. A total of 95% of patients were treated with both radiation and concurrent chemotherapy. Mean radiation dose to point A was 72 Gy. In total, 77% had complete response to primary therapy. Severe (grade 3/4) late radiation toxicities were seen in 10.5% of patients. Stage and total radiation dose to point A were significant predictors of survival for the entire cohort. Among patients receiving at least 72 Gy and brachytherapy, duration of treatment was significantly associated with both disease-free survival and OS. Adherence to both optimal treatment time and radiation dose is significantly associated with improved survival. Total radiation dose is an independent predictor of survival among patients with locally advanced cervical cancer.

Objective To estimate the frequency of occult endometrial cancer in women undergoing hysterectomy for benign indications. Study design We performed a retrospective review of all patients undergoing hysterectomies for benign indications at our institution from 2006 to 2014. A departmental database was used to identify all hysterectomies performed, and institutional tumor registry was used to identify cases of endometrial carcinoma. Occult carcinomas were defined as cases with no suspicion preoperatively and histopathologic diagnosis of endometrial cancer postoperatively. Results A total of 6981 hysterectomies were performed for benign indications. Among these, thirteen patients (0.19%) were found to have occult endometrial cancer, with an overall rate of 1 in 537 patients (95% confidence interval 1:314–1:1008). Twelve patients had stage IA and one had stage IB disease. Median age of women found to have endometrial cancer was 50 years (range 35–72 years). The median BMI was 29.8 kg/m2 (range 21.3–50.4 kg/m2). The most common indications for hysterectomy were abnormal bleeding (47%), postmenopausal bleeding (15%), adnexal mass (15%), prolapse (15%), and endometrial hyperplasia without atypia (8%). Of the postmenopausal women that had bleeding, all patients underwent evaluation of the endometrium, however 75% of samples did not have adequate amount of endometrium to be evaluated and 25% were found to have hyperplasia. Conclusion This is one of the largest single institution cohorts to examine occult malignancy. Unexpected endometrial carcinomas were found to occur in 0.19% or 1:537 (95% confidence interval 1:314–1:1008) hysterectomies for benign indications in our population. Precis Occult endometrial carcinomas are found to occur in 1:537 (0.19%) hysterectomies for benign indications.

Objective To review recent therapies approved by the US Food and Drug Administration for the treatment of gynecologic malignancies. Data sources PubMed, FDA.gov, ASCO.org. Conclusion The landscape for treating gynecologic malignancies is rapidly changing. Maintenance therapy now exists for women with advanced ovarian cancer after completing chemotherapy for both newly diagnosed and platinum-sensitive recurrent ovarian cancer. Anti-angiogenic therapy has many applications in gynecologic malignancies. Immunotherapy can be used in certain situations for women with gynecologic malignancies. Implications for Nursing Practice Biologic agents and immunotherapy have distinct side-effect profiles that nurses need to be aware of to optimize patient care and outcomes.

