Refractory Epithelial Ovarian Cancer Research Articles

Trial START-001: A phase 1/2 study of STAR0602, a first-in-class, selective T cell receptor (TCR)-targeting, bifunctional antibody-fusion molecule, as monotherapy in patients with antigen-rich tumors post checkpoint inhibitor (CPI) treatment.

TPS2671 Background: Many patients do not respond to CPI-based therapies and most responders eventually develop resistance. Thus, the development of more effective therapies for CPI treatment resistance is a significant unmet medical need. STAR0602, a first-in-class, TCR β chain-targeting bifunctional antibody fused to a costimulatory molecule, binds the germline Vβ6/Vβ10 TCRs of human alpha/beta (aβ) T cells, and promotes the selective activation and expansion of CD8+ and CD4+ Vβ6/Vβ10 effector memory T cells by simultaneously engaging direct TCR activation with IL-2 receptor binding and activation in cis. Preclinical studies with STAR0602 and its murine surrogate showed potent single-agent anti-tumor activity in multiple CPI-refractory human organoid and murine syngeneic tumor models, and acceptable tolerability and limited cytokine release in monkeys and mice. Durable anti-tumor responses, with long-term protection from tumor re-challenge, was associated with de novo expansion and tumor infiltration of targeted Vβ T cell subsets with a novel effector memory gene signature and striking increase in TCR repertoire diversity. These data provide strong scientific rationale to investigate the safety and efficacy of STAR0602 in patients with CPI-resistant cancers. Methods: Using a 3+3 trial design, Phase 1 of START-001 is a dose escalation through eight provisional dose levels of STAR0602, administered via an intravenous infusion once every two weeks, to determine a recommended Phase 2 dose (RP2D), based on safety and tolerability, pharmacokinetics, pharmacodynamics, and preliminary anti-tumor activity. Subjects must have one of the following, histologically confirmed solid tumors that are unresectable, locally advanced or metastatic and for which standard curative therapies do not exist or are no longer effective: 1) high mutational burden solid tumors (TMB-H); 2) MSI-H/mismatch repair-deficient (dMMR) cancers; 3) Virally associated tumors including Merkel cell carcinoma, cervical, oropharyngeal, anal, penile, vaginal, and vulval cancers. After an RP2D is selected, Phase 2 (dose expansion at this RP2D) will begin to further investigate the safety and preliminary anti-tumor activity of STAR0602 in 10 provisional cohorts of patients who have the following solid tumors: TMB-H, CPI experienced; TMB-H, no prior CPI experience; MSI-H/dMMR; virally associated tumors; K-RAS wild-type and MSI-L/MMR proficient colorectal cancer (CRC); K-Ras mutant CRC; metastatic triple-negative breast cancer; relapsed and refractory epithelial ovarian cancer; metastatic castration-resistant prostate cancer; primary stage IV or recurrent non-small cell lung cancer. Phase 1 enrollment has begun since January 2023. Clinical trial information: NCT05592626 .

Correlation of cyclin E1 expression and clinical outcomes in a phase 1b dose-escalation study of azenosertib (ZN-c3), a WEE1 inhibitor, in combination with chemotherapy (CT) in patients (pts) with platinum-resistant or refractory (R/R) epithelial ovarian, peritoneal, or fallopian tube cancer (EOC).

