Refractory Ovarian Cancer Research Articles

Abstract CT125: STRO-002-GM1, a first in human, phase 1 study of STRO-002, an anti-folate receptor alpha (FRα) antibody drug conjugate (ADC), in patients with advanced platinum-resistant/refractory epithelial ovarian cancer (OC), including fallopian tube or primary peritoneal cancers

Abstract Introduction: FRα is overexpressed in 80% of OC with minimal expression in normal tissues. STRO-002 is a novel FRα-targeting ADC designed to circumvent limitations of current ADCs. STRO-002 was generated with a cell-free antibody production system (XpressCF™) and site-specific conjugation (XpressCF+™) platform. STRO-002 has a DAR of 4 and contains the tubulin-targeting 3-aminophenyl hemiasterlin warhead SC209, a potent cytotoxin that is rapidly cleared and a weak substrate for P-gp efflux pumps. STRO-002 demonstrated potent cytotoxic activity in multiple FRα-positive tumor cell lines and significant efficacy in OC xenograft models. Herein we report the results of our dose escalation study of STRO-002 in patients (pts) with OC. Methods: STRO-002-GM1 is a Phase I, open-label, multicenter, dose escalation study with dose expansion to identify the maximum tolerated dose (MTD), and recommended Phase II dose (RP2D) in pts with advanced, platinum resistant or refractory OC. There is no patient selection based on FRα expression. STRO-002 is given IV on Day 1 of each 21-day cycle (C) until disease progression. Ocular exams are performed at baseline and every other cycle. No prophylactic corticosteroid eye drops are used. Results: 20 pts have been dosed & 18 pts have completed at least 1 cycle of STRO-002 at 7 dose levels: 0.5, 1.0, 1.8, 2.9, 4.3, 5.2 and 6.0 mg/kg. Median age is 60.5 (r, 48-70). Median ECOG status is 0 (r, 0-1). Median # of prior therapies is 6 (r, 2-10). 55% of pts have prior PARP inhibitors, 85% have prior bevacizumab. Median # of STRO-002 cycles is 3 (r, 1-15). One DLT of grade 3 neuropathy was reported at the 6.0 mg/kg dose level. Two patients have experienced grade 4 neutropenia, an expected and reversible side effect of STRO-002 treatment. 92% of AEs are grade 1 or 2. The most common TEAEs in ≥ 30 % of pts includes fatigue, nausea, decreased appetite and dizziness. No ocular findings have been observed. Emerging PK profile: after 1 hour infusion, total antibody concentrations declined in a log-linear manner with a 22-84 h half-life, dose-exposure relationship appeared linear without accumulation after repeat administration. Six pts have discontinued due to disease progression. 14 pts remain on treatment and dose escalation is ongoing. One patient has achieved a confirmed partial response (PR); 2 patients have confirmed stable disease (cSD) at C5, 2 pts have cSD at C7 and 1 pt has cSD at C13; 3 patients have achieved a confirmed CA-125 response. Conclusions: STRO-002 is the first hemiasterlin-containing ADC generated with cell-free protein synthesis technology to be tested in pts with solid tumors. The preliminary safety profile and evidence of efficacy and clinical benefit in the first 20 OC pts treated with STRO-002 is encouraging, particularly in this heavily pre-treated, platinum resistant/refractory patient population. No ocular toxicity signals have been observed. MTD has not been reached. Updated results and the recommended phase 2 dose will be presented. This study is registered with clinicaltrials.gov identifier NCT03748186. Citation Format: R. Wendel Naumann, Denise Uyar, John W. Moroney, Fadi S. Braiteh, Russell J. Schilder, John P. Diaz, Erika Hamilton, Sami Diab, Lainie P. Martin, David M. O'Malley, Richard T. Penson, Clifford DiLea, Michael Palumbo, Venita DeAlmeida, Shannon Matheny, Arturo Molina. STRO-002-GM1, a first in human, phase 1 study of STRO-002, an anti-folate receptor alpha (FRα) antibody drug conjugate (ADC), in patients with advanced platinum-resistant/refractory epithelial ovarian cancer (OC), including fallopian tube or primary peritoneal cancers [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT125.

Quality of life, vascular endothelial growth factor inhibition, and survival outcomes with combination oral metronomic therapy in platinum refractory epithelial ovarian carcinoma: Results from a randomized study.