BackgroundSIRPα-Fc-CD40L is a hexameric, bi-functional fusion protein consisting of SIRPα (binding affinity to CD47 is 0.628 nM) linked to CD40L (binding affinity to CD40 is 4.74 nM) through an Fc linker protein.1 By augmenting antigen processing and promoting antigen presenting cell (APC) maturation, this molecule is designed to bridge innate and adaptive immunity, enhancing tumor cell phagocytosis and antigen cross-presentation to CD8 T cells.MethodsThe first-in-human, Phase 1 dose escalation study is evaluating SL-172154 as monotherapy in patients (pts) with platinum resistant ovarian, fallopian tube and primary peritoneal cancers. Objectives include evaluation of safety, dose-limiting toxicity (DLT) and recommended phase 2 dose (RP2D), pharmacokinetic (PK) parameters, pharmacodynamic (PD) effects and antitumor activity based on RECIST.ResultsAs of 6 July 2021, 14 heavily pretreated pts (median age, 67 years) were enrolled and treated with intravenous (IV) administration of SL-172154 across 4 dose levels on 2 schedules: schedule 1 (day 1, 8, 15, 29, Q2 weeks) at 0.1, 0.3 mg/kg and schedule 2 (weekly) at 0.3, 1.0, 3.0 mg/kg. The most common treatment-related (>20%) adverse events (AEs) of any grade (G) were fatigue (n=7, 50%), infusion-related reactions (IRR) (n=6, 43%), nausea (n=4, 29%), and decreased appetite (n=3, 21%). Treatment-related IRRs (G1/G2) generally occurred near the end of infusion or immediately post-infusion; the full dose was able to be delivered in each IRR event, and subsequent infusions in patients having IRRs were managed with pre-medications. No treatment related ≥G3 AEs or DLTs have occurred. CD47 receptor occupancy (RO) on leukocytes approached 90% at 1.0 and 3.0 mg/kg. Minimal binding to CD47+ red blood cells was observed at all dose levels. CD40 RO on B cells was >60% at doses ≥0.1 mg/kg and 75%–100% at 1.0 and 3.0 mg/kg. Rapid, transient B cell and monocyte margination was observed following infusion of SL-172154 and was consistent with dose-dependent increases in IL-12, MCP-1, MIP-1β, MIP-1α, and MDC. No appreciable increases in IL-6 or TNFα were noted and there was no correlation between IRRs and cytokine increases. Among 12 evaluable pts, the best response was stable disease in 3 pts.ConclusionsSL-172154 has been well tolerated with no evidence of anemia, thrombocytopenia, liver dysfunction or cytokine release syndrome. A unique serum cytokine signature consistent with CD40 RO and activation has been observed and this signature is maintained following repeat dosing. Dose escalation is ongoing.AcknowledgementsThanks are extended to study participants; Cathrine Leonowens, PhD, Nuventra Pharma Sciences, Durham, NC, United States and Cadence Communications and Research, Thousand Oaks, CA, United States. This study is funded by Shattuck Labs, Inc. Austin, TX and Durham, NC, United States.Trial RegistrationNCT04406623Referencesde Silva S, Fromm G, Shuptrine CW, Johannes K, Patel A, Yoo KJ, et al. CD40 enhances type I interferon responses downstream of CD47 blockade, bridging innate and adaptive immunity. Cancer Immunol Res 2020; 8: 230–245.Ethics ApprovalThis study is being conducted in full conformity with the Declaration of Helsinki and was approved by all IRBs/ethics committees from each clinical site participating in the study. Specific approval numbers can be provided upon request.

Objectives: Niraparib improves progression-free survival (PFS) in newly diagnosed, recurrent, and heavily pretreated ovarian cancer (OC) in patients (pts) after platinum-based chemotherapy in all biomarker-defined subgroups. Bevacizumab-induced hypoxia can drive genomic instability by altering DNA damage repair pathways, including homologous recombination (HR), and it is hypothesized to sensitize tumors to poly(ADP-ribose) polymerase inhibition. OVARIO (NCT03326193) is a single-arm, open-label study evaluating niraparib + bevacizumab treatment in advanced OC after response to first-line (1L) platinum-based chemotherapy + bevacizumab. Methods: All pts with newly diagnosed high-grade serous or endometrioid stage IIIB-IV OC who had a complete response (CR), partial response, or no evidence of disease (NED) after 1L platinum-based chemotherapy + bevacizumab were eligible. Pts receiving neoadjuvant chemotherapy (NACT) or primary debulking surgery were eligible. All pts underwent tissue testing for HR deficiency (HRd) or proficiency (HRp) at enrollment. Bevacizumab dosage was 15 mg/kg q3w up to 22 cycles, including time on 1L chemotherapy. Niraparib, 300 or 200 mg qd, based on baseline body weight and platelet count, was started within 12 weeks of completing 1L treatment and continued for 3 years or until progressive disease or unacceptable toxicity. The primary endpoint was PFS rate at 18 months from treatment initiation of niraparib + bevacizumab maintenance. Results: The study completed enrollment at 105 pts. Most pts were stage III (79%), had serous histology (95%), received NACT (63%), and had CR/NED at the completion of 1L (63%). Overall, 47% of pts were HRd, including HRd-BRCA mutated and HRd-BRCA wild-type. The niraparib starting dose was 200 mg in 78% of pts. At 6 and 12 months, PFS rates were 90% and 75%, respectively. At 12 months, the most common grade ≥3 related treatment-emergent adverse events were thrombocytopenia, anemia, and hypertension (49% of pts had pre-existing hypertension). Further safety data and PFS rates at 18 months will be presented at the meeting. Conclusions: Safety of the niraparib + bevacizumab combination was consistent with the known side effects of each drug as monotherapy, and the preliminary data suggest that the combination is efficacious. ClinicalTrials.gov number: NCT03326193

