Platinum-resistant Ovarian Carcinoma Research Articles

The CHK1 inhibitor prexasertib in BRCA wild-type platinum-resistant recurrent high-grade serous ovarian carcinoma: a phase 2 trial

The multi-cohort phase 2 trial NCT02203513 was designed to evaluate the clinical activity of the CHK1 inhibitor (CHK1i) prexasertib in patients with breast or ovarian cancer. Here we report the activity of CHK1i in platinum-resistant high-grade serous ovarian carcinoma (HGSOC) with measurable and biopsiable disease (cohort 5), or without biopsiable disease (cohort 6). The primary endpoint was objective response rate (ORR). Secondary outcomes were safety and progression-free survival (PFS). 49 heavily pretreated patients were enrolled (24 in cohort 5, 25 in cohort 6). Among the 39 RECISTv1.1-evaluable patients, ORR was 33.3% in cohort 5 and 28.6% in cohort 6. Primary endpoint was not evaluable due to early stop of the trial. The median PFS was 4 months in cohort 5 and 6 months in cohort 6. Toxicity was manageable. Translational research was an exploratory endpoint. Potential biomarkers were investigated using pre-treatment fresh biopsies and serial blood samples. Transcriptomic analysis revealed high levels of DNA replication-related genes (POLA1, POLE, GINS3) associated with lack of clinical benefit [defined post-hoc as PFS < 6 months]. Subsequent preclinical experiments demonstrated significant cytotoxicity of POLA1 silencing in combination with CHK1i in platinum-resistant HGSOC cell line models. Therefore, POLA1 expression may be predictive for CHK1i resistance, and the concurrent POLA1 inhibition may improve the efficacy of CHK1i monotherapy in this hard-to-treat population, deserving further investigation.

Abstract B039: A phase 1/2 study of dendrimer-enhanced (DEP) SN38 (SN38-SPL9111/DEP irinotecan) in patients with advanced solid tumours

Abstract Background: Dendrimers are highly branched nanoparticles that achieve significant tumor targeting of cytotoxic drugs. DEP SN38 (or DEP irinotecan) is a highly optimised dendrimer conjugate of the irinotecan active metabolite, SN38. We report initial results of a phase 1/2 trial evaluating the safety, tolerability and preliminary efficacy of DEP SN38 in patients (pts) with advanced solid tumors, including colorectal (CRC) and platinum-resistant high-grade serous ovarian carcinoma (HGSOC). Methods: Solid tumor pts who had exhausted standard therapy were enrolled (EudraCT2019-001318-40). DEP SN38 given IV 3-weekly (Q3W) was escalated to identify a recommended phase 2 dose (RP2D). Additional dose assessment/expansion cohorts followed at Q3W or Q2W (2-weekly) alone or in combination with 5-fluorouracil and leucovorin (5FU/LV). Efficacy was assessed via RECIST 1.1 criteria and serum tumor biomarkers. Results: Dose escalation (N=7) confirmed a Q3W RP2D of 12.5 mg/m2 SN38 with 1 pt having a dose limiting toxicity (DLT) of grade 4 neutropenia for &amp;gt;7d. Following successful dose expansion, additional dose exploration confirmed a Q2W RP2D of 12.5 mg/m2 SN38 alone or in combination with 5FU/LV. DEP SN38 was well-tolerated for all dose regimens (N=101) with mostly mild/moderate treatment-related adverse events (TRAEs), with no new events compared to those observed with conventional irinotecan. Notably, there were no reports of severe (≥ grade 3) diarrhea with DEP SN38 and no reports of cholinergic symptoms, both being common with conventional irinotecan (~20% and 47% pts, respectively). Moreover, with DEP SN38, severe nausea (2.2% pts) and vomiting (1.1% pts) occurred less frequently than with irinotecan (both ~10% pts).  While febrile neutropenia was observed as a DLT at 15 mg/m2 Q2W monotherapy (2 pts), neutropenia was otherwise uneventful and managed with G-CSF.CRC pts: 38 heavily pre-treated CRC pts were dosed (N=31 evaluable); pts had an average ~4 prior treatment lines with 97% having received at least 1 irinotecan containing line. DEP SN38 achieved a disease control rate (DCR) of 48%, with stable disease up to 72 weeks.HGSOC pts: 23 platinum-resistant HGSOC pts were dosed (N=18 evaluable); pts had received an average ~6 prior treatment lines. DCR for pts dosed Q2W was 100% with 33.3% objective response rate, and 72% DCR for all HGSOC pts. There were 3 partial responses (PR), for up to 27 wks with 1 pt achieving complete tumour and ascites resolution with pts ongoing. 75% of pts achieved CA-125 reductions of up to 98% vs baseline. For DEP SN38 in combination with 5FU/LV, in a cohort of mainly CRC pts (N=6), DCR is 100% including 1 PR, with pts ongoing. Conclusions: DEP SN38 was very well-tolerated with significantly fewer severe gastrointestinal TRAEs compared to conventional irinotecan. Encouraging anti-tumour activity, including prolonged disease control in heavily pre-treated CRC and HGSOC pts, demonstrates promising clinical utility of DEP SN38, both as a monotherapy and as a combination therapy. Recruitment is ongoing. Citation Format: Jia Liu, Anna R Minchom, Alastair Greystoke, Thomas R J Evans, Debashis Sarker, Anthony M Joshua, Cienne Morton, Aisha Gaus, Wing Yau, Rasha Cosman, Dominika Chwialkowska, Jeremy R A Paull, Bernadette M Jean-Francois, Jacinth K Fairley, Nicola J Main, Stephanie R Edmondson, Natalie Cook. A phase 1/2 study of dendrimer-enhanced (DEP) SN38 (SN38-SPL9111/DEP irinotecan) in patients with advanced solid tumours [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B039.

