Platinum-resistant Ovarian Cancer Patients Research Articles

The efficacy, safety, and beneficiary population of angiogenesis inhibitor apatinib plus chemotherapy in recurrent platinum-resistant ovarian cancer patients: A comparative cohort study.

Angiogenesis inhibitor apatinib targets vascular endothelial growth factor receptors and improves the outcomes of patients with gynecologic malignancy. This study aimed to evaluate the efficacy and safety of angiogenesis inhibitor apatinib plus chemotherapy in recurrent platinum-resistant ovarian cancer (RPR-OC) patients. This study retrieved 67 RPR-OC patients who received apatinib plus chemotherapy or chemotherapy alone and divided them into apatinib + chemo (N = 30) and chemo alone (N = 37) groups according to the actual medication. Objective response rate (36.7% vs. 16.2%, p = 0.056) and disease control rate (80.0% vs. 59.5%, p = 0.072) showed an increased trend in apatinib + chemo group versus chemo alone group. The progression-free survival (PFS) (p = 0.010) and overall survival (OS) (p = 0.042) were prolonged in apatinib + chemo group versus chemo alone group. The median (95%confidence interval [CI]) PFS was 5.9 (5.5-6.3) months in apatinib + chemo group and 3.8 (2.0-5.6) months in chemo alone group. The median (95%CI) OS was 20.5 (16.5-24.5) months in apatinib + chemo group and 13.6 (8.6-18.6) months in chemo alone group. Apatinib plus chemotherapy was independently related with better PFS (hazard ratio [HR]: 0.354, p < 0.001) and OS (HR: 0.116, p < 0.001). Subgroup analyses indicated that patients with a more serious disease condition might benefit more from apatinib plus chemotherapy. No difference was found in adverse events of all grade or grade ≥3 between the two groups (all p > 0.05). Angiogenesis inhibitor apatinib plus chemotherapy shows better treatment efficacy than chemotherapy alone with controllable safety profile in RPR-OC patients.

Weekly BH009 in patients with squamous cell carcinoma of the head and neck (SCCHN) and ovarian cancer: Interim phase I results.

e17545 Background: BH009 is a novel polysorbate 80-free formulation of docetaxel that will eliminate hypersensitivity reactions associated with polysorbate 80. BH009 has completed a bioavailability study compared to Taxotere and was found to have a better safety profile to Taxotere with the potential for higher doses. As a result, we conducted a phase I dose escalation study to determine the maximum tolerated dose (MTD), and the safety profile of a weekly BH009 regimen in the treatment of patients with advanced SCCHN and Ovarian cancer. Methods: This phase I study assessed safety of BH009 in patients with advanced SCCHN and Ovarian cancer. BH009 was administered at escalating doses (starting dose 40 mg/m2) as a 1-h i.v. infusion for three consecutive weeks every 28 days without dexamethasone premedication. Results: Up to January 2024, 11 patients were treated with BH009 (4 at 40 mg/m2, 7 at 50 mg/m2). 2 patients with SCCHN, and 9 patients with ovarian cancer. 100% of ovarian cancer patients were recurrent platinum-resistant ovarian cancer (PROC) patients. 82% (9/11) of patients had received prior taxanes, of whom 33% (3/9) had received prior docetaxel. There were no DLT observed in 40 mg/m2 dose groups, and one DLT was observed in the 50 mg/m2 group (grade 3 febrile neutropenia). The MTD for BH009 is expected to exceed 50 mg/m2, which would be higher than that of Taxotere under the same dosing regimen (≥50mg/m2 vs 42mg/m2*), and the overall tolerability was better than Taxotere. In this study, treatment-related adverse events (TRAEs) occurred in 100% (11/11) patients. The most common grade 3/4 TRAEs were Leukopenia (36%, n=4), Anaemia (36%, n=4), and Neutropenia (55%, n=6). Non-hematologic toxicities were generally mild with no grade 4 toxicity observed. No AEs that led to death were related to BH009. Up to January 2024, the DCR is 50% (3/6) after 2 courses of treatment. The ORR in 6 evaluable patients was 33% (2/6, 1 patient with SCCHN at 40 mg/m2, 1 patient with ovarian cancer at 50 mg/m2). One patient (17%, 1/6) with ovarian cancer at 50 mg/m2 dose group received a complete response to the target lesion and the non-target lesion was partially responded after 2 courses of BH009, and this patient had been previously treated with docetaxel, carboplatin, and bevacizumab. Conclusions: The weekly BH009 for three consecutive weeks every 28 days is a feasible schedule with a favorable toxicity profile, and the overall tolerability is better than Taxotere. BH009 has the potential to increase the dose of administration and improve the clinical efficacy. Dose escalation is ongoing. Clinical trial information: NCT06232863 . [Table: see text]

Weekly BH009 in patients with squamous cell carcinoma of the head and neck (SCCHN) and ovarian cancer: Interim phase I results.