Objective To assess whether the addition of oncolytic reovirus (Reolysin®) to weekly paclitaxel prolonged progression-free survival (PFS) in the treatment of women with recurrent or persistent ovarian, tubal or primary peritoneal cancer. Patients and methods Patients with recurrent or persistent epithelial ovarian, tubal, or peritoneal carcinoma, measurable or detectable disease, and three or fewer prior regimens were randomly assigned to paclitaxel (80mg/m 2 intravenously days 1, 8, and 15 every 4weeks) or the combination of paclitaxel (80mg/m 2 intravenously days 1, 8, and 15) plus reovirus 3×10 10 TCID 50 /day intravenously on days 1–5, both every 4weeks until disease progression or toxicity. The primary end point was PFS. The study was designed with 80% power for a one-sided alternative at a 10% level of significance to detect a reduction in the hazard by 37.5%. Results The study accrued 108 patients, 100 of whom were evaluable for toxicity. Median PFS was 4.3months for paclitaxel and 4.4months for paclitaxel plus reovirus (hazard ratio, 1.11; 90% two-sided CI, 0.78 to 1.59; one-sided P=0.687). The proportion responding (overall response rate) to paclitaxel was 20% among 45 patients with measurable disease receiving paclitaxel alone, and 17.4% among the 46 patients treated with the combination. The asymptotic relative probability of responding was 0.87 (90% CI, 0.42 to 1.79). Severe adverse events were more common in the combination regimen than in paclitaxel arm for severe neutropenia (grade≥4, 12% versus 0%), and severe respiratory adverse events (grade≥3, 25% versus 2%). No deaths were considered treatment related. Conclusion The addition of reovirus to weekly paclitaxel in the treatment of women with recurrent or persistent ovarian, tubal or peritoneal cancer did not sufficiently reduce the hazard of progression or death to warrant further investigation.

Objectives Lymphovascular space invasion (LVSI) is an independent risk factor for recurrence and poor survival in early-stage endometrioid endometrial cancer (EEC), but optimal adjuvant treatment is unknown. We aimed to compare the survival of women with early-stage EEC with LVSI treated postoperatively with observation (OBS), radiation (RAD, external beam and/or vaginal brachytherapy), or chemotherapy (CHEMO)+/−RAD. Methods This was a multi-institutional, retrospective cohort study of women with stage I or II EEC with LVSI who underwent hysterectomy+/−lymphadenectomy from 2005 to 2015 and received OBS, RAD, or CHEMO+/−RAD postoperatively. Progression-free survival and overall survival were evaluated using Kaplan-Meier estimates and Cox proportional hazards models. Results In total, 478 women were included; median age was 64 years, median follow-up was 50.3 months. After surgery, 143 (30%) underwent OBS, 232 (48.5%) received RAD, and 103(21.5%) received CHEMO+/−RAD (95% of whom received RAD). Demographics were similar among groups, but those undergoing OBS had lower stage and grade. A total of 101 (21%) women recurred. Progression-free survival (PFS) was improved in both CHEMO+/−RAD (HR = 0.18, 95% CI: 0.09–0.39) and RAD (HR = 0.31, 95% CI: 0.18–0.54) groups compared to OBS, though neither adjuvant therapy was superior to the other. However, in grade 3 tumors, the CHEMO+/−RAD group had superior PFS compared to both RAD (HR 0.25; 95% CI: 0.12–0.52) and OBS cohorts (HR = 0.10, 95% CI: 0.03–0.32). Overall survival did not differ by treatment. Conclusions In early-stage EEC with LVSI, adjuvant therapy improved PFS compared to observation alone. In those with grade 3 EEC, adjuvant chemotherapy with or without radiation improved PFS compared to observation or radiation alone.

The poly ADP ribose polymerase olaparib is currently approved in front line BRCA-associated epithelial ovarian cancer (EOC), platinum-sensitive recurrence agnostic to BRCA status and for gBRCA as treatment in the fourth line and beyond. Women who are diagnosed with advanced stage EOC face a formidable challenge in overcoming their disease and achieving long-term, disease-free survival. The qualifier here is disease free. EOC is largely exquisitely chemosensitive, especially in the treatment naive (first line) setting and the expectation is that the vast majority of women will complete front line platinum-based chemotherapy with a response. When unselected (not selected by BRCA) women are enrolled on clinical trials, the response rate among those who have measurable disease at the time of chemotherapy initiation is 48% for carboplatin/paclitaxel and 67% for carboplatin/paclitaxel plus bevacizumab. When one considers the addition of women who start chemotherapy without measurable disease, they will likely also end chemotherapy without measurable disease and the overall rate of no evidence of disease at conclusion of chemotherapy approaches 80%. Despite this, the majority of women will suffer relapse of their disease, typically within the first 3 years following completion of therapy. Once recurrent, the disease is highly treatable for many years but no longer considered curable. This review will cover indications for olaparib in ovarian cancer as well as ongoing combination trials and rationale for these combinations.