6048 Background: Patients with recurrent and refractory epithelial ovarian cancer (EOC) have dismal outcomes. We evaluated a combination of oral metronomic therapy in platinum refractory EOC vis-à-vis angiogenic marker expression and its impact on patient reported outcomes. Methods: Between October 2017 and September 2019, 75 patients were randomized to receive etoposide (VP-16) (50 mg daily for 14 days) cyclophosphamide (50 mg daily for 28 days) (Arm A, n = 38) or etoposide (VP-16) (50 mg daily for 14 days) cyclophosphamide (50 mg daily for 28 days) and pazopanib (400 mg daily 28 days) every 28 days (Arm B, n = 37). Eligibility criteria included histopathological diagnosis of EOC, platinum refractory disease and ECOG performance status 0-2. Primary endpoint was serological progression free survival (PFS) as defined by Rustin criteria. Quality of Life (QoL) (evaluated using the EORTC QLQC30 and OV 28 questionnaires) and serum vascular endothelial growth factor (VEGF) were ascertained at baseline and after 3rd and 6th cycle. Intention to treat analysis was done. Results: Baseline characteristics were well matched in 2 arms. At a median follow up 14.4 months (95% CI 13.2-15.7), the median serological PFS is better for patients in Arm B 5.1 months (95%CI 3.13-10.33) compared to 3.4 months (95%CI 3-6.53) in arm A ( P= 0.045). Median overall survival (OS) is not reached in arm B versus 11.2 months (95%CI 5.66-NR) in arm A (P= 0.032). Disease progression was seen in 42.1% (n = 16) in Arm A versus 40.5 %(n = 15) in arm B ( P= 0.40). Sixteen patients are maintaining response. Mucositis (29.7% n = 11) and fatigue (13.5%, n = 5) were more in the pazopanib-containing arm ( P= 0.36). Serum VEGF demonstrated significant decline with subsequent cycles of therapy {median values (range): Arm A, baseline; 466.0 pg/mL(123.9-1930) vs. 6 cycles; 92.05pg/ mL(42.34-279.5) P< 0.0001; Arm B, baseline; 382.0 pg/mL(49.44-2054.0) vs 6 cycles; 119.7 pg/mL(18.20-367.5) P= 0.013} without any difference between the two arms ( P= 0.18). QoL symptom scales in both QLQC 30 and OV 28 questionnaires indicated small but significant improvement in pazopanib arm ( P= 0.02) without differences in global (p = 0.96) and physical functioning scales. ( P= 0.68). Conclusions: Addition of pazopanib to etoposide and cyclophosphamide resulted in improvement in serological PFS and OS with a well-tolerated toxicity profile and modest improvement in QoL.Serum VEGF expression requires validation in a larger cohort. Clinical trial information: CTRI/2017/10/010219.

Phase I/II study of weekly topotecan and gefitinib in patients with platinum-resistant ovarian, peritoneal, or fallopian tube cancer.

6059 Background: The epidermal growth factor receptor (EGFR) is expressed in many types of cancer. Fifty to 70% of epithelial ovarian can overexpress EGFR, and its expression has been correlated with poor prognosis features in many cases. While these tumors are chemosensitive to platinum-based therapy, chemoresistance often develops. We conducted a phase I/II trial to examine the efficacy, safety, and toxicity of gefitinib, a tyrosine kinase inhibitor, combined with topotecan in women with recurrent ovarian cancer with EGFR receptor positivity (1+ or greater). Methods: Patients with measurable, recurrent or persistent cancer after treatment with a platinum and paclitaxel-containing regimen were eligible for this study (n = 19). We first used “run-in” dose escalation, in which a conventional 3+3 algorithm was used. Initial treatment was gefitinib 250 mg oral dose daily and topotecan at a dose of 2.0 mg/m2 on days 1, 8, and 15, with cycles repeated every 28 days. Dose escalations were planned for topotecan (Dose Levels 1–3: 2, 3, 4 mg/m2) until the MTD was reached. Next, an additional 10 patients with refractory or progressive ovarian cancer were enrolled in the phase II study. Results: 19 patients received a total of 61 cycles. Median age was 60 years. Histological types of treated patients included 73% serous (n = 14), 12.5% mixed (n = 2), 12.5% transitional (n = 2) and 6.3% clear cell (n = 1). There were 3 patients treated at dose level 1, 3 patients at dose level 2, and 3 patients treated at dose level 3. The maximum tolerated dose was topotecan 4.0mg/m2 IV days 1, 8 and 15, and gefitinib 250mg p.o. QD x28 days. Therefore, dose level 3 was used for the Phase II portion of the trial. Of the 19 patients included in the phase I/II, 3 patients were inevaluable for response to therapy due to toxicity, missed therapy or decline in performance status. Of the 16 patients, 81% patients (n = 13) had progressive disease, 12.5% stable disease (n = 2), and 6% partial response (n = 1). We assessed all 19 patients for adverse events; 60% had treatment-related grade 3 events, primarily blood disorders such as anemia (n = 3, 16%), neutrophil count decrease (n = 4, 21%). Conclusions: This prospective phase I/II clinical trial failed to show sufficient clinical activity of topotecan in combination with gefitinib in patients with EGFR-positive recurrent ovarian, fallopian tube, or peritoneal cancers. The drug combination was relatively well-tolerated in this cohort. As such, the study did not proceed to the next accrual goal secondary to the lack of response. Clinical trial information: NCT00317772.

First-in-human phase I study of intraperitoneally administered interferon-activated autologous monocytes in platinum-resistant or refractory ovarian cancer.