5513 Background: Azenosertib (ZN-c3) is a novel, selective, and orally bioavailable WEE1 inhibitor demonstrating single-agent antitumor activity. Azenosertib may inhibit CT-induced DNA damage repair and provide benefit in pts with platinum R/R EOC. Cyclin E1 amplification/overexpression is present in ≥35% of metastatic ovarian cancer. High expression/amplification of Cyclin E1 is a poor prognostic marker and predictive of lack of response to platinum-based CT. Ovarian models overexpressing Cyclin E1 have exquisite sensitivity to azenosertib in vitro and in vivo; forced Cyclin E1 overexpression sensitizes cell lines with low endogenous Cyclin E1 to azenosertib. Methods: This open-label, multicenter study (NCT04516447) assessed azenosertib + paclitaxel (PAC), carboplatin (Carbo), gemcitabine (GEM), or pegylated liposomal doxorubicin (PLD) in pts with metastatic high-grade serous EOC after ≤2 lines of CT including platinum CT. Primary endpoint is safety and identification of RP2D of each combination. Secondary endpoints include clinical activity. Azenosertib was given continuously or intermittently QD in 21 or 28D cycles until PD or unacceptable toxicity. Results: 103 pts were enrolled; at data cut-off, 94 were efficacy evaluable. 26.6% had a partial response (PR) and median progression free survival (PFS) = 9.03 mo (95%CI: 5.52-11.01). Azenosertib + PAC demonstrated the highest ORR [9/18 (50%)], followed by Carbo [9/27 (33.3%)]; ORR for azenosertib + PLD or + GEM was 14.3% (5/35, 2/14 respectively). 80 pts had available Cyclin E1 expression data by IHC; higher Cyclin E1 (H-score >50) correlated with higher ORR and longer PFS (ORR = 31.3% vs 7.7%; PFS = 10.35 vs 3.25 mo, HR=0.3; Table). Frequent Grade ≥3 TEAEs (%) were neutropenia (44.4), thrombocytopenia (30.3), anemia (12.1), leukopenia (11.1), fatigue (10.1), diarrhea (6.1), nausea (5.1), and vomiting (5.1). Conclusions: Azenosertib + CT is well tolerated and has encouraging clinical activity, with durable responses in pts with platinum R/R EOC. Pts with Cyclin E1 overexpressing tumors, a subgroup with suboptimal benefits from CT, demonstrated significant improvements in ORR and PFS vs pts with tumors having low expression. These data support a planned trial of azenosertib + CT vs CT alone in Cyclin E1 overexpressing platinum R/R EOC. Clinical trial information: NCT04516447 . [Table: see text]

Outcomes and Prognostic Factors of Patients with Platinum- Resistant or Refractory Epithelial Ovarian Cancer, Fallopian Tube Cancer and Peritoneal Cancer.

To determine the survival outcomes and prognostic factors of the patients with recurrent platinumresistant and refractory epithelial ovarian cancer (EOC), tubal, and peritoneal cancer. Women with recurrent platinum-resistant and refractory EOC, tubal and peritoneal cancer who received treatment at the HRH Princess Maha Chakri Sirindhorn Medical Center (MSMC) between January 2010 and December 2019 were included. Demographic data, serum marker, surgical factors, pathological factors and response of treatment were reviewed. Kaplan-Meier was used to calculate survival outcome. Forty patients were recruited in this study (platinum-resistant 24 patients and refractory 16 patients). The median survival times were 19 and 21 months in and platinum-resistant and platinumrefractory patients, respectively. There were no significant differences in overall survival according to age, comorbidity, tumor grading, primary treatment, and secondary surgery. However, histology of clear cell carcinoma may associate with increased risk of death. The median overall survival of patients with clear cell carcinoma, serous carcinoma, and others were 14.4, 22.9, and 32.2, respectively (p = 0.003). Almost 10 years, the survival rate of the patients in these group has not increased despite new treatments option. Novel strategies should be considered in National policy of the treatment for ovarian cancer in our country.

Effectiveness of oral etoposide in recurrent or refractory epithelial ovarian cancer, primary peritoneal cancer and fallopian tube cancer

The aim of treatment in recurrent or refractory epithelial ovarian cancer is palliation. In a patient with platinum-resistant status, several chemotherapy regimens have been reported with similar response rates. Among these agents, the oral etoposide holds an advantage of the route of administration and management in the out-patient setting. This retrospective study was conducted to evaluate the effectiveness of oral etoposide. Data of patients with recurrent or refractory epithelial ovarian, primary peritoneal and fallopian tube cancer who received oral etoposide treatment in Ramathibodi Hospital, Mahidol University from January 1997 to December 2017 were collected. Progression-free survival (PFS) and overall survival (OS) were primary and secondary outcomes, respectively. The oral etoposide at a dose of 50 mg/m2 was prescribed. Sixty-six records were analysed. Median OS and median PFS were 8.3 months (95% confidence interval (CI): 6.8, 10.4) and 3.1 months (95%CI: 2.3, 3.9), respectively. Other factors including age, body mass index (BMI), histopathology subtype, primary treatment, result of the primary surgery, platinum status, site and size of recurrent cancer, treatment after discontinuation of oral etoposide and the line of chemotherapy regimen were not associated with the prognosis. The initial cancer stage was the only independent poor prognostic factor. The main toxicity was neutropenia. Impact Statement What is already known on this subject? After the recurrence of epithelial ovarian cancer, peritoneal cancer or fallopian tube cancer, the aim of treatment in this setting is palliation with accentuating on symptomatic control and enhancing the quality of life. According to previous clinical trials, the chemotherapy regimens which were considered as a second-line or beyond the second-line therapy have been reported with similar response rates. Among these agents, the oral etoposide could be administrated by oral route. There were several articles reported the effectiveness of oral etoposide in different dosage. What do the results of this study add? This study adds that administration of oral etoposide at a dose of 50 mg/m2 showed fairish oncologic outcomes with manageable toxicity. What are the implications of these findings for clinical practice and/ or further research? The results will provide evidence that the oral etoposide can be considerate as a choice of palliative chemotherapy because of an advantage of the route of administration and management in the out-patient setting.