Purpose Our purpose was to assess the feasibility, safety, and efficacy of stereotactic ablative radiation therapy (SAbR) as an alternative for intracavitary/interstitial brachytherapy boost for locally advanced cervical cancer (LACC) after initial chemoradiation. Methods and Materials A single arm institutional phase II study of SAbR as a boost for LACC was conducted. Eligible patients had LACC FIGO 2009 stage IB2-IVB, performance status 0 to 3, and one of the following: medically unfit or refused intracavitary or tumor extent required interstitial brachytherapy for coverage. The cervix planning target volume boost (PTVboost) received 28 Gy in 4 fractions. Results The study was closed with 15 of 21 patients completed owing to concern for toxicity. Median follow-up for this cohort was 19 months. Patients had predominantly advanced stage (III-IV, 53%) with median Charlson comorbidity score of 4. Most tumors were large with a median SAbR boost PTV size of 139 cc (range, 51-268 cc). Tumor size and patient comorbidities probably contributed to the lower-than-expected 2-year local control, progression free, and overall survival of 70.1%, 46.7%, and 53.3%, respectively. The SAbR boost 2 year cumulative grade ≥ 3 toxicity of 26.7% was predominantly rectal (ulcer/fistula).The median SAbR PTV volume was 225 cc versus 95 cc for patients with and without grade ≥ 3 toxicity. On dosimetric analysis, only the percentage of rectal circumference receiving 15 Gy (PRC15) for the SAbR boost was associated with development of grade 3 ulcer or rectovaginal fistula (P = .04), with PRC15 > 62.7% being the strongest predictor of toxicity (AUC, 0.93; sensitivity, 100%; specificity, 90%). Conclusions In this SAbR boost series suboptimal outcomes were probably related to patient selection and very large tumor volume. This approach may still be considered in patients with smaller tumors unable to undergo standard brachytherapy for cervix cancer.

The purpose of this review is to discuss the current understanding of the Tie2-angiopoietin system and its role in tumor growth and metastasis. This review also focuses on preclinical and clinical data published to date that have evaluated Tie2-angiopoietin inhibition. Tie2 inhibition has shown significant promise in preclinical models, notable for decreased tumor burden and fewer sites of metastatic disease across various malignancies. However, data from human clinical trials have shown more mixed results. Trebananib, rebastanib, and MEDI3617 are the three Tie2-angiopoietin inhibitors that have been most widely evaluated in phase I and II trials. Further investigation into these therapies is ongoing. The Tie2-angiopoietin pathway continues to show promise in preclinical and some clinical trials, including studies on recurrent or metastatic breast and renal cell carcinomas. Further evaluation of these therapies, however, is warranted to better understand their optimal clinical utility.