Efficacy and safety of albumin-bound paclitaxel and anlotinib in patients with recurrent platinum-resistant epithelial ovarian, fallopian tube, or peritoneal carcinoma (A-Plus trial): A prospective phase II study (178)

Efficacy and safety of albumin-bound paclitaxel and anlotinib in patients with recurrent platinum-resistant epithelial ovarian, fallopian tube, or peritoneal carcinoma (A-Plus trial): A prospective phase II study (178)

Retracted: Effect of PARP Inhibitor Combined with Bevacizumab on Platinum-Resistant Recurrent Ovarian Epithelial Carcinoma.

[This retracts the article DOI: 10.1155/2022/4600145.].

Single-cell RNA-sequencing analysis reveals divergent transcriptome events between platinum-sensitive and platinum-resistant high-grade serous ovarian carcinoma.

Tumor resistance is one of the main reasons leading to the failure of ovarian cancer treatment. Overcoming platinum resistance remains the greatest challenge in the management of high-grade serous ovarian carcinoma (HGSC). Small conditional RNA-sequencing is a powerful method for exploring the complexity of the cellular components and their interactions in the tumor microenvironment. We profiled the transcriptomes of 35,042 cells from two platinum-sensitive and three platinum resistance HGSC clinical cases downloaded from Gene Expression Omnibus (GSE154600) and annotated tumor cells as platinum-resistant or sensitive based on the clinical trait. The study systematically investigated the inter-tumoral (using differential expression analysis, CellChat, and SCENIC) and intra-tumoral heterogeneity (using enrichment analysis such as gene set enrichment analysis, as well as gene set variation analysis, weighted gene correlation network analysis, and Pseudo-time analysis) of HGSC. A cellular map of HGSC generated by profiling 30,780 cells was revisualized using Uniform Manifold Approximation and Projection. The inter-tumoral heterogeneity was demonstrated with intercellular ligand-receptor interactions of major cell types and regulons networks. FN1, SPP1, and COLLAGEN play important roles in the cross-talk between tumor cells and the tumor microenvironment. HOXA7, HOXA9_extended, TBL1XR1_extended, KLF5, SOX17, and CTCFL regulons consistent with the distribution of platinum-resistant HGSC cells were the high activity regions. The intra-tumoral heterogeneity of HGSC was presented with corresponding functional pathway characteristics, tumor stemness features, and the cellular lineage transition from platinum-sensitive to resistant condition. Epithelial-mesenchymal transition played an important role in platinum resistance, whereas oxidative phosphorylation was the opposite. There was a small subset of cells in platinum-sensitive samples that had transcriptomic characteristics similar to platinum-resistant cells, suggesting that the progression of platinum resistance in ovarian cancer is inevitable. The present study describes a view of HGSC at single-cell resolution that reveals the characteristics of the HGSC heterogeneity and provides a useful framework for future investigation of platinum-resistant.

Efficacy and Safety of Weekly Paclitaxel Plus Vistusertib vs Paclitaxel Alone in Patients With Platinum-Resistant Ovarian High-Grade Serous Carcinoma

Patients with platinum-resistant or refractory ovarian high-grade serous carcinoma (PR-HGSC) have a poor prognosis and few therapeutic options. Preclinical studies support targeting PI3K/AKT/mTOR signaling in this setting, and a phase 1 study of the dual mTORC1/mTORC2 inhibitor vistusertib with weekly paclitaxel showed activity. To evaluate whether the addition of vistusertib to weekly paclitaxel improves clinical outcomes in patients with PR-HGSC. This phase 2, double-blind, placebo-controlled multicenter randomized clinical trial recruited patients from UK cancer centers between January 2016 and March 2018. Patients with PR-HGSC of ovarian, fallopian tube, or primary peritoneal origin and with measurable or evaluable disease (Response Evaluation Criteria in Solid Tumors version 1.1 and/or Gynecological Cancer Intergroup cancer antigen 125 criteria) were eligible. There were no restrictions on number of lines of prior therapy. Data analysis was performed from May 2019 to January 2022. Patients were randomized (1:1) to weekly paclitaxel (80 mg/m2 days 1, 8, and 15 of a 28-day cycle) plus oral vistusertib (50 mg twice daily) or placebo. The primary end point was progression-free survival in the intention-to-treat population. Secondary end points included response rate, overall survival, and quality of life. A total of 140 patients (median [range] age, 63 [36-86] years; 17.9% with platinum-refractory disease; 53.6% with ≥3 prior therapies) were randomized. In the paclitaxel plus vistusertib vs paclitaxel plus placebo groups, there was no difference in progression-free survival (median, 4.5 vs 4.1 months; hazard ratio [HR], 0.84; 80% CI, 0.67-1.07; 1-sided P = .18), overall survival (median, 9.7 vs 11.1 months; HR, 1.21; 80% CI, 0.91-1.60) or response rate (odds ratio, 0.86; 80% CI, 0.55-1.36). Grade 3 to 4 adverse events were 41.2% (weekly paclitaxel plus vistusertib) vs 36.7% (weekly paclitaxel plus placebo), and there was no difference in quality of life. In this randomized clinical trial of weekly paclitaxel and dual mTORC1/2 inhibition in patients with PR-HGSC, vistusertib did not improve clinical activity of weekly paclitaxel. isrctn.org Identifier: ISRCTN16426935.