Randomized phase II trial of durvalumab (anti-PDL1) and tremelimumab (anti-CTLA4) administered in combination versus sequentially for the treatment of recurrent platinum-resistant non-clear cell ovarian cancer (NCT03026062)

<h3>Objectives:</h3> Single agent immune checkpoint blockade (ICB) has demonstrated response rates of 5-15% in patients with recurrent high-grade ovarian cancer (HGOC), with another 15-40% of patients achieving stable disease. Combination ICB using ipilimumab and nivolumab resulted in improved response rates in a mixed population with platinum resistant and sensitive disease. The objective of the current trial was to evaluate sequential versus combination CTLA4 and PDL1 blockade strategies for extending progression free survival (PFS) in patients with platinum resistant/refractory HGOC. <h3>Methods:</h3> Patients were required to have pathologically confirmed platinum resistant or refractory epithelial ovarian cancer, no prior immunotherapy, and PS=0-1 for enrollment. The current abstract includes data only on subjects with high grade serous ovarian cancer (HGSOC), as enrollment of patients with clear cell histology is still ongoing. The primary endpoint was PFS and response was assessed using modified RECIST v1.1. Unlimited numbers of prior regimens were allowed. Patients were adaptively randomized to sequential arm: tremelimumab (3mg/kg q4 weeks x 4 doses) followed by durvalumab (1.5g IV q4 weeks for up to 9 doses) upon progression, or the combination arm: tremelimumab (1mg/kg IV plus durvalumab 1.5g IV q4wk for up to 4 doses followed by durvalumab monotherapy for up to 9 doses). For the Bayesian adaptive randomization, the probability of being assigned to an arm was proportional to the likelihood the arm had better PFS, such that patients were more likely to be randomized to the more effective arm. <h3>Results:</h3> A total of 61 subjects were adaptively randomized to sequential treatment (n=38) or combination therapy (n=23). 46 (79%) patients had wild-type breast cancer gene (<i>BRCA</i>). Median prior lines of therapy was 4 (range: 1-10). There was no difference in median PFS in the sequential arm (1.84 months; 95% CI: 1.77 – 2.17)) compared with the combination arm (1.87 months; 95% CI: 1.77 – 2.43), p=0.402. Similarly, median OS in the sequential and combination arms were 10.61 months (5.95 – 15.34) and 7.26 (4.24 – 15.57), respectively (p=0.810). In the sequential arm no objective responses were observed, although 12 patients (31.6%) exhibited stable disease. In the combination arm, 2 patients had partial response (8.7%) while one additional patient (4.4%) had stable disease. The adverse event profile was consistent with that previously reported for immune checkpoint therapy. <h3>Conclusions:</h3> There was no difference in the median PFS between the combination and sequential durvalumab plus tremelimumab treatment strategy arms in a heavily pretreated population of patients with platinum resistant/refractory HGOC. Response rates were comparable to prior reports, though the combination regimen did not add significant benefit as has been previously described with combination of ipilimumab/nivolumab. Further exploration into subpopulations that may have increased benefit from ICB is warranted.

Phase 1 dose-escalation study of STRO-002, an antifolate receptor alpha (FRα) antibody drug conjugate (ADC), in patients with advanced, progressive platinum-resistant/refractory epithelial ovarian cancer (EOC).