Background: Transcriptional activation of c-MYC through bromodomain and extra-terminal (BET) proteins contributes to the malignant phenotype of OC and TNBC. RO is a novel thienodiazepine, small molecule, non-covalent inhibitor of the BET family of bromodomains. BET inhibition may also play a role in immune modulation via downregulation of CD47 and PD-L1. We hypothesized that RO may enhance the clinical potential of A. We report results of a phase 1b study of RO in combination with A in advanced OC and TNBC (NCT03292172). Methods: Patients with advanced OC or TNBC were eligible. In the dose escalation part, pts received subcutaneous escalating doses of RO (0.30, 0.45, 0.65 mg/kg) on days 1 - 14 of 21-day cycles in combination with A at 1200 mg IV on Day 1 of each cycle. In the expansion part, pts received RO at 0.45 mg/kg. Primary objectives were safety, tolerability and preliminary clinical activity of the combination. Results: Between Nov 2017 and Dec 2018, a total of 36 pts were enrolled, 27 pts in the dose escalation and 9 pts in the expansion part at 6 sites in the US, Canada, Denmark and Australia. The median age was 53 (34 - 72) years. 99 total cycles were completed, with a median of 2 (1-14) cycles per pt. During dose escalation, one pt at 0.65 mg/kg + A experienced a DLT of Grade 3 febrile neutropenia. Grade ≥ 3 treatment emergent AEs in ≥ 5% of all pts were immune-related AEs (irAEs) associated with laboratory findings suggestive of secondary hemophagocytic lymphohistiocytosis (HLH), anemia and hyponatremia (11.1% each), abdominal pain, fatigue and small intestinal obstruction (8.3% each), thrombocytopenia, ALT increased and hyperglycemia (5.6% each). Organ toxicities associated with the 4 cases of suspected HLH included fever and febrile neutropenia, myocarditis, encephalitis and pneumonitis; there was no clear correlation between RO exposure and these events. irAEs were observed in an additional 4 pts. AEs leading to treatment discontinuation were reported in 22.2% of pts, with suspected HLH being the most common AE (11.1%). A total of 15 deaths were reported in the study: 9 deaths due to progressive disease, and 6 deaths reported during long-term follow-up where the cause of death was reported as unknown. Two PRs were noted; one each at 0.30 mg/kg + A and at 0.45 mg/kg + A. 15 pts had SD and 14 pts had PD as best response. Median duration of disease control was 93 (95% CI 51-178) days. Response assessment of 5 pts was missing. Conclusions: While suspected HLH/HLH is rare for RO or A given as monotherapy, the safety profile of the combination was considered unacceptable as noted by the high frequency and severity of irAEs including suspected HLH. A limited anti-tumor activity was observed with PR as best overall response in 2 pts. The trial was terminated early due to the unfavorable risk-benefit profile. Citation Format: Stephanie Lheureux, Iben Spangaard, Erika Hamilton, George Au-Yeung, Debra Richardson, Mark DeMario, Emily Labriola-Tompkins, Barbara Brennan, Eveline Nueesch, Evelyne Chesne, Izolda Franjkovic, Katharina Lechner, Martin Kornacker, Geoffrey I. Shapiro. Dose-Finding/Expansion Phase Ib Study to Evaluate the Safety and Activity of BET Inhibitor RO6870810 (RO) and Atezolizumab (A) in Patients (pts) with Advanced Ovarian Cancer (OC) or Triple Negative Breast Cancer (TNBC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB104.

2502 Background: Human papillomavirus 16 (HPV16) is linked to several cancer types. Treatment options are limited for patients with HPV16 positive (HPV16+) recurrent or metastatic cancers. Generation and maintenance of HPV16+ malignant state require stable expression of HPV16-specific E7 and E6 oncoproteins, also a source of immunogenic neoantigens. HB-201 and HB-202 are replicating live-attenuated vectors based on lymphocytic choriomeningitis virus and Pichinde virus, respectively, which express the same non-oncogenic HPV16 E7E6 fusion protein to induce tumor-specific T-cell responses. This is a first-in-human phase 1/2 study of HB-201 monotherapy and HB-201 & HB-202 alternating 2-vector therapy. Dose escalation is ongoing with a 3+3 design. Methods: Phase 1 is assessing different regimens and dose levels of HB-201 monotherapy and HB-201 & HB-202 alternating 2-vector therapy given intravenously (IV) with or without an initial intratumoral administration. The patient population includes HPV16+ head and neck squamous cell carcinoma (HNSCC) and other HPV16+ cancers. Safety, tolerability, and preliminary antitumor activity by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 or immune RECIST are assessed. Results: As of Jan 2021, 25 patients with a median of 3 prior anticancer treatments have been enrolled. All had HPV16+ confirmed genotype; the most common primary site was oropharynx (72%). No dose-limiting toxicities were reported. Treatment-emergent adverse events (TEAEs) occurred in 21 patients (84%), were generally mild or moderate, with events related to study drug reported in 14 patients (56%). TEAEs reported in >10% of patients regardless of causality included fatigue, pyrexia, nausea, decreased appetite, anemia, arthralgia, chills, constipation, diarrhea, hypertension, influenza-like illness, pneumonia, and vomiting. Serious TEAEs developed in 6 patients (24%), including 1 with grade 5 hemorrhagic shock deemed unrelated to study drug. Grade 3 fatigue was the only serious or grade ≥3 TEAE assessed as related to study drug. TEAEs caused no treatment discontinuation. There were 18 patients evaluable for efficacy. For the 16 patients on HB-201 monotherapy, assessment of target lesions showed 2 partial responses (including 1 patient with an unconfirmed immune CR) and 6 patients had stable disease (SD). For the 2 patients on HB-201 & HB-202 alternating therapy, both had SD. So far, the longest duration of response was 4.8 months (144 days) and the maximum decrease in tumor diameter was 60%, both seen in HNSCC patients receiving HB-201 IV. Conclusions: HB-201 monotherapy and HB-201 & HB-202 2-vector alternating therapy were generally well-tolerated and showed preliminary antitumor activity as monotherapy in heavily pre-treated patients with HPV16+ HNSCC and other solid tumors. Clinical trial information: NCT04180215.