5P Physiologically relevant treatment models to investigate epigenetic mechanisms driving platinum resistance in ovarian high grade serous carcinoma

The prognosis for patients with platinum-resistant ovarian High Grade Serous Carcinoma (HGSC) remains poor. BriTROC-1 data indicate that genomic alterations alone cannot explain acquired platinum resistance. We investigate epigenetic changes that may drive platinum resistance in HGSC. Using in an in vitro two-dimensional model, we recreated multiple cycles of chemotherapy. We utilised both established cell lines and primary cultures derived from HGSC ascites. Following cell characterisation (p53, PAX8 IHC), carboplatin sensitivity was assessed (sulforhodamine B assay). Cells were then pulsed with four cycles of carboplatin (50μM for 6 hours) with a week of recovery between each cycle. Methylation (Illumina 850k array), transcriptomic (RNAseq) and chromatin accessibility (ATACseq) assays were performed. Cells were also imaged using Stochastic Optical Reconstruction Microscopy. Firstly, we focused on RNAseq analysis to evaluate genes (and related biological processes) that are consistently enriched following carboplatin cycles and the unique genes that are conversely enriched at cycle level. We attempted to identify uniformly up-/down-regulated pathways across the different cultures. These data were compared with the same results obtained from the OvCar4, an established HGSC cell line and IVR01, an in-vivo resistant OvCar4 derivative. The ATACseq and methylation analyses are still ongoing, aiming to identify possible concordant changes in the chromatin accessibility and the methylation patterns that will allow us to clarify the changes observed in transcriptomic. The preliminary data obtained from the RNAseq analysis show that the highest number of enriched genes seems to occur after the first Carboplatin cycle, with a lower number of progressively enriched genes across all other ones. No constant biological processes were identified for the moment, across the different primary cell cultures. Further comparisons will be certainly needed. Understanding the epigenetic landscape of HGSC using physiologically relevant models will allow us to identify possible therapeutic targets that could eventually prevent platinum resistance.

Patient self-reporting of tolerability using PRO-CTCAE in a randomized double-blind, placebo-controlled phase II trial comparing gemcitabine in combination with adavosertib or placebo in patients with platinum resistant or refractory epithelial ovarian carcinoma

BackgroundA double-blind, randomized, placebo-controlled, phase 2 trial assessed gemcitabine in combination with the wee1 inhibitor adavosertib or placebo in platinum resistant or refractory high grade serous ovarian cancer (HGSOC), demonstrating improved progression free and overall survival favouring the adavosertib/gemcitabine arm. An exploratory objective of the study included the PRO-CTCAE assessment, to capture self-reporting of frequency, severity and/or interference of symptomatic adverse events (syAEs). MethodsPRO-CTCAE items at baseline, days 1 and 15 of each cycle and off treatment, were completed in two centres, with the objective of characterizing syAEs in the first three months of therapy. The maximum post-baseline score proportion for each syAE was tabulated per patient. The 12-week area under the curve (AUC12w) as a measure of syAE over-time and incremental AUC12w (iAUC12w) for adjustment to baseline syAEs. ResultsSixty-one patients were approached for PRO-CTCAE surveys and 55 were evaluable. Among patients with HGSOC, 28 received gemcitabine/adavosertib (arm A) and 19 gemcitabine/placebo (arm B). Survey completion rates were high. The proportion of participants with positive (≥1) PRO-CTCAE scores was higher for difficulty swallowing with gemcitabine/adavosertib (arm A 35.7% vs arm B 5.3%, p = 0.02). The high score (≥3) syAEs showed more frequent diarrhea with gemcitabine/adavosertib (arm A 25% vs arm B 0%, p = 0.03). The proportions of worsening syAEs over time were higher in patients receiving gemcitabine/adavosertib for difficulty swallowing (arm A 35.7% vs arm B 5.3%; p = 0.03) and fatigue severity (arm A 71.43% vs arm B 42.1%; p = 0.04). ConclusionsThe longitudinal assessment of patient self-reported tolerability showed greater difficulty swallowing and fatigue severity in patients receiving gemcitabine/adavosertib, compared to gemcitabine/placebo. PRO-CTCAE provides complementary and objective assessment of drug tolerability from a patient's perspective.

Anlotinib in patients with recurrent platinum-resistant or platinum-refractory ovarian carcinoma: A prospective, single-center, single-arm, phase II clinical trial (033)