5550 Background: STRO-002-GM1 is a Phase 1, open-label study in patients (pts) with advanced, platinum resistant or refractory EOC. STRO-002 is a novel FRα-targeting ADC with a precise DAR of 4 using site-specific conjugation technology to circumvent limitations of current ADCs. STRO-002 induces immunogenic cell death and contains the tubulin-targeting 3-aminophenyl hemiasterlin warhead SC209, a potent cytotoxin that is a weak substrate for P-gp. Methods: STRO-002 is given IV on Day 1 of each 21-day cycle until disease progression. Ocular exams are performed at baseline and every other cycle. Prophylactic corticosteroid eyedrops are not administered. FRα expression was not required for eligibility and retrospective analysis of FRα expression in archival tumor tissue is ongoing. Results: Enrollment has been completed with 39 pts treated at 9 dose levels (0.5 to 6.4 mg/kg). Data cut-off is Jan 30, 2021. Median age was 61 years (range 48-79). Median number of prior systemic therapies was 6 (range 2-11). 86% of treatment emergent adverse events (AEs) were Grade 1-2. The most common treatment related Grade 3 and 4 AEs were reversible neutrophil count decreased (36%) and neutropenia (33%), Grade 3 arthralgia (12.8%) and neuropathy (7.7%). Two pts developed neutropenic fever that resolved with antibiotic therapy. 34 pts were treated at clinically active doses (≥ 2.9 mg/kg) and 31/34 are evaluable for RECIST 1.1 response. Objective responses were seen in 10/31 pts - 1 CR, 4 confirmed PR, and 5 unconfirmed PR (imaging studies under review in 1 pt with uPR). Disease control rate (CR+PR+SD) is 74% at ≥ 12 weeks and 61% at ≥ 16 weeks. 5 pts remain on treatment with 3 ongoing at &gt; 74 weeks. FRα-expression results are available in 14 pts treated at ≥ 2.9 mg/kg with 50% low, 21% medium and 29% high FRα-expressing tumors per PS2+ scoring algorithm. 12/13 pts with H-scores of ≥ 105 achieved disease control with PR or SD. Maximum plasma concentrations of STRO-002 were achieved at the end of the 1 hour infusion and exposure increased in an apparent dose proportionate/linear manner. Conclusions: STRO-002 is a novel FRα-targeting ADC with an encouraging emerging safety and efficacy profile in heavily pretreated relapsed/refractory EOC. No ocular toxicity signals have been observed. Durable responses and anti-tumor activity have been demonstrated across a broad range of FRα expression levels in evaluable pts treated at ≥ 2.9 mg/kg. 48% (15/31) of pts were on treatment without disease progression for ≥ 24 weeks and 13% (4/31) remain on treatment for over a year, suggesting that STRO-002 is well tolerated in long-term responding patients. A randomized expansion cohort comparing STRO-002 at 4.3 mg/kg vs 5.2 mg/kg dose levels in less heavily pretreated EOC pts is ongoing. Clinical trial information: NCT03748186.

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&lt; 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.

Pazopanib and Oral Cyclophosphamide in Women With Platinum-Resistant or -Refractory Epithelial Ovarian Cancer.

PURPOSEWomen with recurrent, multiply-treated epithelial ovarian cancer (EOC) have unfavorable prognosis with limited treatment options after failure of platinum-based regimens. We report here a retrospective analysis of women with recurrent, platinum-resistant EOC treated with an oral regimen of pazopanib and cyclophosphamide.PATIENTS AND METHODSWomen with recurrent platinum-resistant or -refractory EOC were treated with pazopanib (600 mg orally daily in 2 divided doses, 400 and 200 mg) and cyclophosphamide (50 mg orally daily for 21 days every 28 days) until disease progression or unacceptable toxicity.RESULTSTwenty patients (17 with platinum-resistant and 3 with platinum-refractory disease) were treated between April 2014 and April 2018. Patients had a median age of 52 years (range, 40-60 years) and median of 4 previous lines of chemotherapy (range, 2-8 previous lines), including 3 patients with progressive disease on bevacizumab. Patients received a median of 6 cycles (range, 2-48 cycles) of pazopanib and cyclophosphamide, with best responses of partial response in 9 patients (45%, including 1 of 3 patients treated previously with bevacizumab), stable disease in 6 patients (30%), and disease progression in 5 patients (25%). The median progression-free survival time was 5.5 months, and median overall survival was 9.5 months. Common adverse events (grade 3 or 4) were fatigue (25%), diarrhea (15%), hand-foot syndrome (10%), mucositis (10%), transaminitis (5%), and hypertension (5%). Dose reduction as a result of toxicity was required in 14 patients (70%), and no patient stopped treatment as a result of toxicity.CONCLUSIONPazopanib plus oral cyclophosphamide is a well-tolerated regimen with clinically relevant benefit in patients with platinum-resistant or -refractory EOC.