e17545 Background: BH009 is a novel polysorbate 80-free formulation of docetaxel that will eliminate hypersensitivity reactions associated with polysorbate 80. BH009 has completed a bioavailability study compared to Taxotere and was found to have a better safety profile to Taxotere with the potential for higher doses. As a result, we conducted a phase I dose escalation study to determine the maximum tolerated dose (MTD), and the safety profile of a weekly BH009 regimen in the treatment of patients with advanced SCCHN and Ovarian cancer. Methods: This phase I study assessed safety of BH009 in patients with advanced SCCHN and Ovarian cancer. BH009 was administered at escalating doses (starting dose 40 mg/m2) as a 1-h i.v. infusion for three consecutive weeks every 28 days without dexamethasone premedication. Results: Up to January 2024, 11 patients were treated with BH009 (4 at 40 mg/m2, 7 at 50 mg/m2). 2 patients with SCCHN, and 9 patients with ovarian cancer. 100% of ovarian cancer patients were recurrent platinum-resistant ovarian cancer (PROC) patients. 82% (9/11) of patients had received prior taxanes, of whom 33% (3/9) had received prior docetaxel. There were no DLT observed in 40 mg/m2 dose groups, and one DLT was observed in the 50 mg/m2 group (grade 3 febrile neutropenia). The MTD for BH009 is expected to exceed 50 mg/m2, which would be higher than that of Taxotere under the same dosing regimen (≥50mg/m2 vs 42mg/m2*), and the overall tolerability was better than Taxotere. In this study, treatment-related adverse events (TRAEs) occurred in 100% (11/11) patients. The most common grade 3/4 TRAEs were Leukopenia (36%, n=4), Anaemia (36%, n=4), and Neutropenia (55%, n=6). Non-hematologic toxicities were generally mild with no grade 4 toxicity observed. No AEs that led to death were related to BH009. Up to January 2024, the DCR is 50% (3/6) after 2 courses of treatment. The ORR in 6 evaluable patients was 33% (2/6, 1 patient with SCCHN at 40 mg/m2, 1 patient with ovarian cancer at 50 mg/m2). One patient (17%, 1/6) with ovarian cancer at 50 mg/m2 dose group received a complete response to the target lesion and the non-target lesion was partially responded after 2 courses of BH009, and this patient had been previously treated with docetaxel, carboplatin, and bevacizumab. Conclusions: The weekly BH009 for three consecutive weeks every 28 days is a feasible schedule with a favorable toxicity profile, and the overall tolerability is better than Taxotere. BH009 has the potential to increase the dose of administration and improve the clinical efficacy. Dose escalation is ongoing. Clinical trial information: NCT06232863 . [Table: see text]

Comparison of target agent treatment strategies for platinum-resistant recurrent ovarian cancer: A Bayesian network meta-analysis.

We aimed to compare 7 newer immunotherapies and targeted therapies for platinum-resistant relapsed ovarian cancer. We conducted a comprehensive search of PubMed, EMBASE, and Cochrane Library electronic databases for phase III trials involving platinum-resistant recurrent ovarian cancer (PRrOC) patients treated with immunotherapy or targeted therapy in combination with chemotherapy. The quality of the included trials was assessed using the GRADE method. The primary outcome of comparison was progression-free survival, and secondary outcomes included overall survival and safety. This analysis included 7 randomized phase III controlled trials, encompassing 2485 PRrOC patients. Combining bevacizumab plus chemotherapy and lurbinectedin demonstrated statistically significant differences in progression-free survival compared to all other regimens of interest. However, no statistically significant differences were observed in the overall survival. Nivolumab and mirvetuximab exhibited fewer serious adverse events than the other regimens of interest. Our findings indicate that bevacizumab combined with chemotherapy and lurbinectedin monotherapy has significant efficacy in patients with PRrOC. For patients with PRrOC who have exhausted treatment options, nivolumab and mirvetuximab may be considered as alternatives because of their better safety profiles.

Development of a Prognostic Risk Model Based on Oxidative StressRelated Genes for Platinum-Resistant Ovarian Cancer Patients.

Ovarian Cancer (OC) is a heterogeneous malignancy with poor outcomes. Oxidative stress plays a crucial role in developing drug resistance. However, the relationships between Oxidative Stress-related Genes (OSRGs) and the prognosis of platinum-resistant OC remain unclear. This study aimed to develop an OSRGs-based prognostic risk model for platinum-resistant OC patients. Gene Set Enrichment Analysis (GSEA) was performed to determine the expression difference of OSRGs between platinum-resistant and -sensitive OC patients. Cox regression analyses were used to identify the prognostic OSRGs and establish a risk score model. The model was validated by using an external dataset. Machine learning was used to determine the prognostic OSRGs associated with platinum resistance. Finally, the biological functions of selected OSRG were determined via in vitro cellular experiments. Three gene sets associated with oxidative stress-related pathways were enriched (p < 0.05), and 105 OSRGs were found to be differentially expressed between platinum-resistant and - sensitive OC (p < 0.05). Twenty prognosis-associated OSRGs were identified (HR: 0:562-5.437; 95% CI: 0.319-20.148; p < 0.005), and seven independent OSRGs were used to construct a prognostic risk score model, which accurately predicted the survival of OC patients (1-, 3-, and 5-year AUC=0.69, 0.75, and 0.67, respectively). The prognostic potential of this model was confirmed in the validation cohort. Machine learning showed five prognostic OSRGs (SPHK1, PXDNL, C1QA, WRN, and SETX) to be strongly correlated with platinum resistance in OC patients. Cellular experiments showed that WRN significantly promoted the malignancy and platinum resistance of OC cells. The OSRGs-based risk score model can efficiently predict the prognosis and platinum resistance of OC patients. This model may improve the risk stratification of OC patients in the clinic.

Abstract CT139: Immunological activity of oncolytic adenovirus encoding TNFα and IL-2 (TILT-123) in combination with pembrolizumab in platinum resistant or refractory ovarian cancer patients