Objectives: Patients with platinum-resistant recurrent ovarian cancer lack effective treatment. This phase II study (ChiCTR2000029654) was conducted to evaluate the efficacy and safety of anlotinib, a new multi-tyrosine kinase inhibitor (TKI) for tumor angiogenesis and proliferative signaling, monotherapy in patients with platinum-resistant or refractory ovarian carcinoma (OC). We presented the updated progression-free survival (PFS), objective response rate (ORR), and safety data in more patients. Methods: Patients who had histologically confirmed high-grade serous gonadal ovarian cancer (including salpingo carcinoma and peritoneal carcinoma), had experienced disease progression during or within six months of discontinuation, received at least two lines of platinum-based chemotherapy, or previously received second-line or more chemotherapy, were eligible for the study. No prior targeted therapy and intraperitoneal radiotherapy, and ECOG PS 0-2 were required for enrollment. Patients had at least one lesion (measurable and/or nonmeasurable) that could be accurately assessed at baseline by computed tomography/magnetic resonance imaging. Patients received anlotinib 12mg orally once daily (d1-14; 21 days per cycle) until disease progression, death, unacceptable toxicity, or consent withdrawal. Therapeutic effects were evaluated every six weeks. The primary endpoint was ORR and the secondary endpoints included disease control rate (DCR), progression-free survival (PFS), and overall survival (OS) by RECIST 1.1. Results: From March 2019 to April 2021, 31 patients (female) with a median age of 59 years (range: 39-73), FIGO histopathological stage IC (1, 3.5%), IIC (2, 6.9%), IIIC (20, 69.0%) and IV (6, 20.7%) were enrolled. Twenty-seven of these patients were evaluable. In the efficacy-evaluable population (n=27), the therapeutic evaluation showed that complete response, partial response, stable disease, and progressive disease was 3.7%, 22.22%, 40.74%, and 33.33%, respectively, yielding the ORR of 25.9% (7/27; 95% CI: 11.1-46.3).The DCR was 66.7% (18/27; 95% CI: 46.0-83.5). The median PFS was 5.32 months (95% CI: 4.31-6.33). The median OS was not reached. The most common adverse events (AEs) were grade 1 or 2, which included hypertension (41.94%), fatigue (22.58%), hand-foot syndrome (29.03%), gingival bleeding (4.76%), hand-foot syndrome (4.76%), renal dysfunction (4.76%) and cancer pain (4.76%). The grade 3 AEs only included myocardial infarction (4.76%) and urine occult blood (4.76%). No higher AEs and treatment-related death were observed. Conclusions: Anlotinib showed an encouraging antitumor activity for patients with recurrent platinum-resistant or refractory ovarian carcinoma. Adverse events were consistent with the established safety profiles of anlotinib. We will report more data in the future. Objectives: Patients with platinum-resistant recurrent ovarian cancer lack effective treatment. This phase II study (ChiCTR2000029654) was conducted to evaluate the efficacy and safety of anlotinib, a new multi-tyrosine kinase inhibitor (TKI) for tumor angiogenesis and proliferative signaling, monotherapy in patients with platinum-resistant or refractory ovarian carcinoma (OC). We presented the updated progression-free survival (PFS), objective response rate (ORR), and safety data in more patients. Methods: Patients who had histologically confirmed high-grade serous gonadal ovarian cancer (including salpingo carcinoma and peritoneal carcinoma), had experienced disease progression during or within six months of discontinuation, received at least two lines of platinum-based chemotherapy, or previously received second-line or more chemotherapy, were eligible for the study. No prior targeted therapy and intraperitoneal radiotherapy, and ECOG PS 0-2 were required for enrollment. Patients had at least one lesion (measurable and/or nonmeasurable) that could be accurately assessed at baseline by computed tomography/magnetic resonance imaging. Patients received anlotinib 12mg orally once daily (d1-14; 21 days per cycle) until disease progression, death, unacceptable toxicity, or consent withdrawal. Therapeutic effects were evaluated every six weeks. The primary endpoint was ORR and the secondary endpoints included disease control rate (DCR), progression-free survival (PFS), and overall survival (OS) by RECIST 1.1. Results: From March 2019 to April 2021, 31 patients (female) with a median age of 59 years (range: 39-73), FIGO histopathological stage IC (1, 3.5%), IIC (2, 6.9%), IIIC (20, 69.0%) and IV (6, 20.7%) were enrolled. Twenty-seven of these patients were evaluable. In the efficacy-evaluable population (n=27), the therapeutic evaluation showed that complete response, partial response, stable disease, and progressive disease was 3.7%, 22.22%, 40.74%, and 33.33%, respectively, yielding the ORR of 25.9% (7/27; 95% CI: 11.1-46.3).The DCR was 66.7% (18/27; 95% CI: 46.0-83.5). The median PFS was 5.32 months (95% CI: 4.31-6.33). The median OS was not reached. The most common adverse events (AEs) were grade 1 or 2, which included hypertension (41.94%), fatigue (22.58%), hand-foot syndrome (29.03%), gingival bleeding (4.76%), hand-foot syndrome (4.76%), renal dysfunction (4.76%) and cancer pain (4.76%). The grade 3 AEs only included myocardial infarction (4.76%) and urine occult blood (4.76%). No higher AEs and treatment-related death were observed. Conclusions: Anlotinib showed an encouraging antitumor activity for patients with recurrent platinum-resistant or refractory ovarian carcinoma. Adverse events were consistent with the established safety profiles of anlotinib. We will report more data in the future.

Effect of PARP Inhibitor Combined with Bevacizumab on Platinum-Resistant Recurrent Ovarian Epithelial Carcinoma.