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

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.

Abstract 75: A phase I trial of mesenchymal stem cells transfected with a plasmid secreting interferon beta in advanced ovarian cancer

Abstract Background: Standard treatment for ovarian cancer with a platinum and taxane is effective initially but associated with significant relapse. Our group was first to demonstrate genetically modified MSC preferentially engraft and secrete gene products such as interferon beta (IFNB) at tumor sites, resulting in complete responses in animal models (Studeny M et al. Cancer Res 2002;62:3603; JNCI 2004;96:1593). Methods: We conducted a single-center phase 1 trial to evaluate the safety, feasibility tumor response of mesenchymal stem cells transfected with plasmid secreting IFNB administered via intraperitoneal infusion (IPI) for women with advanced refractory epithelial ovarian cancer. We electroporated MSC derived from male donors with a plasmid vector containing the IFNB gene (MSC-IFNB). MSC-IFNB were then administered on an outpatient basis via IPI. Pretreatment biopsy, peritoneal fluid sample, blood draw, and a CT were performed at enrollment. Results: Three patients were enrolled at dose level 1 (105 MSC/kg) and received 4 weekly IPI of MSC-IFNB between 6-10/2016. After the 4th dose we performed a restaging CT and a biopsy, which was examined by FISH for the presence of male Y-chromosome positive MSCs, for production of IFNB assessed by multispectral multiplexed IHC, presence of injected MSCs, changes in immune cell phenotypes, and tumor cell death. We demonstrated detectable production of IFNB in the serum of patient 1, and at week 4 detection of IFNB in the peritoneal fluid, suggesting injected MSC-IFNB produce IFNB locally. We performed multispectral analysis to identify and quantitate the constituents of the ovarian tumor microenvironment in pre- and post-treatment biopsy specimens. We focused on ovarian tumor cells (CK3/5+,AE1+), as well as stromal cells (αSMA+), and IFNB. We observed in all 3 patients colocalization of IFNB (red) with αSMA-(green,) suggesting MSC homing and production of IFNB at tumor stroma interface. To confirm the presence of injected MSC (derived from male donors), we then analyzed the pre- and post-treatment tumor biopsies for presence of the “XY” chromosome by FISH. We identified “XY” chromosomes MSC only in the post-tumor biopsy, suggesting incorporation of injected MSC at the tumor site. There were no infusion- or MSC-related adverse events and 1 patient had stable disease on CT scan at 4 months after treatment. Conclusion: We demonstrate, for the first time, proof of principle that MSC-IFNB home to and are incorporated into tumors and locally produce beta-interferon after IP injection in patients with ovarian cancer. We anticipate increased responses at higher MSC dose levels and envision MSC-IFNB may be used in combination with immunotherapies and chemotherapy, as we have shown in animal models that MSC-IFNB modulate the immune phenoptype of the tumor, recruit FOXp3 immune cells, and facilitate long-term control of tumor growth and metastases. Citation Format: Michael Andreeff, Frank C. Marini, Shannon N. Westin, Robert L. Coleman, Peter F. Thall, Vivian Aljahdami, Muzaffar H. Qazilbash, Katy Rezvani, Melissa Timmons, Lauren Heese, Rui-Yu Wang, Richard E. Champlin, Elizabeth J. Shpall, Amanda Olson. A phase I trial of mesenchymal stem cells transfected with a plasmid secreting interferon beta in advanced ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 75.

Efficacy of ChemoID® guided drug selection for palliative chemotherapy in advanced recurrent high-grade ovarian adenocarcinoma: Case study