Abstract Background TILT-123 (Ad5/3-E2F-D24-hTNFα-IRES-hIL-2) is a serotype chimeric dual safety device oncolytic adenovirus armed with tumor necrosis factor alpha and interleukin-2. It was designed to improve efficacy of T-cell therapies such as immune checkpoint blockade or adoptive cell transfer. We present biological and immunological endpoints from an open-label phase 1 dose escalation study of TILT-123 in combination with anti-PD-1 pembrolizumab in platinum resistant or refractory ovarian cancer patients. Experimental procedures In this dose escalation trial (NCT05271318), patients were first injected with an intravenous (i.v.) dose of TILT-123 ranging from 3x1011 to 4x1012 virus particles (VP), followed by five intratumoural (i.t.) or intraperitoneal (i.p.) injections ranging from 1x1011 to 5x1011 VP. Patients also received intravenous injections of 200 mg pembrolizumab every three weeks starting 36 days after the first dose of TILT-123. The primary endpoint was safety, while efficacy by RECIST1.1 was a secondary endpoint. Collection of tumor biopsies, circulating immune cells, serum, saliva, urine and feces enabled multi-omic evaluation of mechanism of action and identification of predictive biomarkers. Summary of data As of January 2nd 2024, 15 patients received trial therapy. No dose-limiting toxicities were observed and the most frequent AEs associated with therapy included chills and nausea (&amp;gt;10% of patients). Stable disease by RECIST 1.1 was seen in 67% in 12 evaluable patients. TILT-123 replication was detected in both injected and non-injected tumors as assessed by qPCR and anti-hexon IHC. Multiplex immunofluorescence demonstrated induction of robust immunological activity in both injected and non-injected tumors, including significant increase in granzyme B+, PD-1+ CD4+ and CD8+ T cells as well as PD-1+ NK cells. Baseline intratumoral CD4+, FOXP3+ regulatory T cells were not associated with clinical response. Tertiary lymphoid structures and lymphoid aggregates were identified in patients showing long term disease control. Low to medium titers of neutralizing antibodies against 5/3 chimeric adenovirus were detected in 57% of patients at baseline and were not a predictive factor of disease control. No patients had high titers at baseline. Conclusion TILT-123 in combination with anti-PD-1 pembrolizumab was safe and resulted in disease control in both platinum resistant and refractory ovarian cancer patients. Analysis of biological samples revealed insights into mechanism of action, including an immune profile predictive of clinical response. These results, together with those from four other trials (NCT04695327, NCT04217473, NCT06125197 and NCT05222932) set the stage for continued clinical evaluation of TILT-123. Citation Format: James H. Clubb, Matthew S. Block, Johanna Mäenpää, Santeri Pakola, Lyna Haybout, Dafne C. Quixabeira, Tatiana Kudling, Mirte van der Heijden, Elise Jirovec, Tuomo Alanko, Daniel A. Adamo, Susan Ramadan, Jorma Sormunen, Juha Kononen, Julia W. Cohen, Nadena Singh, John Goldfinch, Suvi Sorsa, Riikka Havunen, Claudia Kistler, João M. Santos, Víctor Cervera-Carrascon, Akseli Hemminki. Immunological activity of oncolytic adenovirus encoding TNFα and IL-2 (TILT-123) in combination with pembrolizumab in platinum resistant or refractory ovarian cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT139.

AUF1-induced circular RNA hsa_circ_0010467 promotes platinum resistance of ovarian cancer through miR-637/LIF/STAT3 axis.

Increasing evidences has indicated that primary and acquired resistance of ovarian cancer (OC) to platinum is mediated by multiple molecular and cellular factors. Understanding these mechanisms could promote the therapeutic efficiency for patients with OC. Here, we screened the expression pattern of circRNAs in samples derived from platinum-resistant and platinum-sensitive OC patients using RNA-sequencing (RNA-seq). The expression of hsa_circ_0010467 was validated by Sanger sequencing, RT-qPCR, and fluorescence in situ hybridization (FISH) assays. Overexpression and knockdown experiments were performed to explore the function of hsa_circ_0010467. The effects of hsa_circ_0010467 on enhancing platinum treatment were validated in OC cells, mouse model and patient-derived organoid (PDO). RNA pull-down, RNA immunoprecipitation (RIP), and dual-luciferase reporter assays were performed to investigate the interaction between hsa_circ_0010467 and proteins. Increased expression of hsa_circ_0010467 is observed in platinum-resistant OC cells, tissues and serum exosomes, which is positively correlated with advanced tumor stage and poor prognosis of OC patients. Hsa_circ_0010467 is found to maintain the platinum resistance via inducing tumor cell stemness, and silencing hsa_circ_0010467 substantially increases the efficacy of platinum treatment on inhibiting OC cell proliferation. Further investigation reveals that hsa_circ_0010467 acts as a miR-637 sponge to mediate the repressive effect of miR-637 on leukemia inhibitory factor (LIF) and activates the LIF/STAT3 signaling pathway. We further discover that AUF1 could promote the biogenesis of hsa_circ_0010467 in OC. Our study uncovers the mechanism that hsa_circ_0010467 mediates the platinum resistance of OC through AUF1/hsa_circ_0010467/miR-637/LIF/STAT3 axis, and provides potential targets for the treatment of platinum-resistant OC patients.

Phase 1/1b study of PRGN-3005 autologous UltraCAR-T cells manufactured overnight for infusion next day to advanced stage platinum resistant ovarian cancer patients.

5590 Background: Relapsed or refractory (r/r) ovarian cancer patients (pts) have limited treatment options. PRGN-3005 UltraCAR-T cells express a chimeric antigen receptor (CAR) targeting unshed MUC16, membrane bound IL-15 (mbIL15) and a kill switch with robust activity in preclinical models. UltraCAR-T investigational therapies are manufactured overnight using the proprietary UltraPorator electroporation system at the medical center and administered to patients one day after gene transfer. Methods: The Phase 1/1b study of PRGN-3005 evaluates the safety and recommended Phase 2 dose (RP2D) of PRGN-3005 in pts with r/r ovarian cancer (NCT03907527). In Phase 1, pts received PRGN-3005 without lymphodepletion (LD) via Intraperitoneal (IP) infusion (Cohort 1, C1) or Intravenous (IV) infusion (Cohort 2, C2) at Dose level 1-3. Dose level 3, IV infusion was further evaluated in pts treated with cyclophosphamide LD (60mg/kg/day on days -4 to -3 (IV LD)). As of the February 6, 2023 data cut-off, 25 evaluable pts have been treated in C1 (n = 12), C2 (n = 6), and IV LD (n = 7). Pts had a median age of 64 years (38-76) and were heavily pre-treated with a median of 8 prior regimens (4-11). Pts treated in C1 received 1 to 65.5 x 105 cells/kg, pts treated in C2 received 0.1 to 50 x 105 cells/kg and pts treated in IV LD received 0.1 to 39 x 105 cells/kg. Results: PRGN-3005 was well tolerated at up to 65.5 x 105 cells/kg. There have been no deaths, dose-limiting toxicities, neurotoxicity, grade ≥3 Cytokine Release Syndrome (CRS), or unexpected on-target/off-target toxicities related to PRGN-3005, and no use of the kill switch as of data cut-off. Grade 1 CRS occurred in 3/7 IV LD pts and one pt had transient grade 2 CRS, which resolved in &lt; 24 hours. Plasma levels of IL-15 did not increase with treatment confirming mbIL15 is not shed. A dose dependent increase in PRGN-3005 was observed in peripheral blood of patients even in the absence of LD, and i n vivo persistence of PRGN-3005 could be observed in some patients for up to 9 months post infusion. Response was evaluated per RECIST 1.1, and 20% of all subjects experienced a response in at least 1 target lesion. In the IV LD pts, the disease control rate (DCR) was 85.7% at first restaging, with a decreased target tumor burden in 4/7 (57%), and a 27.4% average decrease in CA125. One pt had a 28% decrease in target tumor burden after receiving a second infusion of PRGN-3005 after 12 months. Conclusions: PRGN-3005 UltraCAR-T targeting MUC16 has been well tolerated with minimal toxicity. PRGN-3005 demonstrated a dose-dependent expansion and persistence in blood with or without LD. Encouraging DCR rates and a reduction in overall tumor burden have been observed in heavily pretreated, ovarian cancer pts treated with LD. The study continues to enroll to the Phase 1b expansion phase and is treating pts at DL3 with LD with an option to receive a second dose. Clinical trial information: NCT03907527 .