Objective This study was aimed at investigating the efficacy of PARP inhibitor combined with bevacizumab in the treatment of platinum-resistant recurrent ovarian epithelial carcinoma. Methods A total of 84 patients with platinum-resistant recurrent ovarian epithelial carcinoma treated in our hospital from May 2017 to June 2018 were selected as the research objects. The patients were divided into observation group (n = 42) and control group (n = 42) according to random number table method. The observation group was treated with olaparib combined with bevacizumab, while the control group was treated with albumin-bound paclitaxel combined with bevacizumab, and the clinical efficacy of the two groups was observed. The levels of serum carbohydrate antigen 125 (CA125), carbohydrate antigen 199 (CA199), and epididymal protein 4 (HE4) were determined. The levels of miRNA124, mirNA-21, and miRNA-203 in the two groups were detected. The incidence of adverse reactions was compared between the two groups. The quality of life of the two groups was assessed using FACT-G scale. The drug safety of the two groups was observed. All patients were followed up for 3 years, and the survival time of the two groups was recorded. The Kaplan-Meier method was used to analyze the survival of the two groups. Results The overall response rate (ORR) (69.05%) and disease control rate (DCR) (88.10%) of the observation group were higher than those of the control group (40.48% and 66.67%), and the differences were statistically significant (both P < 0.05). After treatment, the levels of serum CA125, CA199, HE4, miRNA124, miRNA-21, and miRNA-203 and the improvement degree of quality of life score in the observation group were greater than those in the control group, with statistical significances (all P < 0.05).The 1-year, 2-year, and 3-year survival rates of the observation group (97.62%, 88.10%, and 80.95%) were higher than those of the control group (71.43%, 57.14%, and 47.62%), with statistical significances (all P > 0.05). Conclusion PARP inhibitor combined with bevacizumab had good effect in the treatment of platinum-resistant recurrent ovarian epithelial carcinoma and can effectively improve the survival time and quality of life of patients.

4P Targeting PI3K/AKT/mTOR pathway in platinum-resistant ovarian high-grade serous carcinoma: Translational analysis from the randomized phase II OCTOPUS trial

In arm 1 of the phase II randomised OCTOPUS trial (ISRCTN16426935), no significant differences in Progression-Free Survival (PFS) or Overall Survival were observed with the addition of vistusertib (V), a dual mTORC1/2 inhibitor, to weekly paclitaxel (wP) in platinum-resistant/refractory ovarian high-grade serous carcinoma. However, preliminary immunohistochemistry (IHC) data suggested that PTEN status may be predictive of benefit of addition of V to wP. Aim: We evaluated if PTEN expression (scored using quantitative digital IHC) or specific genomic features might be predictive of V benefit.

Anlotinib plus letrozole in patients with platinum-resistant recurrent ovarian cancer: A prospective, single-arm, open-label, phase II study.

e17545 Background: Studies have suggested that estrogen regulates the malignant transformation of ovarian surface epithelial cells, stimulates the growth and migration of cancer cells. and promotes the VEGF expression in epithelial ovarian cancer. Anlotinib is a novel multi-target tyrosine kinase inhibitor, inhibiting tumor angiogenesis and proliferative signaling. In this study, we evaluate the activity of anlotinib combined with letrozole in patients with estrogen receptor positive, platinum-resistant recurrent ovarian carcinoma (NCT04720807). Methods: Patients who have previously received two or more chemotherapy treatments, with histopathologically confirmed high-grade serous ovarian cancer (including salpingo carcinoma and peritoneal carcinoma), estrogen receptor (ER) positive and ECOG 0-2 were considered eligible for enrollment. Anlotinib was taken orally (10mg mg qd, d1-14, 21 days per cycle), and letrozole was taken orally (2.5mg qd, d1-21, 21 days per cycle). The treatment was continued until disease progression, death, or intolerant toxicity. The primary endpoint was objective response rate (ORR) and the secondary endpoints included disease control rate (DCR), duration of remission (DOR) progression free survival (PFS), overall survival (OS) and safety. Results: Between September 2020 and November 2021, 13 patients with a median age of 62 years (range:53-72), FIGO histopathological stage IC (23.1%), IIIC (53.8%) and IV (23.1%) were enrolled. Twelve of these patients have been evaluated for efficacy. In the efficacy-evaluable population (n=12), the therapeutic evaluation showed that 2 and 7 patients achieved partial response and Stable disease respectively, yielding the ORR of 16.7% (2/12, 95% CI: 3.3 to 54.3). The DCR was 75% (9/12, 95% CI: 39.3 to 93.3). The median PFS was 6.25 months (95% CI: 2.3m to not reached) and the median OS was not reached. The most common adverse events (AEs) were grade 1 or 2, which included laryngitis (69.2%), hypertension (53.8%), stomatitis (38.5%), diarrhea (30.8%), hand-foot syndrome (23.1%), and hyperuricemia (23.1%). The grade 3 AEs were hypertension (38.5%), diarrhea (7.7%) and hyperuricemia (7.7%). No higher AEs or treatment-related death were observed. Conclusions: Conclusions Anlotinib plus letrozole showed a promising efficacy with a favorable toxicity profile for patients with platinum-resistant recurrent ovarian cancer. The trial is ongoing and more data will be provided in the future. Clinical trial information: NCT04720807.

A phase 1 adoptive cell therapy using drug-enhanced, tumor-infiltrating lymphocytes, DeTIL-0255, in adults with advanced malignancies.