Notwithstanding tremendous advances in surgery, primary chemotherapy, and novel treatments for recurrent disease, the diagnosis of advanced epithelial ovarian cancer (EOC) in 2016 remains ultimately fatal in the majority of cases. Advanced therapy refractory EOC patients are often treated in hospice and with chemotherapy palliative care. The main goals of chemotherapy for recurrent/refractory ovarian cancer are the palliation of disease-related symptoms, and improvement of quality and quantity of life. Unfortunately, there is contradicting evidence suggesting that chemotherapy has a role in palliation of symptoms with an apparent improvement in quality of life. Anticancer drugs have a high rate of failure and chemotherapy response assays have been used to identify which drugs are more likely to be effective against those of gynecological origin. ChemoID® is a functional drug response assay which measures the sensitivity of cancer stem cells (CSCs) and bulk of tumor cells to chemotherapy to determine the most effective combination of anticancer drugs for solid tumors. We present a clinical case that demonstrates the utility of ChemoID® guidance to commonly available drugs with identified toxicity profiles and predictable cost profile available at POS, along with rapid response in correcting symptomatic disease features, and minimal treatment burden from toxicities. We observed in the reported case the survival and symptom management benefits of ChemoID® guided therapy even after plateau of response to cisplatin. Further studies are indicated to increase the clinical adoption of ChemoID® for gynecological malignancies in the palliative setting.

Cost Effectiveness Analysis of Different Management Strategies between Best Supportive Care and Second-line Chemotherapy for Platinum-resistant or Refractory Ovarian Cancer.

There is no standard treatment for patients with platinum-resistant or refractory epithelial ovarian cancer. Single agent chemotherapies have evidence of more efficacy and less toxicity than combination therapy. Most are very expensive, with appreciable toxicity and minimal survival. Since it is difficult to make comparison between outcomes, economic analysis of single-agent chemotherapy regimens and best supportive care may help to make decisions about an appropriate management for the affected patients. To evaluate the cost effectiveness of second-line chemotherapy compared with best supportive care for patients with platinum-resistant or refractory epithelial ovarian cancer. A Markov model was used to estimate the effectiveness and total costs associated with treatments. The hypothetical patient population comprised women aged 55 with platinum-resistant or refractory epithelial ovarian cancer. Four types of alternative treatment options were evaluated: 1) gemcitabine followed by BSC; 2) pegylated liposomal doxorubicin (PLD) followed by BSC; 3) gemcitabine followed by topotecan; and 4) PLD followed by topotecan. Baseline comparator of alternative treatments was BSC. Time horizon of the analysis was 2 years. Health care provider perspective and 3% discount rate were used to determine the costs of medical treatment in this study. Quality-adjusted life-years (QALY) were used to measure the treatment effectiveness. Treatment effectiveness data were derived from the literature. Costs were calculated from unit cost treatment of epithelial ovarian cancer patients at various stages of disease in King Chulalongkorn Memorial Hospital (KCMH) in the year 2011. Parameter uncertainty was tested in probabilistic sensitivity analysis by using Monte Carlo simulation. One-way sensitivity analysis was used to explore each variable's impact on the uncertainty of the results. Approximated life expectancy of best supportive care was 0.182 years and its total cost was 26,862 Baht. All four alternative treatments increased life expectancy. Life expectancy of gemcitabine followed by BSC, PLD followed by BSC, gemcitabine followed by topotecan and PLD followed by topotecan was 0.510, 0.513, 0.566, and 0.570 years, respectively. The total cost of gemcitabine followed by BSC, PLD followed by BSC, gemcitabine followed by topotecan and PLD followed by topotecan was 113,000, 124,302, 139,788 and 151,135 Baht, respectively. PLD followed by topotecan had the highest expected quality-adjusted life-years but was the most expensive of all the above strategies. The incremental cost-effectiveness ratios (ICER) of gemcitabine followed by BSC, PLD followed by BSC, gemcitabine followed by topotecan and PLD followed by topotecan was 344,643, 385,322, 385,856, and 420,299 Baht, respectively. All of the second-line chemotherapy strategies showed certain benefits due to an increased life- year gained compared with best supportive care. Moreover, gemcitabine as second-line chemotherapy followed by best supportive care in progressive disease case was likely to be more effective strategy with less cost from health care provider perspective. Gemcitabine was the most cost-effective treatment among all four alternative treatments. ICER is only an economic factor. Treatment decisions should be based on the patient benefit.