1 Background: This phase I study evaluated the safety and tolerability of autologous intraperitoneal monocytes treated with SYLATRON (Peginterferon alfa-2b) and ACTIMMUNE (Interferon gamma-1b). Methods: For the dose escalation portion, 3-6 patients with platinum-resistant or refractory ovarian cancer were enrolled into 4 cohorts and treated intraperitoneally (IP) with Peginterferon alfa-2b (25-250 mcg) and Interferon gamma-1b (5-50 mcg), with or without autologous monocytes (75-750 x 106 cells), in order to determine the recommended phase II dose (RP2D). A total of six patients were treated at the RP2D. Patients received the combination of interferons+/- monocytes via IP catheter once every 28 days. Results: 18 patients were enrolled (median age, 61 years; median 5 prior therapies). 1 of 3 patients at the second dose level experienced a dose-limiting toxicity (DLT, grade 3 anemia) and so this cohort was expanded to 6 patients; no subsequent DLTs were observed. The RP2D was defined as 250 mcg/50/mcg/750 x 106 cells on the basis of overall safety and tolerability. The only treatment–related grade 3 or higher adverse events occurring in more than one patient were lymphocyte decrease (33.3%) and abdominal pain (11.1%). Preliminary assessment of efficacy is ongoing. The best response observed has been partial response (PR) in 2/11 evaluable patients, with one patient having a 61% reduction in target lesion size. An additional 4/11 patients had stable disease, and 3 patients remained on treatment for >6 cycles. Exploratory biomarker analyses are ongoing to to further elucidate changes in the immune cell population and correlate with response. An expansion cohort of 10 patients at the RP2D is currently enrolling. Conclusions: This is the first-in-human study of the combination of IP peginterferon alfa-2b, interferon gamma-1b, and autologous monocytes, and the combination displays good tolerability and antitumor activity in a heavily pretreated population, supporting further investigation. Clinical trial information: NCT02948426.

A phase Ib study of the anti-CD47 antibody magrolimab with the PD-L1 inhibitor avelumab (A) in solid tumor (ST) and ovarian cancer (OC) patients.

18 Background: Magrolimab (M, Hu5F9-G4) is an antibody targeting CD47, a “don’t eat me” signal for macrophages that enhances ovarian cancer cell phagocytosis in preclinical models in combination with the PD-L1 inhibitor avelumab. CD47 blockade can also enhance cross-priming of T cells. Methods: In Part 1 (P1) M+A doses were escalated in ST patients (pts) while Part 2 (P2) enrolled platinum-resistant or refractory OC pts. All received a 1 mg/kg Day 1 priming dose of M to mitigate on-target anemia due to macrophage-mediated extravascular hemolysis followed by 30 or 45 mg/kg maintenance doses in P1 or 45 mg/kg in P2, in combination with 800 mg of A Q2 wks. Results: In the 34 total pts (13 in P1 and 21 in P2), median age was 66 years (range 47-88), and median # of prior therapies was 5 (range 1-10). In P1, no dose limiting toxicities occurred. In P1+P2, no Grade (G) 4 or 5 treatment-related adverse events (TRAEs) occurred. TRAEs of any G in > 20% pts included headache 62%, fatigue 47%, infusion related reaction 44%, pyrexia 38%, chills 35%, nausea 35%, anemia 24%, and vomiting 21%. In P1, a patient (pt) with metastatic papillary adenocarcinoma of the finger on 45 mg/kg of M had a confirmed partial response (PR) lasting for 4 months before progressing. In P2, 1 pt had an unconfirmed PR but progressed per RECIST v1.1 on the next scan achieving a best response of stable disease (SD). In the 18 OC P1+P2 pts with at least one response evaluation, 56% had SD and 44% had progression. Analysis of tumor biopsies for immune cells infiltration and CD47, PD-L1, and other marker expression is ongoing. In the 13 OC tumors analyzed to date, only 2 were PD-L1 positive. One PD-L1+ tumor had PD-L1 expression only on infiltrating immune cells. The other PD-L1+ had tumor cell expression and was the only OC pt with tumor shrinkage. This supports the potential importance of PD-L1 expression for this combination. Pharmacokinetic profiles will be presented. Conclusions: M+A is a novel, well-tolerated combination treatment regimen with 1 observed PR in a ST pt and a 56% SD rate in OC pts. Tumor shrinkage was noted in the only OC pt with tumor cell expression of PD-L1 which warrants further evaluation in PD-L1+ OC pts. Clinical trial information: NCT03558139.

Abstract AP27: A PHASE 2 STUDY OF TPIV200/HUFR-1 (A MULTI-EPITOPE FOLATE RECEPTOR ALPHA VACCINE) IN COMBINATION WITH DURVALUMAB IN PATIENTS WITH PLATINUM RESISTANT OVARIAN CANCER