Cost-effective analysis of rotational intraperitoneal aerosol chemotherapy (RIPAC) in patients with platinum-resistant ovarian cancer.

e17585 Background: We developed RIPAC, which improves distribution and penetration compared to pressurized intraperitoneal aerosol chemotherapy (PIPAC). To introduce this newly developed device in the real world, we analyzed the cost-effectiveness of rotational intraperitoneal aerosol chemotherapy (RIPAC) device to improve quality of life (QoL) compared to conventional palliative chemotherapy for platinum-resistant ovarian cancer patients. Methods: A decision tree was designed to compare the quality-adjusted life year (QALY) and cost consisting of RIPAC and palliative chemotherapy regimens, such as pegylated liposomal doxorubicin (PLD), gemcitabine (GEM), and topotecan (TOP). Also, to reflect the clinician’s variable preferred regimens for palliative chemotherapy, the average direct and indirect medical costs of belotecan, docetaxel, vinorelbine, and vinblastine were also considered in addition to the three regimens (ANY). The model included quality of life which was measured by European Organization for Research and Treatment of Cancer (EORTC)-Quality of life Questionnaire 30 (QLQ-C30) data gathered from previous clinical trial reports on PIPAC and palliative chemotherapy for recurrent ovarian cancer willingness-to-pay (WTP) threshold was set at US$40,000 per quality-adjusted life year saved. Results: To complete three cycles of palliative chemotherapy using PLD, GEM, TOP, and ANY, the total medical costs were US$15,267, US$9,013, US$16,144, and US$12,631, respectively, and the corresponding QALYs for each regimen were 0.633, 0.553, 0.783, and 0.65. Since RIPAC has not yet been introduced into the medical market, when the maximum RIPAC cost is calculated from ANY considering WTP, the cost of RIPAC excluding the ward, outpatient, and anesthesia-related costs among direct medical costs was estimated to be up to US$4,391. Conclusions: The cost-effective analysis results for the palliative treatment of recurrent ovarian cancer implied that RIPAC could be a cost-effective strategy to improve the QoL of platinum-resistant recurrent ovarian cancer patients.

Bevacizumab exposure and tumor response in patients with platinum resistant epithelial ovarian cancer.

3093 Background: There is a high unmet medical need for disease control in platinum resistant epithelial ovarian cancer patients (PROC). PemBOv trial (NCT03596281) showed promising results with the combination of pembrolizumab plus short-term flat dose bevacizumab with or without pegylated liposomal doxorubicin (PLD) based chemotherapy. However, overall, 20 % of pts showed trough levels for bevacizumab below the targeted threshold of plasma levels associated with efficacy. Based on the PemBOv data, the current analysis aimed to develop a pharmacometric model to characterize the tumor growth early kinetics and quantify the effect of treatment in the study cohorts. A focus was made on the association between bevacizumab exposure and tumor response. Methods: Tumor growth kinetic was studied to predict the clinical outcome. Population pharmacodynamic non-linear mixed-effects modeling approach was used to characterize tumor size evolution in patients. The Kkill parameter expressed as week-1 was defined to best describe the shrinkage in tumor size depending on the treatments. In addition, Exposure-Response relationships was performed to evaluate whether bevacizumab plasma levels were associated with the previously determined Kkill parameter. The exposure to bevacizumab was defined by the trough level at the second treatment cycle (PreC2, µg/ml). Results: A strong difference in Kkill values was found between cohort A (pembrolizumab plus PLD, n=6, Kkill = 0.00091 week-1) and either cohorts B (pembrolizumab + bevacizumab, n=19, Kkill = 0.002) and C (pembrolizumab + bevacizumab + PLD, n=19, Kkill = 0.02 week-1) respectively, whereas little difference was observed between cohorts B and C. This difference indicates higher tumor shrinkage in cohorts B and C as compared to cohort A. No clear Exposure-Response relationship was evidenced between bevacizumab plasma levels and tumor shrinkage. Still, in patients treated with bevacizumab plus pembrolizumab (cohorts B and C), mean bevacizumab exposure was higher in patients with an ORR and Stable disease of at least 4 months as compared with patients with no clinical benefit (i.e., 69.4 VS. 48 ug/ml). Association between bevacizumab levels and clinical outcome deserves further investigations. Because Kkill can be estimated in an early fashion through in silico modeling, this could be evaluated as a surrogate marker to forecast clinical outcome. Conclusions: Bevacizumab exposure correlated with ORR and clinical benefit in PROC patients treated with bevacizumab plus pembrolizumab plus minus PLD, since higher plasma trough levels were associated with better clinical outcome. The early Kkill in silico modeling could pave the way for the development of prediction models for personalized treatments of PROC patients. Clinical trial information: NCT03596281 .