TPS5602 Background: Tumor-infiltrating lymphocytes (TIL) are a heterogeneous population of T cells that recognize multiple endogenous tumor antigens but may have developed an exhausted phenotype due to the tumor microenvironment. While existing TIL therapies produce durable responses in patients with melanoma, cervical, and head and neck cancers, poor in vitro cell expansion, limited short-lived in vivo persistence, and diminishing potency restrict this approach’s broader application. DeTIL-0255 (drug-enhanced TIL [DeTIL]) is an autologous adoptive cell therapy (ACT) derived from a patient’s tumor and expanded ex vivo with NX-0255, a small-molecule inhibitor of the E3 ligase, Casitas B-lineage lymphoma proto-oncogene B (CBL-B). CBL-B is expressed in T cells, where it functions as a regulator of immune cell activation, in part by requiring CD28 co-stimulation in addition to T-cell receptor activation. Desirable properties enhanced by DeTIL-0255 when compared with TIL include increased number of stem-like CD39-/CD69-, and CD8+ T cells associated with persistence, as well as enhanced cytolytic function. ACT with T cells expanded ex vivo using NX-0255 demonstrated increased anti-tumor activity, longer survival, increased stem-like phenotype, and persistence of tumor antigen-specific T cells in mouse tumor models. Adoptive cell transfer of DeTIL-0255, therefore, may exhibit broader functional activity than conventional TIL, potentially conferring improved anti-tumor activity and response. Methods: NX-DeTIL-0255-201 is a Phase 1 multicenter, open-label study of DeTIL-0255 administered with systemic high-dose IL-2 following nonmyeloablative lymphodepleting chemotherapy in patients with advanced gynecological malignancies for whom standard therapy with proven clinical benefit does not exist, is no longer effective, or is inappropriate. The primary objectives are to evaluate the safety, tolerability, and preliminary antitumor activity of DeTIL-0255. A safety run-in will consist of 3 to 6 patients treated with DeTIL-0255 and evaluated for dose-limiting toxicity (DLT). The DLT period starts with DeTIL-0255 infusion and ends after a total of 28 days. The safety run-in will investigate DeTIL-0255 at a dose range of 1 to 150 x 109 CD3+ T cells (exact dose varying based on expansion potential of DeTIL-0255 from tumor biopsies). Following the safety run-in, cohort expansion will further evaluate the safety and antitumor activity of DeTIL-0255 in patients with recurrent/persistent platinum-resistant epithelial ovarian cancer, cervical carcinoma, and endometrial cancer. Key eligibility criteria include measurable disease, a resectable lesion for TIL harvest, ≥2 prior lines of therapy, and an Eastern Cooperative Oncology Group performance status 0 or 1. The study is expected to enroll ̃54 patients in ̃10 sites across the United States. Clinical trial information: NCT05107739.

Surgery in platinum-resistant recurrent epithelial ovarian carcinoma.

BACKGROUNDOvarian cancer is one of the three most common malignant tumors of the female reproductive tract and ranks first in terms of mortality among gynecological tumors. Epithelial ovarian carcinoma (EOC) is the most common ovarian malignancy, accounting for 90% of all primary ovarian tumors. The clinical value of cytoreductive surgery in patients with platinum-resistant recurrent EOC remains largely unclear.AIMTo evaluate the feasibility of secondary cytoreductive surgery for treating platinum-resistant recurrent EOC.METHODSThis was a retrospective study of the clinical data of patients with platinum-resistant EOC admitted to the Cancer Hospital of the University of Chinese Academy of Sciences between September 2012 and June 2018. Patient baseline data were obtained from clinical records. Routine follow-up of disease progression was performed as follows. CA125 assessment and physical examination were performed every 3 wk during treatment, including gynecological examination. Imaging assessment was carried out every 12 wk by B-mode ultrasound, computed tomography, or magnetic resonance imaging. The primary outcome was progression-free survival (PFS). Secondary outcomes included overall survival (OS), chemotherapy-free interval (CFI), and complications. Follow-up ended on April 15, 2019.RESULTSA total of 38 patients were included. R0 resection was achieved in 25 (65.8%) patients and R1/2 in 13 (34.2%). Twenty-five (65.8%) patients required organ resection. Nine (23.7%) patients had operative complications, 36 (94.7%) received chemotherapy, and five (13.2%) had targeted therapy. Median PFS and OS were 10 (95%CI: 8.27-11.73) months and 28 (95%CI: 12.75-43.25) months, respectively; median CFI was 9 (95%CI: 8.06-9.94) months. R0 resection and postoperative chemotherapy significantly prolonged PFS and OS (all P < 0.05), and R0 resection also significantly prolonged CFI (P < 0.05). Grade ≥ 3 complications were observed, including rectovaginal fistula (n = 1), intestinal and urinary fistulas (n = 1), and renal failure-associated death (n = 1). Except for the patient who died after surgery, all other patients with complications were successfully managed. Two patients developed intestinal obstruction and showed improvement after conservative treatment.CONCLUSIONSecondary cytoreductive surgery is feasible for treating platinum-resistant recurrent EOC. These findings provide important references for the selection of clinical therapeutic regimens.

Potential efficacy of weekly low-dose administration of bevacizumab as a combination therapy for platinum-resistant ovarian carcinoma: a retrospective analysis

BackgroundBevacizumab (Bev) plays the central role of the adjuvant therapy for patients with ovarian carcinoma. The aim of our study was to examine whether differences in the administration of Bev influence the prognosis of patients.MethodsPatients with ovarian carcinoma who received treatment at two hospitals between 1999 and 2020 were identified. Patients treated with weekly low-dose administration of Bev (100 mg Bev on days 1 and 8 and 200 mg Bev on day 15, monthly) at one hospital (group A) and those with monthly high-dose administration of Bev (15 mg/kg of Bev on day 1, monthly) at another hospital (group B) were retrospectively compared.ResultsAmong the total patients, 44 were assigned to group A and 33 were assigned to group B. More patients in group A had advanced disease (p = 0.03) and a lower dose of Bev at the first time during the first cycle administration (p < 0.01) than in group B. Progression-free survival (PFS) was better in group A than in group B (p < 0.01). Multivariate analysis revealed that group A was a better prognostic factor for PFS (hazard ratio 0.53, p = 0.03). Stable duration was longer in group A than in group B (p < 0.01). The incidences of adverse effects, including hematological toxicities such as neutropenia (p = 0.01) and nonhematological toxicities such as hypertension (p < 0.01), intestinal obstruction (p < 0.01), and thromboembolic events (p < 0.01), were lower in group A than in group B.ConclusionsWeekly low-dose administration of Bev might improve prognosis and decrease the frequency of adverse effects associated with this drug although the prospective study was needed to get corroboration.