Abstract INTRODUCTION: Therapy with single-agent immune checkpoint inhibitors in ovarian cancer (OC) to date has demonstrated marginal benefit, calling for rational combinations. Vaccination against tumor-associated antigens (TAA's) is a potential strategy to increase therapeutic efficacy by enhancing immunogenicity. Folate receptor alpha (FRα) is overexpressed in the majority of ovarian cancers (OC) and presents a compelling antigenic target for immunotherapy. TPIV200 is a GM-CSF-adjuvanted multi-epitope peptide anti-FRα vaccine targeting the most highly-antigenic moieties of FRα, which in recent phase I studies elicited durable immune response in over 90% of patients with ovarian and breast cancer. The current phase II study sought to examine whether a combination of TPIV200 with PD-L1 inhibitor durvalumab would result in enhanced anti-tumor immunity and therapeutic efficacy in patients with advanced platinum-resistant OC. METHODS: Twenty-seven patients with platinum resistant or refractory OC were enrolled over a 10-month period. Treatment was administered in 28-day cycles. Patients were treated with TPIV200 and GM-CSF on day 1 for 6 cycles and durvalumab on days 1 and 15 at 10mg/kg for 12 cycles. Radiologic assessments were conducted every 12 weeks. Treatment was continued until completion, evidence of clinical or radiologic progression, intolerance, or withdrawal. Exploratory correlative endpoints included tissue microenvironment analyses, including expression of PD-L1 and FRα, and peripheral vaccine-specific immune responses. RESULTS: The study enrolled 27 women with advanced OC. Median age at enrollment was 64 (42-76). Median number of prior lines of therapy was 3 (range 1-8). Of these patients, 85% (23) had high grade serous OC. There were no objective responses seen on the study. PFS rate at 24 weeks was 22%, with median PFS of 12 weeks. Six patients remained on treatment beyond 24 weeks. The majority of patients post-progression went on to receive subsequent standard therapy with durable clinical benefit. At the median follow up of 15.4 months, median OS was not reached. CONCLUSIONS: TPIV200/huFR-1 and durvalumab can be safely combined in heavily-pretreated patients with platinum-resistant OC. A subset of patients exhibited durable disease stabilization. Post-immunotherapy follow up was suggestive of improved clinical benefit from standard therapies, creating a rationale for exploration of these agents in combination with chemotherapy. Citation Format: Dmitriy Zamarin, Oladapo Yeku, Rosin E. O'Cearbhaill, Karen A. Cadoo, Jacqueline Gallagher, Sara Kravetz, Autumn McDonnell, Tiffany Troso-Sandoval, Paul Sabbatini, Stuart Lichtman, William Tew, Vicky Makker, Rachel N. Grisham, David M. Hyman, Carol Aghajanian, Jason Konner. A PHASE 2 STUDY OF TPIV200/HUFR-1 (A MULTI-EPITOPE FOLATE RECEPTOR ALPHA VACCINE) IN COMBINATION WITH DURVALUMAB IN PATIENTS WITH PLATINUM RESISTANT OVARIAN CANCER [abstract]. In: Proceedings of the 12th Biennial Ovarian Cancer Research Symposium; Sep 13-15, 2018; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2019;25(22 Suppl):Abstract nr AP27.

Potential clinical application of tumor-infiltrating lymphocyte therapy for ovarian epithelial cancer prior or post-resistance to chemotherapy.

Immunotherapy has become a powerful treatment option for several solid tumor types. The presence of tumor-infiltrating lymphocytes (TIL) is correlated with better prognosis in ovarian cancer, pointing at the possibility to benefit from harnessing their anti-tumor activity. This preclinical study explores the feasibility of adoptive cell therapy (ACT) with TIL using an improved culture method. TIL from high-grade serous ovarian cancer were cultured using a combination of IL-2 with agonistic antibodies targeting 4-1BB and CD3. The cells were phenotyped using flow cytometry in the fresh tissue and after expansion. Tumor reactivity was assessed against HLA-matched ovarian cancer cell lines via IFN-γ ELISPOT. Ovarian cancer is highly infiltrated with CD8+ TIL that are preferentially and robustly expanded with the addition of the agonistic antibodies. With a 95% success rate, the TIL are grown to ≥ 100 × 106 cells in 2-3weeks without over differentiation. In addition, the CD8+ TIL grown with this method showed HLA-restricted tumor recognition. These results indicate the viability of TIL ACT for refractory ovarian cancer by allowing for the large expansion of anti-tumor TIL in a short time and consistent manner.

1031P - OCTAVE: A phase I study of enadenotucirev, an oncolytic group B adenovirus, in combination with weekly paclitaxel in platinum-resistant epithelial ovarian cancer

BackgroundEnadenotucirev (EnAd) is a tumor selective Ad11/Ad3 group B adenovirus that has demonstrated pre-clinical activity in a model of platinum-resistant ovarian cancer. Synergy has also been reported between oncolytic adenoviruses and microtubule manipulating drugs such as paclitaxel (Pxl). This study aims to establish the tolerability and preliminary efficacy of EnAd delivered in combination with Pxl. Here we present data from the intravenous (IV) dose expansion group. MethodsPatients with platinum-resistant or refractory ovarian cancer received a minimum of two 28-days cycles of IV infusional EnAd (1x1012 viral particles) on days 1, 3 and 5, and IV Pxl (80mg/m2) on days 9, 16 and 23. Baseline and on-treatment biopsies were taken. Primary endpoint was safety and tolerability; additional endpoints included, response rate (RECISTv1.1/GCIG CA125 criteria) and duration of response. ResultsTwenty patients, median age 60.5 years (range 37-78) who had received a median of 4 prior lines of therapy (range 1-12) were enrolled. Adverse events reported from the combination of EnAd and Pxl were as previously described (for both agents individually), with ‘flu-like symptoms reported in the majority of patients following EnAd administration. Hematological changes including neutropenia, previously identified at higher doses of EnAd IV monotherapy, were reported at the dose level tested in this study population. Virus kinetics, cytokine and anti-virus antibody responses were consistent with previous results with EnAd. As of 03May19, Investigator-assessed ORR is 37.5% (6/16), with median DoR of 16 weeks (range 8-32). Reductions in CA125 broadly follow the pattern of tumor regression, with 36% (4/11) achieving response according to GCIG CA125 criteria. Disease control rate (RECIST CR, PR, SD) is 75% (12/16). To date, matched biopsies (N=2) have been analysed for pharmacodynamic markers, providing preliminary evidence of increased CD8 T cell infiltration in on-treatment tumour biopsies. ConclusionsThe combination of EnAd and Pxl has manageable tolerability. Favorable disease control is noted in this recurrent platinum-resistant population, which is worthy of further investigation. Clinical trial identification2013-001276-38. Legal entity responsible for the studyPsiOxus Therapeutics Ltd. FundingPsiOxus Therapeutics Ltd. DisclosureR. Brown: Shareholder / Stockholder / Stock options, Full / Part-time employment: PsiOxus Therapeutics Ltds. D. Krige: Full / Part-time employment: PsiOxus Therapeutics Ltds. J. Bendall: Full / Part-time employment: PsiOxus Therapeutics Ltds. G. Di Genova: Full / Part-time employment: PsiOxus Therapeutics Ltds. H. McElwaine-Johnn: Leadership role, Shareholder / Stockholder / Stock options, Full / Part-time employment: PsiOxus Therapeutics Ltds. All other authors have declared no conflicts of interest.