Abstract 2153: Cyclin E1 protein overexpression sensitizes ovarian cancer cells to ZN-c3, a novel, selective and oral bioavailable inhibitor of Wee1

Abstract CCNE1 gene amplification is associated with overexpression of Cyclin E1 protein and is an important oncogenic driver. CCNE1 amplification is common in high grade serous ovarian carcinomas (HGSOC) and is associated with platinum resistance and poor patient outcomes. Importantly, Cyclin E1 overexpression can also occur in the absence of gene amplification in ovarian cancer. Overexpression of Cyclin E1 increases CDK2 activity and accelerates entry into S phase of cell cycle, resulting in replication stress and rendering cells more dependent on DNA repair. WEE1 participates in the DNA damage response by controlling essential checkpoints of the cell cycle, preventing cells from entering mitosis and allowing for DNA repair before cell cycle progression. Thus, we hypothesize that ovarian cancers overexpressing Cyclin E1, either via CCNE1 gene amplification or through other independent mechanisms, are more sensitive to WEE1 inhibition. Here, we tested this hypothesis in a range of preclinical cancer models using azenosertib, a novel, selective, and orally bioavailable WEE1 inhibitor currently in clinical development. Ovarian cancer cell lines overexpressing Cyclin E1 protein (Cyclin E1high) were more sensitive to azenosertib than ovarian cancer cell lines with lower levels of Cyclin E1 protein (Cyclin E1low) inducing significant cytotoxic effects (GRmax &amp;lt; -0.5). In Cyclin E1low ovarian cancer cell lines, overexpression of Cyclin E1 increased sensitivity to azenosertib. In contrast, silencing of CDK2 in Cyclin E1high cells reduced sensitivity to azenosertib. In vivo, higher levels of baseline expression of Cyclin E1 in tumor cells were associated with better response to azenosertib, with tumor growth inhibition (TGI) ranging from 51.5% in a Cyclin E1low SKOV3 model to 88% in a Cyclin E1high OVCAR3 model. Azenosertib synergized with chemotherapy agents in multiple ovarian cancer models. In vitro, we report that Cyclin E1high cancer cells were more sensitive to the combination of azenosertib and chemotherapeutics than Cyclin E1low cancer cells. In vivo, the synergy between azenosertib and paclitaxel was stronger in Cyclin E1high OVCAR3 model (46% reduction of initial tumor volume/104% TGI) than Cyclin E1low A2780 model (85% TGI). Taken together, these data suggest that Cyclin E1 overexpression via gene amplification or independent mechanisms sensitize ovarian cancer cells to azenosertib alone or in combination with chemotherapy. This observation supports the use of Cyclin E1 expression to enrich for azenosertib responders in ovarian cancer and possibly other tumor types. Two subsets of Cyclin E1-driven platinum resistant ovarian cancer patients, as defined by gene amplification or protein overexpression, are being enrolled in an azenosertib monotherapy trial. Citation Format: Jianhui Ma, Wen Liu, Heekyung Chung, Hooman Izadi, Petrus DeJong, Olivier Harismendy, Jia li, Fernando Doñate, Ahmed Samatar, Mark Lackner, Laure Escoubet, Kevin Bunker, Daehwan Kim, Nathan Jameson, Tugba Yildiran Ozmen, Kangjin Jeong, Dong Zhang, Wen-An Pan, Gordon Mills. Cyclin E1 protein overexpression sensitizes ovarian cancer cells to ZN-c3, a novel, selective and oral bioavailable inhibitor of Wee1 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2153.

BRCA mutation carriers suffering from ovarian cancer as a model for treatment decision in higher lines - Place for platinum reinduction.

Ovarian carcinoma is a malignancy with the highest mortality among gynecological cancers. Mutations in BRCA1/2 genes are believed to be a favorable prognostic factor and that, in general, the biological behavior of ovarian cancer in BRCA-positive individuals differs from others. However, some clinically relevant issues (i.e., prediction of response to chemotherapy and treatment of platinum-resistant BRCA-positive patients) remain unclear. (1) The aim of this study was to examine the prevalence of germline BRCA mutations in unselected recurrent ovarian cancer patient population, (2) analyze whether biological behavior of BRCA-positive tumors differs from others, and (3) analyze the effect of platinum reinduction in platinum-resistant BRCA-positive patients. This was a single-institution retrospective analysis. Consecutive recurrent ovarian cancer patients from years 2012 to 2020 were included; their BRCA1/2 mutational status was analyzed and correlated with progression-free survival (PFS), type of treatment, and response to treatment. Statistical significance of differences between and among patients was tested for continuous variables by the Mann-Whitney U-test or the Kruskal-Wallis test; a maximum likelihood Chi-square test was used for categorical variables. Two hundred and forty-three recurrent ovarian cancer patients were included. The median follow-up was 37 months. Pathogenic mutation in BRCA1 or BRCA2 gene was found in 18.1% of patients. There was no difference in PFS comparing BRCA-positive to BRCA-negative patients (median PFS: 10.2 vs. 10.1 months, P = 0.874); there was a difference in PFS comparing BRCA-negative versus BRCA-positive platinum-sensitive patients (9.4 vs. 14.3 months, P = 0.002). BRCA-positive platinum-resistant patients reinduced with platinum achieved a median PFS of 8 months (compared to those receiving nonplatinum treatment, median PFS: 4 months, P = 0.062). Germline BRCA mutations are not exclusive to platinum-sensitive ovarian cancer patients; even in platinum-resistant patients, mutation can be detected. We found no difference in PFS for platinum-sensitive BRCA-positive and BRCA-negative patients. Platinum reinduction may be considered for BRCA-positive platinum-resistant ovarian cancer patients to prolong PFS. Even these data describe only a small population, it supports the clinical practice of platinum-based chemotherapy use in platinum-resistant BRCA-positive patients.

574P Myriad MyChoice plus intermediate performance to discriminate platinum-resistant high-grade ovarian cancer patients

PARPi are indicated as maintenance therapy after 1st line chemotherapy, for patients (pts) with high-grade ovarian cancer (HGOC) in case of BRCA mutation, high genomic instability score (GIS), or objective response to platinum. Herein, GIS is required straight away, for all pts with HGOC to select the best maintenance strategy between bevacizumab, PARPi or both combined. Around 10% of HGOC are platinum-refractory with progressive disease during or within 4 weeks of last platinum, and additional 10% present no objective response (OR-) to platinum, and both are not eligible for PARPi.