Onvansertib and paclitaxel combined in platinum-resistant ovarian carcinomas.

Background:Ovarian carcinoma is extremely sensitive to (platinum-based) chemotherapy; however, most patients will relapse with platinum-resistant disease, badly affecting their prognosis. Effective therapies for relapsing resistant tumors are urgently needed.Methods:We used patient-derived xenografts (PDXs) of ovarian carcinoma resistant to cisplatin (DDP) to test in vivo the combination of paclitaxel (15 mg/kg i.v. once a week for 3 weeks) and onvansertib, a plk1 inhibitor, (50 mg/kg orally 4 days a week for 3 weeks). The PDX models were subcutaneously (s.c.) or orthotopically transplanted in nude mice and antitumor efficacy was evaluated as tumor growth inhibition and survival advantages of the combination over untreated and single agent treatment.Results:The combination of onvansertib and paclitaxel was very well tolerated with weight loss no greater than 15% in the combination group compared with the control group. In the orthotopically transplanted PDXs, single onvansertib and paclitaxel treatments prolonged survival; however, the combined treatment was much more active, with median survival from three- to six-fold times that of untreated mice. Findings were similar with the s.c. transplanted PDX, though there was greater heterogeneity in tumor response. Ex vivo tumors treated with the combination showed greater induction of γH2AX, marker of apoptosis and DNA damage, and pSer10H3, a marker of mitotic block.Conclusion:The efficacy of onvansertib and paclitaxel combination in these preclinical ovarian cancer models supports the clinical translatability of this combination as an effective therapeutic approach for platinum-resistant high-grade ovarian carcinoma.

736P Preliminary results of anlotinib and niraparib dual therapy evaluation in platinum-resistant recurrent ovarian cancer (ANNIE): A multicenter, single-arm, phase II trial

Patients with platinum-resistant ovarian cancer have a poor prognosis. Effective treatment options for these patients are limited. In this study (ANNIE), we evaluate the activity of niraparib combined with anlotinib in patients with platinum resistant recurrent ovarian carcinoma.

Phase I study of GAS6/AXL inhibitor (AVB-500) in recurrent, platinum-resistant ovarian carcinoma

<h3>Objectives:</h3> AVB-500 is a first-in-class Fc fusion protein that binds the GAS6 ligand thereby inhibiting AXL signaling. Both GAS6 and AXL are highly expressed in high-grade serous ovarian cancer (HSGOC). The purpose of this study was to evaluate safety, tolerability, and preliminary efficacy of AVB-500 in combination with pegylated liposomal doxorubicin (PLD) and paclitaxel (Pac) and determine the RP2D. <h3>Methods:</h3> Patients were enrolled in escalating dose cohorts of AVB-500 10mg/kg to 20mg/kg at q2 weeks in combination with weekly Pac 80mg/m²D1, 8, 15 q28 days or PLD 40mg/m²D1 q28 days and assessed for safety, pharmacokinetics, pharmacodynamics, and response (via RECIST v1.1, assessed by investigator). A safety review committee reviewed each cohort prior to escalation to the next higher dose level. <h3>Results:</h3> A total of 53 patients with platinum-resistant HGSOC ovarian adenocarcinoma (PROC) were enrolled. A total of 23 patients received Pac + AVB-500 and 30 patients received PLD + AVB-500. No patients experienced a dose-limiting toxicity (DLT). A total of 53% (28/53)of patients experienced a grade 3-4 adverse event. No grade 5 events were observed. The majority of events were related to known chemotherapy side effects. No subject discontinued study therapy due to an adverse event. Confirmed ORR with Pac+AVB-500 was 35% (8/23) and 15% (4/26) in the PLD+AVB-500 subgroup. ORR in the Pac subgroup after 1-2 prior lines was 40% with a platinum-free interval (PFI) ≥3 months, and 60% with a PFI of <3 months. Pac treated patients who had not been exposed to bevacizumab had a 60% ORR vs 15% in the Bev pre-treated subgroup. An exposure-response analysis identified serum AVB-500 C1D15 trough levels of >13.8mg/L as the minimal efficacious concentration (MEC). Among the Pac treated subgroup, the ORR was 39% vs 22% and median overall survival (OS) was 10.3 months vs 6.7 months in the MEC-high and MEC-low groups, respectively (Figure 1). Additionally, serum soluble AXL/GAS6 ratio was measured at baseline as an indicator of pathway activation. Among the Pac treated subgroup, the ORR was 42.9% vs 0% for those with ratios >0.773 compared to those with ratios ≤0.773. <h3>Conclusions:</h3> AVB-500 is a novel Fc fusion protein that binds the GAS6 ligand and targets GAS6/AXL pathway. AVB-500was found to be safe and tolerable in this Ph1B trial in combination with Paclitaxel or PLD. The RP2D was based upon PK/PD parameters. This Ph1B trial suggesteda higher ORR in the Pac treated subgroup, particularlywith C1D15 trough levels >13.8mg/L (most consistently achieved at the 15mg/kg dose level). Exploratory analysis also suggested that improved response rates may be observed in patients who have not been exposed to bevacizumab. The serum soluble AXL/GAS6 ratio may serve as a potential biomarker of pathway activation and identify patients who most benefit from Pac+AVB-500. Further development of AVB-500 15 mg/kg Q2W in combination with Pac is warranted in PROC.