Etirinotecan pegol in women with recurrent platinum-resistant or refractory ovarian cancer

ABSTRACTIntroduction: A PEGylated form of irinotecan, a topoisomerase I inhibitor, is now available in commerce; its safety and efficacy have been tested in platinum resistant/refractory ovarian cancer (PROC) patients. This novel agent is known as Etirinotecan Pegol (EP). EP, like irinotecan, exerts its action through its principal metabolite SN-38.Areas covered: This drug evaluation article focuses on the most recent investigations and clinical progress regarding EP, a long-acting polymer conjugate of irinotecan for the treatment of PROC.Expert opinion: EP provides prolonged and continuous exposure of SN-38 in tumors, when compared to its parent drug irinotecan. Results from phase II studies are comparable in terms of efficacy to other agents of proven use in PROC. A limitation of the use of EP is the schedule-dependent toxicities (mainly diarrhea and dehydration). In the future, EP could be investigated in association with other agents, even in attempts to restore sensitivity to other treatments. PROC remains a very difficult setting and EP might be a valid agent for patients with good performance status that have exhausted therapeutic options. In such a setting, participation in clinical trials is strongly encouraged.

Avelumab alone or in combination with pegylated liposomal doxorubicin versus pegylated liposomal doxorubicin alone in platinum-resistant or refractory epithelial ovarian cancer: Primary and biomarker analysis of the phase III JAVELIN Ovarian 200 trial

Avelumab alone or in combination with pegylated liposomal doxorubicin versus pegylated liposomal doxorubicin alone in platinum-resistant or refractory epithelial ovarian cancer: Primary and biomarker analysis of the phase III JAVELIN Ovarian 200 trial

ENGOT-OV44/FIRST study: A randomized, double-blind, adaptive, phase III study of platinum-based therapy with dostarlimab (TSR-042) + niraparib versus standard-of-care (SOC) platinum-based therapy as first-line treatment of stage 3/4 non-mucinous epithelial ovarian cancer (OC).

TPS5600 Background: Despite surgery and SOC therapy (paclitaxel and carboplatin ± bevacizumab[bev]), 5-year survival rates remain low for patients (pts) with FIGO stage 3/4 OC. Niraparib (ZEJULA) is the first selective poly(ADP-ribose) polymerase inhibitor (PARPi) approved in the US and Europe for maintenance treatment in pts with recurrent OC regardless of BRCAmut status. Preclinical data suggest synergy with PARPi + anti-PD-1 blockade. Niraparib + pembrolizumab has shown clinical efficacy in pts with platinum-resistant or secondary refractory OC regardless of biomarker status. Dostarlimab is an anti–PD-1 humanized monoclonal with clinical activity as monotherapy in early phase trials. The primary objective of the currently enrolling FIRST trial is to compare PFS (per RECIST v1.1) in pts treated with SOC + dostarlimab + niraparib to SOC. Methods: Eligible pts (up to 912) are FIGO stage 3 (with residual disease, CC0 high risk, or planned neoadjuvant therapy) or stage 4, non-mucinous epithelial OC and ECOG score < 2. After 1 cycle of SOC, pts are stratified by concurrent bev use, BRCAmut/HRR status, and disease burden then randomized as 1:1:2 to 1 of 3 arms (Table). An innovative feature of ENGOT-OV44/FIRST (NCT03602859; EUDRACT 2018-000413-20) is the pre-planned adaptive study design to adapt the control arm to the evolving SOCs in OC, allowing pts in the control arm to receive up to date SOC. These adaptations will occur when practice-changing data are released. Following publication of SOLO1 results, BRCAmut pts will only be randomized to arm 2 or 3 to ensure they receive niraparib. Further adaptations may be incorporated as new data become available, leading to stop randomization in arm 1 or 2 of pts based on their biomarker status. Clinical trial information: NCT03602859. [Table: see text]

Radiopharmaceuticals for Relapsed or Refractory Ovarian Cancers.