GLS1 is a protective factor in patients with ovarian clear cell carcinoma and its expression does not correlate with ARID1A-mutated tumors.

Targeting glutamine metabolism has emerged as a novel therapeutic strategy for several human cancers, including ovarian cancer. The primary target of this approach is the kidney isoform of glutaminase, glutaminase 1 (GLS1), a key enzyme in glutamine metabolism that is overexpressed in several human cancers. A first-in-class inhibitor of GLS1, called CB839 (Telaglenastat), has been investigated in several clinical trials, with promising results. The first clinical trial of CB839 in platinum-resistant ovarian cancer patients is forthcoming. ARID1A-mutated ovarian clear cell carcinoma (OCCC) is a relatively indolent and chemoresistant ovarian cancer histotype. In OCCC-derived cells ARID1A simultaneously drives GLS1 expression and metabolism reprograming. In ARID1A-mutated OCCC-derived mouse models, loss of ARID1A corresponds to GLS1 upregulation and increases sensitivity to GLS1 inhibition. Thus, targeting of GLS1 with CB839 has been suggested as a targeted approach for OCCC patients with tumors harboring ARID1A-mutations. Here, we investigated whether GLS1 is differentially expressed between OCCC patients whose tumors are ARID1A positive and patients whose tumors are ARID1A negative. In clinical specimens of OCCC, we found that GLS1 overexpression was not correlated with ARID1A loss. In addition, GLS1 overexpression was associated with better clinical outcomes. Our findings have implications for human trials using experimental therapeutics targeting GLS1.

Clinical and molecular characteristics of AMBITION patients who received olaparib plus cediranib or olaparib plus durvalumab for homologous recombination repair mutated, platinum-resistant ovarian cancer (KGOG 3045) (032)

Objectives: AMBITION is a multi-center, open-label, five-arm, uncontrolled, umbrella trial in platinum-resistant ovarian cancer patients (NCT03699449). Here, we present an exploratory analysis of clinical and molecular characteristics associated with the benefit of two olaparib-based regimens in the homologous recombination repair (HRR) gene mutation cohort. Methods: Between December 2018 and October 2020, 30 patients who had mutations in HRR genes were randomized, and received either olaparib 200mg bid + cediranib 30mg QD (arm 1; n=16) or olaparib 300mg bid + durvalumab 1500mg q4w (arm 2; n=14). From the pre-treatment biopsy (n=22) and archival (n=8) tumor samples, next-generation whole-exome and whole-transcriptomic sequencing were conducted. We also evaluated tumor immunologic signatures, including the PD-L1 (SP263) assay and tumor-infiltrating lymphocytes (TILs). Clinical and molecular features were compared between responders and non-responders. Results: Arms 1 and 2 showed an acceptable objective response rate at 50.0% and 42.9%, respectively. The responders (n=14) had 12.4 months of a median duration of response. Overall, no differences in serum CA-125 levels, ECOG performance status, histologic subtype, prior lines of therapy, and last treatment-free interval were observed between the responders and non-responders. Intratumoral TILs and stromal TILs were also similar between the responders and non-responders. While all responders had BRCA1/2 mutations, 54.5% of non-responders had BRCA1/2 mutations. DNA damage repair pathways were enriched in the responders. Especially, enrichment of DNA mismatch repair and nucleotide excision repair pathways were associated with prolonged progression-free survival (PFS). In arm 1, cell cycle pathway enrichment significantly improved PFS (p=0.006), but PD-L1 expression did not. In arm 2, patients with PD-L1 ≥1% of tumor cells showed significantly better PFS than those with PD-L1 <1% (p=0.027), and the responders had a significantly higher level of myeloid-derived suppressor cell recruiting score than the non-responders (p=0.041). Objectives: AMBITION is a multi-center, open-label, five-arm, uncontrolled, umbrella trial in platinum-resistant ovarian cancer patients (NCT03699449). Here, we present an exploratory analysis of clinical and molecular characteristics associated with the benefit of two olaparib-based regimens in the homologous recombination repair (HRR) gene mutation cohort. Methods: Between December 2018 and October 2020, 30 patients who had mutations in HRR genes were randomized, and received either olaparib 200mg bid + cediranib 30mg QD (arm 1; n=16) or olaparib 300mg bid + durvalumab 1500mg q4w (arm 2; n=14). From the pre-treatment biopsy (n=22) and archival (n=8) tumor samples, next-generation whole-exome and whole-transcriptomic sequencing were conducted. We also evaluated tumor immunologic signatures, including the PD-L1 (SP263) assay and tumor-infiltrating lymphocytes (TILs). Clinical and molecular features were compared between responders and non-responders. Results: Arms 1 and 2 showed an acceptable objective response rate at 50.0% and 42.9%, respectively. The responders (n=14) had 12.4 months of a median duration of response. Overall, no differences in serum CA-125 levels, ECOG performance status, histologic subtype, prior lines of therapy, and last treatment-free interval were observed between the responders and non-responders. Intratumoral TILs and stromal TILs were also similar between the responders and non-responders. While all responders had BRCA1/2 mutations, 54.5% of non-responders had BRCA1/2 mutations. DNA damage repair pathways were enriched in the responders. Especially, enrichment of DNA mismatch repair and nucleotide excision repair pathways were associated with prolonged progression-free survival (PFS). In arm 1, cell cycle pathway enrichment significantly improved PFS (p=0.006), but PD-L1 expression did not. In arm 2, patients with PD-L1 ≥1% of tumor cells showed significantly better PFS than those with PD-L1 <1% (p=0.027), and the responders had a significantly higher level of myeloid-derived suppressor cell recruiting score than the non-responders (p=0.041).