TPS5607 Background: XMT-1536 (upifitamab rilsodotin), is a first-in-class Dolaflexin ADC targeting NaPi2b, a sodium-dependent phosphate transport protein, broadly expressed in solid tumors such as serous epithelial ovarian cancer (OC) and non-small cell lung adenocarcinoma. XMT-1536 uses the Dolaflexin platform to deliver approximately 10 DolaLock auristatin payload molecules per antibody and is being evaluated in a Phase I study (NCT03319628). Observation of preliminary antitumor activity was reported in the ovarian cancer expansion cohort, including in patients previously treated with bevacizumab and PARPi (Tolcher et al, ASCO 2019; Richardson et al, ASCO 2019; Hamilton et al, ESMO 2020). Updated data on the OC cohort included 31 patients with higher NaPi2b expression as of December 2020 (Mersana Therapeutics, 2021). In these patients, the ORR was 32% and the DCR was 74%. Complete responses were observed in 2 patients with platinum-resistant ovarian cancer, both of whom had received prior treatment with bevacizumab and PARP inhibitors. Platinum resistant ovarian cancer remains a serious unmet medical need as treatment options are limited and response rates to these treatments are low. Based on the favorable safety and efficacy profile of XMT-1536, UPLIFT was designed as a Phase 2 single-arm registrational cohort of patients with platinum resistant ovarian cancer as part of the ongoing Phase I FIH dose escalation and expansion study to accelerate development and provide a streamlined pathway to regulatory review. Methods: The UPLIFT cohort is enrolling patients with platinum resistant high grade serous ovarian, fallopian tube and primary peritoneal cancer with up to 4 prior lines of therapy. The RP2D of XMT-1536 was determined to be 43 mg/m2 administered intravenously every 4 weeks (q4w) and will be the dose evaluated in the UPLIFT cohort. UPLIFT will enroll approximately 180 patients with platinum-resistant advanced ovarian cancer to obtain approximately 100 patients with higher NaPi2b expression. Prior bevacizumab is required for those patients with 1 or 2 prior lines of therapy. Tumor samples (fresh or archived) will be collected prior to enrollment for retrospective tumor tissue evaluation of NaPi2b expression. The primary objective is assessment of confirmed objective response rate to XMT-1536 as assessed by Investigator in patients with higher NaPi2b expression. Secondary endpoints include confirmed objective response rate regardless of NaPi2b expression, duration of response, and adverse events. Correlative aims include assessing blood and tissue biomarkers for association with clinical benefit. This study is being conducted in collaboration with ENGOT and GOG. Patients will be enrolled globally. Clinical trial information: NCT03319628.