Targeted radiopharmaceuticals for therapeutic use deliver radionuclides directly to tumor anywhere in the body, and therefore, have renewed interest for clinical development in women with disseminated chemorefractory ovarian cancers. About two in every five women with advanced stage ovarian cancer outlive their disease after the first treatment phase, with the rest rendered incurable due to the chemorefractory nature of their disease. The National Cancer Institute (NCI) Cancer Therapy Evaluation Program conducted 67 phase I or phase Ib trials among women with relapsed or refractory ovarian cancer between 1989 and 2017 in an effort to uncover tolerable and effective drug combinations intended to increase survival rates. None of these early clinical development phase trials involved radiopharmaceuticals. Here, the NCI provides its perspective on targeted radiopharmaceutical conjugates alone or in combination with its experimental therapeutics portfolio for women with relapsed or refractory ovarian cancer. An infrastructure build for Federal radiopharmaceutical medical monitoring and adverse event reporting has begun.

Abstract A069: NIM15 blockade – A new stroma-targeting approach for the treatment of epithelial ovarian cancer

Abstract Despite the immense research over the past decade in the cancer immunology field, which has led to several clinical trials and FDA and EMA approvals of biologicals for the reinvigoration of T-cell-mediated cancer cell killing in diverse tumor entities, the long-term survival of patients with advanced epithelial ovarian cancer is still devastating. These results therefore imply the need for a more intensive investigation of the tumor microenvironment in this cancer type in order to enhance disease outcome and improve the effectiveness of current immunotherapeutics. We herein show for the first time efficacy data of a novel treatment approach for the specific targeting of the stromal tumor compartment in a human tissue explant culture model of high-grade serous ovarian cancer. Antibody-mediated blockade of NIM15, a protein suspected to be predominantly expressed by tumor-associated macrophages and cancer-associated-fibroblasts in ovarian cancer, has the potential to polarize the immune landscape in a subset of patients from a stromal-dense and immunosuppressive one into a Th1-M1-supportive microenvironment, as measured by cytokine pattern analyses and semiautomated immune cell quantification. Abrogating the effects of secreted NIM15 unleashes in vitro proliferation of T-cell subsets and increases the production of cytokines and chemokines involved in innate and adaptive antitumor immune responses in our tissue culture explant model. In order to unravel the mechanistic relations behind the observed effects, we plan further experiments to prove whether these might be due to a disruption of the collagen-dense tumor stroma and a repolarization of the secretory profile of tumor-associated macrophages and fibroblasts. In summary, we hope to develop a pharmacologic tool that converts immune-depleted, “cold” cancer types into T-cell infiltrated ones and therewith provide a rationale for combination treatment approaches, like anti-PD1 blockade or adoptive cell transfer, to further ameliorate the so far poor response of metastasized, refractory ovarian cancer. Citation Format: Dyke Ferber, Meggy Suarez-Carmona, Frank Momburg, Marten Meyer, Rebecca Rothenheber, Bénédicte M.A. Lenoir, Sarah Schott, Inka Zoernig, Dirk Jäger, Niels Halama. NIM15 blockade – A new stroma-targeting approach for the treatment of epithelial ovarian cancer [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A069.

In Vivo Persistence and Function of Adaptive NK Cell Infusions (FATE-NK100) from CMV Seropositive Haploidentical Related Donors

Adoptive transfer of peripheral blood natural killer (NK) cells from related haploidentical donors incubated in IL-2 persist and expand in vivo and induce clinical responses in patients with AML or ovarian cancer. Individuals who have been exposed to human cytomegalovirus (CMV) have a unique subset of CD57+/NKG2C+ NK cells that are long lived with properties of immunologic memory, potent mediators of antibody dependent cellular cytotoxicity (ADCC), and resistant to tumor suppressive mechanisms. We developed a 7 day culture process (including GSK3b inhibition and IL-15) to produce a purified adaptive NK cell product (FATE-NK100) from CMV seropositive related haploidentical donors. We are testing this product in two phase 1 clinical trials, one for refractory ovarian cancer (NCT03213964) and one for refractory AML (NCT03050216). After intermediate dose Cy/Flu, 4 patients with ovarian cancer have safely received FATE-NK100 cells delivered intraperitoneally with 6 doses of 6 million units of IL-2 given every other day. Ascites samples demonstrate persistence of the donor NK cell product based on flow cytometric analysis of donor vs. recipient HLA on NK cells. At dose cohorts 2 and 3 (maximum), all subjects had intraperitoneal NK cells of donor origin at Day 5-7 (60-90%), persisting at Day 9 (10-40%) and up to 21 days after infusion in one patient. Importantly, functional assays of the in vivo samples from the patients demonstrate high proliferation based on Ki67 and superior function compared to endogenous patient NK cells based on CD107a degranulation and IFNg production when stimulated with K562 (Figure 1). Clinical activity has been observed and the patient with NK persistence at Day 21 had stable disease and was eligible for re-treatment. The in vivo persistence and function of the FATE-NK100 product was maintained after redosing. Similarly, in 4 evaluable patients with AML treated after higher dose Cy/Flu with IV FATE-NK100 and 6 doses of subcutaneous IL-2 6mu, NK cells of donor origin were detected in the peripheral blood at Day 7 (55-100%), persisting up to 28 days in one patient. All patients at dose cohort 2 achieved clearance of their refractory AML at Day 14 (morphologic leukemia free state) and we await enrollment to the 3rd (maximum) dose cohort (3-10 × 107 NC/kg). In summary, FATE-NK100 cell infusions persist in vivo in both the peritoneum and peripheral blood and exhibit potent functional activity.