Abstract CT506: Exposure-response analysis of batiraxcept and application to recommended phase 2 dose in platinum-resistant ovarian and clear cell renal cancers

Abstract Purpose: Batiraxcept is a novel Fc fusion protein that inhibits the growth arrest-specific (GAS)/AXL signaling pathway by binding the sole activating GAS6 ligand, which reduces AXL signaled invasion and migration of highly metastatic cells in vitro and inhibits metastatic disease in nonclinical models of aggressive human cancers. We used dose-exposure (D-E) and exposure-response (E-R) modeling and simulation to identify a recommended Phase 2 dose (RP2D). The D-E modeling is expected to apply to any cancer and batiraxcept combination, while the E-R modeling may be disease specific. Patients and Methods: A population pharmacokinetic (PK)/pharmacodynamic (PD) model was applied to exposure data from healthy volunteers (n=24, Phase (P) 1 study, single ascending dose cohort [NCT03401528]) and platinum-resistant ovarian cancer (PROC) patients (n=42, P1b study [NCT03639246]) treated with either batiraxcept+paclitaxel or batiraxcept+pegylated liposomal doxorubicin to capture the D-E relationship of batiraxcept. A Cox Proportional Hazards Model was applied to progression-free survival (PFS) observed from the PROC patients, to capture the E-R relationship of batiraxcept. The models were used to study PFS in prospective studies of 5, 10, 15, and 20 mg/kg administered iv once every 2 weeks at the 10th, 50th (median), and 90th percentile of expected exposure metrics. In a separate P1b study in 2L+clear cell renal cell carcinoma (ccRCC), 23 patients were dosed with 15mg/kg or 20mg/kg batiraxcept in combination with standard of care cabozantinib [NCT04300140]. PK, PD, and clinical response data from both doses tested in ccRCC were compared to the modeling predictions generated from the PROC study. Results: The PROC E-R analysis predicted that a dose of 15mg/kg would provide exposure levels associated with longer PFS, and a 20mg/kg dose did not add additional benefit. Fifteen mg/kg was identified as the RP2D from the PROC P1b study and is the batiraxcept dose being evaluated in combination with standard of care weekly paclitaxel in the ongoing PROC P3 study [NCT04729608]. PK and PD data from the ccRCC P1b study compare favorably with simulations from the PROC D-E model. Consistent with simulations from the PROC E-R analysis, the 20mg/kg dose did not provide additional benefit above that seen with the 15mg/kg dose in the ccRCC P1b study, indicating these doses are at the plateau of drug effect. Conclusion: Consistent with emerging U.S. Food and Drug Administration guidance around a more thoughtful approach to dose selection in cancer (“Project Optimus”), E-R analysis supported the identification of batiraxcept 15mg/kg as the RP2D in the PROC P1b study. Furthermore, PK/PD and preliminary activity of batiraxcept 15mg/kg+cabozantinib are consistent with these data and support the batiraxcept RP2D of 15mg/kg across different tumor types and combinations with batiraxcept. Citation Format: Gail Mcintyre, Reshma Rangwala, Michael G. Dodds, Olivier Barriere. Exposure-response analysis of batiraxcept and application to recommended phase 2 dose in platinum-resistant ovarian and clear cell renal cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT506.

PemBOv trial: Pembrolizumab plus bevacizumab with or without pegylated liposomal doxorubicin-based chemotherapy in patients with platinum-resistant ovarian cancer.

5575 Background: Few platinum resistant ovarian cancer (PROvC) patients respond to anti-PD1 monotherapy (ORR 7.6%) with little impact on survival (OS 10.1 mo). Among responders the median duration of response is impressive (18.7 mo) (Hamanishi 2021). Methods: We have evaluated the combination of pembrolizumab (200mg), with bevacizumab (400mg) for 6 cycles plus minus peglyated liposomal doxorubicin (PLD) q3w in PROvC patients with no limit in previous treatment lines, allowed to be previously treated with bevacizumab. An initial safety run evaluated the dual combination of pembrolizumab plus PLD (cohort A). The triple combination was evaluated at MTD-1 and at MTD of PLD (30mg/m2 q3w) (cohort C). The dual combination of pembrolizumab + bevacizumab was run in parallel (cohort B). This is an open label phase I trial with a modified toxicity probability interval design. The evaluation criteria endpoints were safety and efficacy. Pharmacokinetics of bevacizumab were evaluated. NCT03596281 Results: A total of 47 patients (pts) were enrolled between January 2019 and February 2021. Median age was 70 years (38-77). 30/12 pts (63.8/25.5%) had an initial FIGO stage III/IV, 44 pts (93.6%) had a HGSOC. 40 pts (85.1%) underwent surgery, out of which 13 pts (32.5%) had a primary debulking. BRCA mutations were present in 9 pts (19.1%). Pts had a median of 3 previous treatment lines (0-13), including pretreatment with antiangiogenic agents in 36 (76.6%) and PARP inhibitors in 21 pts (44.7%). No DLT was reported. Grade 3/4 treatment-related adverse events were reported in 2 pts (30%), 4 (20%) and 11 (50%) in cohorts A, B and C respectively. The ORR was 0, 26.3 (95% CI 6.5-46.1) and 30% (9.9-50.1) with a DCR of 0, 78.9 and 75% in cohorts A, B and C respectively. According to investigator assessment, the median PFS was 2.1, 4.7 and 4.8 mo (table). The blinded independent central review is currently under evaluation. A large inter-patient variability in bevacizumab plasma concentrations was observed among patients. The 400 mg flat dosing achieved residual concentrations similar to that of 5 mg/kg Q2W or 7.5 mg/kg q3w (51± 30 μg/ml in cohort B and 63 ± 55 μg/ml in cohort C (p&gt;0.05) after C1). Overall, 22 % of pts of cohort B and 18 % of cohort C showed trough levels below the targeted threshold (i.e. &lt; 25 μg/ml). Correlative studies are ongoing. Conclusions: Short-term flat dose bevacizumab potentiates the response to anti-PD1 therapy even in the absence of chemotherapy in heavily pre-treated PROvC patients. The long-term treatment with bevacizumab could potentially improve the outcome. The combination of anti-PD-1 plus anti-angiogenic agents should be a backbone for the treatment of PROvC patients. Clinical trial information: NCT03596281. [Table: see text]

A phase Ia/Ib study of CBP-1008, a bispecific ligand drug conjugate, in patients with advanced solid tumors.