5527 Background: Treatment options for patients with recurrent cervical and endometrial cancer remain limited. Even with optimum care, median survival has stalled at 12-17 months. The PARP inhibitor rucaparib has demonstrated activity in both BRCA wild-type and mutant cancers. Furthermore, preclinical studies suggest a synergistic effect of PARP inhibitors and antiangiogenic agents. We hypothesized that the combination of rucaparib and the VEGF inhibitor bevacizumab would yield a clinically-significant anti-cancer effect in patients with persistent or recurrent cervical or endometrial carcinoma. Methods: NCT03476798 is a phase II trial of adults with histologically-documented carcinoma of the cervix or endometrium. Patients with evaluable lesions who had undergone at least one prior line of systemic therapy, had adequate performance status and organ function, with a life expectancy of at least three months were eligible. Biopsies were obtained prior to treatment initiation for assessment of baseline tumor biomarkers, including ARID1A mutation status. Each cycle comprised 21 days. Rucaparib was administered orally at 600 mg, twice daily. Bevacizumab was administered by IV at 15 mg/kg on day 1 of each cycle. The primary objective was to estimate the proportion of patients with persistent or recurrent cervical or endometrial cancer who survive progression-free for at least six months (PFS6). Kaplan-Meier analysis was used to estimate progression-free survival. Results: There were 28 evaluable patients; six had cervical and 22 had endometrial cancer. Median age was 60.5 years (range, 30-74). Self-reported patient races were White (82.1%), Black (10.7%), and Native American (7.1%). Self-identified Hispanic or Latina patients comprised 3.6% of the cohort. Twenty-two of 28 patients had progressive disease by six months [survival distribution function estimate = 0.214 (lower CI, 0.087; upper CI, 0.378)]. Of the six patients who achieved PFS6, one had cervical and five had endometrial cancer. Six patients had a mutation in the ARID1A gene and those patients achieved PFS6 at a rate of 66.7%. Conclusions: The study hypothesis was evaluated in a two-stage design, and the interim analysis occurred once 28 evaluable patients were enrolled. In order to move on to the second stage, at least seven patients needed to remain progression-free at six months, but only six did. Thus, the study was ended after the interim analysis. The combination of rucaparib and bevacizumab did not provide the expected clinical benefit in this cohort of patients, but may warrant further exploration in patients with ARID1A mutations. Clinical trial information: NCT03476798.

5576 Background: Rebastinib is a first-in-class investigational, orally administered, potent and selective switch-control kinase inhibitor of tunica interna endothelial cell kinase (TIE2). This is a 2-part open-label, multicenter Phase 1b/2 study of rebastinib in combination with paclitaxel. Here we provide updated results (ASCO 2020) from the fully enrolled endometrial cancer (EC) cohort of the study. Methods: Part 2 of the study has five disease-specific cohorts (EC, platinum-resistant ovarian cancer, gynecological carcinosarcoma, TNBC and inflammatory breast cancer). Patients were treated at the RP2D and evaluated for efficacy (RECIST v1.1) and safety (CTCAE v5.0). Results: As of Jan 8, 2021, 38 EC patients were enrolled (median age of 66 years); 42% were of grade 2/3 endometroid histological subtype. All patients received at least 1 prior line of paclitaxel in combination with carboplatin and 79% of patients received ≥3 prior anti-cancer regimens. Sixteen of 38 patients were initially treated with a starting dose of rebastinib 100 mg BID, 11 of which dose reduced to 50 mg BID, and 22 patients were treated with a starting dose of rebastinib 50 mg BID, in combination with paclitaxel 80 mg/m2 IV weekly (days 1, 8, 15 of 28-day cycle). In 33 evaluable patients with median follow-up of 5.9 months, the ORR was 33% and clinical benefit rate at 8 and 16 weeks was 70% and 55%, respectively, including 11 PRs (8 confirmed) and 12 SDs. Treatment-emergent adverse events ( > 20% of patients; mostly ≤ grade 2) included fatigue (n = 18), constipation, peripheral edema (each at n = 16), peripheral sensory neuropathy, nausea (each at n = 15), dyspnea (n = 13), alopecia, hypokalemia (each at n = 11), diarrhea, hypomagnesemia (each at n = 10), dry mouth, dysgeusia (each at n = 9), arthralgia, hypertension, dehydration, GERD and muscular weakness (each at n = 8). Serious adverse events (SAE) at least possibly related to rebastinib included muscular weakness (n = 2 at 100 mg BID, n = 1 at 50 mg BID), nausea (n = 2), acute myocardial infarction, atrial flutter, dehydration, non-infective encephalitis, peritonsillitis, and stress cardiomyopathy (each at n = 1) and were resolved after dose interruption. Conclusions: The updated results of rebastinib at 50 mg BID in combination with paclitaxel showed encouraging preliminary anti-tumor activity and an acceptable safety profile in heavily pretreated EC patients, and supports further development in patients with EC (NCT03601897). Clinical trial information: NCT03601897.