Efficacy and Safety of Avelumab for Patients With Recurrent or Refractory Ovarian Cancer

ImportanceCurrent treatment options for progressive ovarian cancer provide limited benefit, particularly in patients whose disease has become resistant to platinum-based chemotherapy.ObjectiveTo assess the efficacy and safety of avelumab, an anti–programmed death-ligand 1 agent, in a cohort of patients with previously treated recurrent or refractory ovarian cancer.Design, Setting, and ParticipantsIn an expansion cohort of a phase 1b, open-label study (JAVELIN Solid Tumor), 125 patients with advanced ovarian cancer who had received chemotherapy including a platinum agent were enrolled between November 6, 2013, and August 27, 2015. Statistical analysis was performed from December 31, 2016, to October 9, 2018.InterventionPatients received avelumab, 10 mg/kg, every 2 weeks until disease progression, unacceptable toxic effects, or withdrawal from the study.Main Outcomes and MeasuresPrespecified end points in this cohort included confirmed best overall response (per Response Evaluation Criteria In Solid Tumors, version 1.1), immune-related best overall response, duration of response, progression-free survival, overall survival, results of programmed death-ligand 1 expression–based analyses, and safety.ResultsA total of 125 women (median age, 62.0 years [range, 27-84 years]) who had received a median of 3 prior lines of treatment (range, 0-10) for advanced disease were enrolled in the study. Patients received avelumab for a median of 2.8 months (range, 0.5-27.4 months), with a median follow-up of 26.6 months (range, 16-38 months). A confirmed objective response occurred in 12 patients (9.6%; 95% CI, 5.1%-16.2%), including a complete response in 1 patient (0.8%) and a partial response in 11 patients (8.8%). The 1-year progression-free survival rate was 10.2% (95% CI, 5.4%-16.7%) and median overall survival was 11.2 months (95% CI, 8.7-15.4 months). Infusion-related reactions occurred in 25 patients (20.0%). Other frequent treatment-related adverse events (any grade event occurring in ≥10% of patients) were fatigue (17 [13.6%]), diarrhea (15 [12.0%]), and nausea (14 [11.2%]). Grade 3 or higher treatment-related adverse events occurred in 9 patients (7.2%), of which only the level of lipase increased (3 [2.4%]) occurred in more than 1 patient. Twenty-one patients (16.8%) had an immune-related adverse event of any grade. No treatment-related deaths occurred.Conclusions and RelevanceAvelumab demonstrated antitumor activity and acceptable safety in heavily pretreated patients with recurrent or refractory ovarian cancer.Trial RegistrationClinicalTrials.gov identifier: NCT01772004

Delta tocotrienol in recurrent ovarian cancer. A phase II trial

Delta tocotrienol has anti-neoplastic activity as demonstrated in several in-vitro and in-vivo investigations. The effect relies on inhibition of different pathways. It also has antiangiogenic activity, and an additive effect to bevacizumab may be expected.The present study was a phase II trial of bevacizumab combined with tocotrienol in chemotherapy refractory ovarian cancer. The study also included analysis of circulating tumor specific HOXA9 methylated DNA (HOXA9 meth-ctDNA) during treatment.The study included 23 patients. The rate of disease stabilization was 70% with very low toxicity. The median PFS was 6.9 months and the median OS 10.9 months, which is rather high compared to the current literature. A division of the patients according to level of HOXA9 meth-ctDNA already after the first cycle of chemotherapy resulted in two groups of patients with different prognoses. Patients with an increasing level of HOXA9 meth-ctDNA had a median PFS and OS of 1.4 and 4.3 months, respectively, compared to 7.8 and 12 months in the group with stable or decreasing levels.The combination of bevacizumab and tocotrienol is potent in chemotherapy refractory ovarian cancer. The level of HOXA9 meth-ctDNA after one cycle of chemotherapy holds important prognostic information.

Oral metronomic chemotherapy for recurrent & refractory epithelial ovarian cancer: A retrospective analysis.