3000 Background: Folate receptor α (FRα) and vanilloid subfamily member 6 of transient receptor potential channels (TRPV6) are overexpressed in many solid tumors hence could be promising therapeutic targets. CBP-1008 is a first-in-class bi-specific ligand drug targeting FRα and TRPV6 carrying monomethyl auristatin E (MMAE) as payload. Here we report the first-in-human, multicenter, phase Ia/Ib study designed to explore the safety, pharmacokinetics and efficacy of CBP-1008 in advanced solid tumors. Methods: CBP-1008 was administered by intravenous infusion. Phase Ia study included a dose-escalation period initiated by accelerated titration (0.015, 0.03mg/kg d1,15; q28d) and then switched to 3+3 scheme (0.12, 0.15, 0.17, 0.18mg/kg d1,15; q28d) and a dose expansion period. Phase Ib clinical expansion study included 3 cohorts, platinum-resistant ovarian cancer (OC), metastatic triple negative breast cancer (TNBC) and other solid tumors. The primary objective was to assess the safety and preliminary efficacy. Results: As of January 13, 2022, 106 patients received at least one dose of study drug were enrolled (phase Ia: n = 30; phase Ib: n = 76) and received median 3 prior regimens. Included tumor species were OC (n = 52), TNBC (n = 20), ER+/Her2+ breast cancer (BC) (n = 16), lung cancer (n = 3), pancreatic cancer (n = 2) and others (n = 13). In phase Ia study, DLTs were observed in 3 patients (0.12, 0.15, 0.18mg/kg, n = 1 each), including grade 4 hypophosphatemia, neutropenia, febrile neutropenia, and grade 3 hyperglycemia, alanine aminotransferase (ALT). MTD was not yet reached. Majority of adverse events were mild to moderate. The most common grade 3/4 treatment-emerging adverse events (TEAEs) were neutropenia (37.7%), AST elevation (6.6%), ALT elevation (5.7%), hyperglycemia (2.8%), hypohemoglobinemia (2.8%) and nausea (1.9%). Drug-related death was not observed. A total of 69 patients at dose of 0.15mg/kg or above were evaluable for efficacy assessment. There were 11 patients achieved partial response (PR) (OC n = 8, ER+/Her2+ BC n = 2, TNBC n = 1) and 30 patients achieved stable disease (SD). In 32 advanced platinum-resistant OC patients with FRα and/or TRPV6-positive expression, 6 PR and 16 SD were observed. Moreover, 6/18 PR (33.3%) and 8/18 SD (44.4%) were observed in enriched OC patients who showed high score of FRα/TRPV6 receptor. Conclusions: The preliminary results showed that CBP-1008 has manageable safety profile. Antitumor activity was observed in patients with FRα/TRPV6 receptor expression, especially in platinum-resistant OC cohort with high score of the two receptors. Clinical trial information: NCT04740398.

Immune characterization in platinum resistant ovarian cancer patients treated with pembrolizumab and guadecitabine

Abstract Immune checkpoint inhibitors (ICI) have limited activity in ovarian cancer (OC). Accumulating preclinical and early clinical results support that interventions targeting the epigenome could elicit an inflamed tumor milieu to augment ICI. Here we explore the clinical and biological activity of guadecitabine, a second generation Hypomethylating agents (HMA), given in low dose as a priming strategy before pembrolizumab, a humanized anti-PD1 antibody in a clinical trial for patients with recurrent, platinum-resistant OC. Among 35 evaluable patients, there were 3 partial responses (8.6%) and 8 (22.9%) patients with stable disease, resulting in clinical benefit rate (CBR) of 31.4%. Median duration of clinical benefit was 6.8 months. High dimensional immune profiling of PBMCs showed higher frequency of naive and/or central memory CD4+ T cells and of classical monocytes in patients with durable CBR. Higher baseline density of CD8+ T and CD20+ B cells and presence of tertiary lymphoid structures in tumors were associated with durable CBR. The molecular features such as expression levels of PD-L1 or A2AR linked to therapeutic benefit for resistant OC. Our study provides an in-depth view of the immune milieu of platinum resistant OC and of the effects of the combination of HMAs and pembrolizumab on the interactions between immune cell populations and tumor cells. Supported by USAMRMC/CDMRP (W81XWH170141)

An effective AKT inhibitor-PARP inhibitor combination therapy for recurrent ovarian cancer

BackgroundAlthough the use of PARP inhibitor has received considerable amount of attention in ovarian cancer, PARP inhibitor resistance still emerges with disease progression. PI3K/AKT pathway inhibitors have been proposed to synergize with PARP inhibition to slow tumor growth, but the exact molecular mechanisms are still elusive.MethodsUtilizing tumor samples from recurrent EOC patients with platinum resistance and prior PARP inhibitor use, Mini PDX and PDX models were established to study the anti-tumor effect of AKT inhibitor (LAE003) and LAE003/PARP inhibitor (Olaparib) in combination. Five ovarian cancer cell lines were treated with Olaparib or LAE003 or in combination in vitro. Cell viability and apoptosis rate were measured after the treatments. Combination index by the Chou–Talalay was used to evaluate in vitro combination effect of Olaparib and LAE003. The protein expression level of PARP1 and PAR was measured by Western blot in cell lines and by immunohistochemistry in PDX tumor tissues.ResultsTumor cells from two out of five platinum-resistant ovarian cancer patients previously treated with PARP inhibitor were sensitive to AKT inhibition in Mini-PDX study. Inhibition of AKT further increased the response of tumor cells to Olaparib in a PDX model derived from a recurrent platinum-resistant ovarian cancer patient. Additive anti-proliferation effect of LAE003 and Olaparib was also observed in three ovarian cancer cell lines with high PARP1 protein level. Interestingly, mechanism study revealed that AKT inhibition decreased PARP enzyme activity as measured by PAR level and/or reduced PARP1 protein level in the tumor cell lines and PDX tumor tissues, which may explain the observed combined anti-tumor effect of LAE003 and Olaparib.ConclusionCollectively, our results suggest that the combination of AKT inhibitor and PARP inhibitor could be a viable approach for clinical testing in recurrent ovarian cancer patients.