Salvage Chemotherapy in Recurrent Platinum-Resistant or Refractory Epithelial Ovarian Cancer with Carboplatin and Distearoylphosphatidylcholine Pegylated Liposomal Doxorubicin (Lipo-Dox®)

To evaluate the efficacy and safety of distearoylphosphatidylcholine pegylated liposomal doxorubicin (DPLD) combined with carboplatin for the treatment of platinum resistant or refractory epithelial ovarian cancer (EOC) or fallopian tube cancer. A retrospective analysis of women who received DPLD with carboplatin for recurrent EOC or fallopian tube cancer in King Chulalongkorn Memorial Hospital Thailand from January 2006 to August 2011 was conducted. Patients were identified from the medical records and data on demographic factors, stage, histology, surgical findings, cytoreduction status, and prior chemotherapies were abstracted. The efficacy and toxicity of DPLD/carboplatin were evaluated. Progression-free (PFS) and overall survival (OS) were estimated by the Kaplan-Meier method. A total of 65 patients, 64 with platinum resistant or refractory epithelial ovarian cancer and 1 with fallopian tube cancer, were enrolled. DPLD and carboplatin were given for an average of 4.46 cycles per patient with a total of 273 cycles. Among the 65 evaluable patients, 0% achieved CR, 7.69% PR, 15.4% SD and 76.% PD. The overall response rate was 23.1%. With a median follow-up of 27.4 months, the median progression-free and median overall survival in the 36 patients was 4.46 months and 8.76 months respectively. In the aspect of side effects, palmar-plantar erythrodysesthesia (PPE) occurred in 33.3% (Grade I 22.2%, Grade II 11.1%) and mucositis in 41.7% (Grade I 27.8%, Grade II 13.9%) of all treatment cycles, all Grade 1 or 2. Anemia, leukopenia and thrombocytopenia occurred in 58.3% (Grade I 41.7%, Grade II 16.7%), 66.7% (Grade I 47.2%, Grade II 19.4%), and 22.2% (Grade I 16.6%, Grade II 5.56%) of cycle respectively, and were mostly Grade 1 or 2. DPLD, the second-generation PLD drug combined with carboplatin every 4 weeks, is effective and has low toxicity for treatment of patients with recurrent platinum-resistant or refractory epithelial ovarian cancer.

126 Relationship Between Complement Factors and CC Chemokines and the Pharmacokinetics (PK) and Pharmacodynamics (PD) of PEGylated Liposomal Doxorubicin (PLD) in Patients with Refractory Epithelial Ovarian Cancer (EOC)

126 Relationship Between Complement Factors and CC Chemokines and the Pharmacokinetics (PK) and Pharmacodynamics (PD) of PEGylated Liposomal Doxorubicin (PLD) in Patients with Refractory Epithelial Ovarian Cancer (EOC)

Perifosine plus docetaxel in patients with platinum and taxane resistant or refractory high-grade epithelial ovarian cancer

ObjectivesOn the basis of reversal of taxane resistance with AKT inhibition, we initiated a phase I trial of the AKT inhibitor perifosine with docetaxel in taxane and platinum-resistant or refractory epithelial ovarian cancer. MethodsPatients with pathologically confirmed high-grade epithelial ovarian cancer (taxane resistant, n=10; taxane refractory, n=11) were enrolled. Peripheral blood samples and tumor biopsies were obtained and 18F-FDG-PET and DCE-MRI scans were performed for pharmacodynamic and imaging studies. ResultsPatients received a total of 42 treatment cycles. No dose-limiting toxicity was observed. The median progression-free survival and overall survival were 1.9months and 4.5months, respectively. One patient with a PTEN mutation achieved a partial remission (PR) for 7.5months, and another patient with a PIK3CA mutation had stable disease (SD) for 4months. Two other patients without apparent PI3K pathway aberrations achieved SD. Two patients with KRAS mutations demonstrated rapid progression. Decreased phosphorylated S6 correlated with 18F-FDG-PET responses. ConclusionsPatients tolerated perifosine 150mg PO daily plus docetaxel at 75mg/m2 every 4weeks. Further clinical evaluation of effects of perifosine with docetaxel on biological markers and efficacy in patients with ovarian cancer with defined PI3K pathway mutational status is warranted.

Long-term remission in a patient with heavily pretreated, advanced ovarian cancer achieved by bevacizumab and metronomic cyclophosphamide treatment

Vascular endothelial growth factor seems to be a promoter of tumor progression for epithelial ovarian cancer. New drugs such as bevacizumab, either alone or in combination with metronomic chemotherapy, suppress tumor growth and have proved to be effective in various tumor types. We present a 60-year-old patient with heavily pretreated, recurrent epithelial ovarian cancer, who received bevacizumab (10 mg/m(2)) every 2 weeks in combination with metronomic administered low-dose cyclophosphamide (50 mg/day orally) after failing four explorative laparotomies and multiple chemotherapy regimes. At the time of writing, February 2011, she was being treated with this combination therapy for 24 months and the progression-free survival still continues. Treatment of advanced, refractory epithelial ovarian cancer with bevacizumab in combination with low-dose cyclophosphamide could be a very effective salvage treatment option in heavily pretreated patients.