Background & objectives:Advanced epithelial ovarian cancer (EOC) is associated with dismal outcome and progression-free survival (PFS) shortens with each subsequent relapse. For patients with recurrent and platinum refractory disease, therapeutic options are limited. Oral metronomic therapy (OMT) is associated with symptomatic relief and stable response in a significant proportion of patients. We retrospectively evaluated the outcome of patients with EOC treated with OMT at a tertiary care hospital in north India.Methods:Between January 2011 to December 2017, 36 EOC patients received OMT. Patients’ median age was 50 yr (range, 38-81 yr) and they had received a median of two lines of prior chemotherapy. OMT regimen included a combination of cyclophosphamide, etoposide (VP-16) and celecoxib with or without pazopanib along with supportive care. Response rates and outcomes were ascertained using the Gynecological Cancer Intergroup Guidelines. The toxicity was graded according to the Common Terminology Criteria for Adverse Events v.4.03.Results:The median CA-125 before initiating OMT was 160 U/ml (range, 42.23-5330 U/ml). The median interval between last chemotherapy and starting OMT regimen was 159 days (range, 1-1211 days). The overall response rate was 50 per cent. The median progression-free survival (PFS) was 8.2 months [95% confidence interval (CI): 5.03-10.33], and the median overall survival was 38 months (95% CI: 25.6-NR). Patients who received two lines of chemotherapy before OMT (P=0.052) and those who received pazopanib-based OMT (P=0.0513) had better PFS.Interpretation & conclusions:For patients with relapse and refractory EOC, OMT could be a reasonable option. A combination of oral etoposide (VP-16) and pazopanib needs further evaluation in a large number of patients in a randomized trial.

Anti-cancer Immunotherapy Epitope-peptides Vaccination in Patients with Refractory/Persistent Disease of Cervical Cancer and Ovarian Cancer (Phase 1 Studies)

Despite the improvement of treatments, refractory or chemotherapy resistant ovarian and cervical cancers have been still incurable. In such tumors, the actionable salvage gene-pathways of up-regulating lung cancer 10 (URLC10), hypoxia inducible factor (HIF) and its core protein HIG2- tumor growth factor beta (TGF beta)- the Caenorhabditis elegans SMA (small worm phenotype) and Drosophila Mothers Against Decapentaplegic (SMAD), maternal embryonic leucine zipper kinase (MELK)- forkhead box M1 (FOXM1) which induces and stimulates stathmin concerning cell (vascular endothelial cell and tumor cell) migration and counter pathway of P53, and holliday junction recognition protein (HJURP)-histone H3-like centromeric protein A (CEMPA)-Histone, which play important roles in tumor proliferation, metastasis and cell cycling. They had been shifted from original driver gene such as Ras-MAPK or PIK3CA-mTOR. Furthermore, tumor specific micro-environmental factors such as vascular endothelial growth factor (VEGF) receptors facilitate tumor new-angiogenesis, invasion and metastasis, as well. We found human leukocyte antigen (HLA)-A*2402 and 0201 restricted epitope neo-antigens or, epitope peptides of VEGF receptor 1 and 2, using micro-cDNA assay form clinical samples. The peptides consisted in nine to eleven mer peptides, which were presented by HLA (major histocompatibility 1) on cell membrane. We administered the multiple peptides subcutaneously as vaccination and it activated intrinsic cell immune system of cytotoxic T cell (CTL). We conducted a phase 1/2 study of those peptides vaccine (PV) cocktails to elucidate their toxicity profiles and efficacy from 4 June 2010 to Jan 2013 for phase 1 studies, and subsequently continued phase 2 studies at outpatient’s clinic of our hospital. PV were administered at a dose of 1mg of each peptide with MONTANIDE*ISA51 (SEPPIC Co. Ltd, France). Enrollees were obtained written informed consent after our IRB approval on 3 June 2010. In results, no major adverse events were seen except dermatologic reactions at injection site. One patient showed complete response, two showed partial response and 10 showed stable disease out of 22 evaluable patients. Median overall survival was 5 months and 9 months in HLA-A2402 and 0201 group, respectively. In conclusion, these findings suggest the peptides cocktail vaccines were safe and applicable for advanced/recurrent OC.

New therapeutic strategies for refractory ovarian cancer with molecular targeted drugs targeting EpCAM-positive cancer stem cells

New therapeutic strategies for refractory ovarian cancer with molecular targeted drugs targeting EpCAM-positive cancer stem cells

Bevacizumab improves overall survival in platinum refractory ovarian cancer patients: A retrospective study

ObjectiveThe objective of this study was to determine the effectiveness of bevacizumab (BV) in combination with chemotherapeutic regimens for prolonging progression-free survival (PFS) as well as overall survival (OS) in patients with platinum-refractory ovarian cancer. Materials and methodsWe retrospectively reviewed the medical records of platinum-refractory ovarian cancer patients receiving chemotherapy between January 2010 and August 2015 in the Department of Gynecology at the Saitama Medical Center, Jichi Medical University. After excluding for prior malignant disease, 57 patients were enrolled. The study end points included PFS and OS. ResultsMedian PFS and OS rates of patients with and without BV were 6.0 (1.9–10.1) and 3.0 (2.1–3.8), and 12.0 (7.7–23.2) and 7.0 (3.7–10.2), respectively, (PFS: P = 0.005 and OS: P = 0.008). Following univariate analysis, stage, Eastern Cooperative Oncology Group performance status, chemotherapy regimens after platinum-refractory diagnosis, BV treatment status, ascites, and abdominal/gastrointestinal symptom with chemotherapy were significant factors. However, following multivariate analysis, chemotherapy regimens after platinum-refractory diagnosis, BV treatment status, and worsening symptoms with chemotherapy were significant factors. Hypertension and proteinuria rates were significantly more frequent in BV-treated patients, but severe adverse events were not significant. BV significantly improved OS in platinum-refractory ovarian cancer patients. ConclusionOur findings may potentially aid in developing treatment strategies for platinum-refractory patients with poor prognoses.