Purpose Interstitial brachytherapy is an essential component of definitive treatment for locally advanced gynecological malignancies. Although many outpatient centers are capable of delivering the radiation component of brachytherapy, they are not associated with an operative center for implant placement, limiting the ability to deliver appropriate care. In this study, we report on our experience with noncolocated implant placement and radiation delivery, and the impact of patient stabilization improvements on patient safety. Methods and Materials Between 9/2010 and 11/2014, 25 patients with gynecologic malignancy underwent interstitial implantation and subsequent transport for high-dose-rate brachytherapy treatment. From 9/2010 to 10/2012, patients were transported using a standard ambulance stretcher; from 11/2012 to 11/2014, patients were placed on a patient positioning board or a WAFFLE support. Potential transport-associated toxicity was assessed, and the association between standard and augmented transport types and toxicity was analyzed. Results A total of 234 transports were performed. Median cost of transport was $150 per transport. There were 14 (10 patients) potential transportation-associated toxicities, including two lacerations/local trauma, three infections, and nine ulcers. There were 6 Grade 3 toxicities, all in the standard group. There was no association between stretcher type and laceration or ulcers, but enhanced support was associated with fewer overall toxicities, Grade 3 toxicities, and infections. Conclusions Noncolocated implantation and treatment is safe and facilitates optimal therapy. Toxicities potentially associated with transport are minimal and seem to be reduced by augmented stabilization. Understanding that this is a reasonable way to deliver brachytherapy may allow more stand-alone centers to deliver high-quality care for patients and improve gynecologic cancer outcomes in the United States.

78 Background: Overexpression of the cell-cell adhesion protein P-cadherin has been associated with a more aggressive cancer cell phenotype, cancer stem cell properties, tumor invasion and metastasis. We determined the safety and recommended Phase II dose of the yttrium-labeled P-cadherin-targeted 90Y-FF-21101 monoclonal antibody (mAb) in patients (pts) with advanced tumors, and focused our expansion study in advanced colorectal (CRC) and pancreatic-biliary cancers (non-CRC tumors). We report the safety, efficacy, and correlative pharmacokinetics (PK)/pharmacodynamics (PD) in this cohort. Methods: Pts enrolled must have progressed on all standard therapies. 25 mCi/m2 (8 mCi/mg mAb) 90Y-FF-21101 was administered intravenously every 12 weeks (wks) until disease progression or unacceptable toxicity. Disease response was assessed based on RECIST v1.1 every 8 wks (1 cycle = 28 days). Serum mAb PK, existence of anti-drug antibodies (ADA) and tumor P-cadherin expression were also evaluated. Results: 31 pts [mean age 63 (range, 39-89); 14F/17M; median number of prior therapies, 3 (range, 1-11)] with CRC (18) and non-CRC tumors [pancreatic (8), cholangiocarcinoma (3), duodenal (2)] received a median of 1 (range, 1-2) dose of 90Y-FF-21101. Median duration on study was 8.1 (3.9 – 27) wks (CRC) and 8 (1.1-17.1) wks (pancreatic-biliary). Myelosuppression was the most common treatment-related adverse event [thrombocytopenia (87%; Grade (Gr) 3/4 in 45%), lymphopenia (74%; Gr 3/4 in 61%), anemia (52%; Gr 3/4 in 13%), leukopenia (32%; Gr 3/4 in 16%)], in addition to fatigue (68%, 1 Gr 3) and nausea (39%, 1 Gr 3). Three pts required dose reduction to 20 mCi/m2 with subsequent infusion after Gr 3/4 thrombocytopenia [(pancreatic (2), CRC (1)]. The clinical benefit rate in pts with CRC based on stable disease (SD) for ≥8 wks is 43.8% (7/16 pts), with a median PFS of 8.1 wks and OS of 27 wks [median PFS, 7.9 wks; OS, 17.1 wks in non-CRC]. Longer-term SD was maintained in 2 pts with CRC for 17-24 wks; one continues on treatment. Enrollment is ongoing in the non-CRC cohort. FF-21101 has a mean t1/2 of approximately 65 hours, and post-treatment ADA titers have been observed in < 5% of pts. Tumor P-cadherin expression analysis by IHC demonstrated H-scores > 150 in 88% (14/16) of CRC pts, 75% (9/12) for non-CRC; 2 CRC pts with SD ≥17 wks had H-scores ≥190. Conclusions: 90Y-FF-21101 administered every 12 wks demonstrated expected toxicities and has been generally well-tolerated, with preliminary evidence of benefit demonstrated in heavily pre-treated pts with advanced CRC. The optimal dose and schedule for this radioimmunotherapeutic will continue to be explored, along with pre-treatment P-cadherin expression as a predictive biomarker for disease response. Clinical trial information: NCT02454010.