Efficacy and safety of weekly paclitaxel in elderly patients with heavily pretreated platinum-resistant ovarian carcinoma.

e17552 Background: In platinum-resistant ovarian cancer treatment, single-agent paclitaxel can be used alone or in combination with bevacizumab. We aimed to assess the efficacy and safety profile of a weekly paclitaxel (WP) scheme in heavily pretreated platinum-resistant high-grade serous ovarian carcinoma. Methods: We retrospectively analyzed 30 adult patients with platinum-resistant high-grade serous ovarian carcinoma treated with WP at our institution between 2015 and 2020. Patients with platinum-resistant ovarian, fallopian tube or primary carcinoma of the peritoneum who had received at least 3 doses of WP (80 mg/m2) alone or in combination with bevacizumab until disease progression or unacceptable toxicity were included in the analysis. Progression-free survival was assessed according to the Response Evaluation Criteria in Solid Tumors version 1.1. Information about toxicity was gathered from medical reports and lab tests. Kaplan-Meier curves and Log-rank test were performed for survival estimates. Results: In our sample, the median age was 68 years (IQR: 60-75) and the median number of previous lines of systemic treatment was 3 (range 1-5). 40% of patients received WP in combination with bevacizumab. The disease control rate was 60.7% (42.9% partial response and 17.8% stable disease). In the overall analysis, the median progression-free survival (mPFS) was 5.0 months (95% CI: 2.0-7.1 months). The presence of ascites significantly shortened the mPFS compared to patients without it (1.1 vs 5.1 months, p &lt; 0.001). Even though the addition of bevacizumab to WP improved the mPFS, the difference was not statistically significant compared to WP alone (7.1 vs 4.06 months, p=0.30). Peripheral neuropathy was the most common adverse event (78% all grades, 18% grade 3). No grade 3 hematologic toxicity was registered. Treatment was discontinued in 6 patients (20%) – 4 due to peripheral neuropathy and two because of toxicoderma. Conclusions: In our sample, WP was an active and safe regimen in heavily pretreated platinum-resistant ovarian carcinoma. WP was well tolerated in elderly patients. The presence of ascites was associated to a shorter PFS in patients treated with WP compared to ascites-free patients.

BDB001, an intravenously administered toll-like receptor 7 and 8 (TLR7/8) agonist, in combination with pembrolizumab in advanced solid tumors: Phase 1 safety and efficacy results.

2512 Background: BDB001 is an intravenously administered TLR 7/8 dual agonist immune modulator capable of reprogramming dendritic cells to produce antitumor activities. BDB001 monotherapy has demonstrated favorable tolerability and robust systemic immune activation leading to durable clinical responses in a phase I dose escalation trial. Here, we report on the safety and efficacy of BDB001 in combination with pembrolizumab in a phase I dose escalation trial in advanced solid tumors (NCT03486301). Methods: BDB001-101 is a phase 1, open label, dose escalation/expansion trial of BDB001 (IV, Q1W) in combination with pembrolizumab (IV, Q3W) in patients with advanced solid tumors. The primary endpoint was safety and tolerability. Secondary endpoints included efficacy, pharmacokinetics and pharmacodynamic profiling of immune activation. Results: Twenty-three subjects with 13 different tumor types were enrolled across 4 dose levels. Sixty one percent were female, median age was 63 years (range, 33-86), median number of prior therapies was 3 (range, 1-8), and 48% of tumors had progressed on prior anti-PD-(L)1 therapy. Overall, BDB001 in combination with pembrolizumab was well tolerated and dose-limiting toxicities were not observed. The most common treatment related adverse events (TRAEs) were fever (39.1%), fatigue (39.1%), chills/rigor (34.8%), pruritus/rash (21.7%), and nausea (13.0%). Most of these TRAEs were grade 1 or 2 and transient. Only 3 (13.0%) subjects experienced grade 3 TRAEs of fatigue, rash, stomatitis, and alkaline phosphatase elevation. There were no grade 4 or 5 TRAEs. Pharmacodynamic evaluation of plasma cytokine levels showed robust increases in interferon gamma and interferon inducible protein-10 (IP-10) at BDB001 Dose Level 3 and 4. Preliminary efficacy evaluation of the 14 subjects treated at Dose Level 3 and 4 showed durable and deep clinical responses in 4 (29%) subjects with anti-PD-(L)1 mAb refractory melanoma, hepatocellular carcinoma, cholangiocarcinoma, and platinum-resistant ovarian carcinoma. The responses were observed by the initial efficacy assessment at 9-weeks, with some seen as early as 4-weeks. In addition, 4 (29%) subjects had stable disease for a disease control rate of 57%. To date, median time on treatment is 14.4 weeks (range, 6.0 – 42.1+) with 3 subjects still active on treatment. Conclusions: Intravenously administered BDB001 in combination with pembrolizumab is well tolerated. Rapid and deep clinical responses were observed, supported by robust systemic immune activation. BDB001 in combination with pembrolizumab is a promising novel therapeutic option for patients with advanced solid tumors and is being evaluated in an ongoing dose expansion trial. Clinical trial information: NCT03486301.