Intraperitoneal treatment with the trifunctional bispecific antibody Catumaxomab in patients with platinum-resistant epithelial ovarian cancer: A phase IIa study of the AGO Study Group

Objective The aim of this study was to select the best catumaxomab regimen for further investigation in ovarian cancer based on confirmed tumour response. Methods Randomised open-label phase IIa study in women with platinum-resistant or -refractory epithelial ovarian cancer. Catumaxomab (6-hour intraperitoneal infusion on days 0, 3, 7 and 10) was administered at a low (10, 10, 10 and 10 μg) or high dose (10, 20, 50 and 100 μg). Responders were patients with either a complete (CR) or partial (PR) response. Results Forty-five patients were randomised to receive either low dose (23) or high dose (22). There were no responders in the low-dose versus one patient (5%) in the high-dose group with a PR. In the low-dose group, two patients (9%) had stable disease compared with five patients (23%) in the high-dose group. Catumaxomab was well tolerated and there was no difference between the dose groups in the incidence of treatment-induced adverse events, the most common of which were gastrointestinal and injection-site reactions. Conclusion Catumaxomab had modest activity in platinum-resistant ovarian cancer. The high-dose regimen was associated with a slightly better therapeutic index than the low dose regimen.

A Pilot Study of Gemcitabine and Epirubicin Combination Chemotherapy as a Salvage Regimen for Recurrent Platinum Resistant and/or Refractory Epithelial Ovarian Cancer

BACKGROUND AND OBJECTIVES: The objective of this study was to assess the antitumor activity and toxicity profile of gemcitabine combined with epirubicin in patients with recurrent platinum refractory ovarian epithelial cancer. PATIENTS AND METHODS: Patients with recurrent platinum refractory ovarian cancer and with adequate hematologic, renal and hepatic function and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 - 2 were enrolled. The regimen was Gemcitabine 1000 mg/m2 (day 1, 8) and Epirubicin 60 mg/m2 (day 1), the cycle was repeated at interval of 21 days. RESULTS: Twenty eight patients were recruited and received 156 cycles of gemcitabine-epirubicin combination chemotherapy (median 6 cycles). Overall response rate was 42.9% (95% CI equal 24.5 to 62.7) and tumor control rate was 75% (95% CI equal 55.1 to 89.3). No complete responses were observed. Median progression-free and median overall survival times were 7 and 15 months, respectively. The most common grade 3/4 hematological toxicities were neutropenia (57.1%), anemia (10.7%), and thrombocytopenia (7.1%), while the most common grade 3/4 non-hematological toxicities were mucositis (14.3%) and vomiting (3.6%). No treatment related deaths were observed. CONCLUSION: Gemcitabine combined with epirubicin regimen appeared to offer an acceptable clinical profile in patients with recurrent platinum-refractory epithelial ovarian cancer.

The Efficacy and Toxicity of Belotecan (CKD-602), A Camptothecin Analogue Topoisomerase I Inhibitor, in Patients with Recurrent or Refractory Epithelial Ovarian Cancer

This study evaluated the efficacy and toxicity of belotecan (CKD-602), a new camptothecin analogue topoisomerase i inhibitor, in patients with recurrent or refractory epithelial ovarian cancer. Data from 63 patients who had been treated with intravenous belotecan (0.5 mg/m2/day), administered for 5 days every 3 weeks at a single institute in Seoul, Korea, were collected retrospectively. The overall response rate was 30.2% including 9 patients with complete remission (CR) and the progression free survival was a median of 6.5 (0.7 - 29.7) months. The platinumsensitive group had a significantly higher response rate and longer progression-free survival more than the platinum- resistant group. The most common adverse effect of belotecan was hematologic toxicity which was tolerable. As a single chemotherapy agent, belotecan was effective in treating recurrent or refractory epithelial ovarian cancer, and had acceptable toxicity. Further studies of the efficacy of belotecan in combination with platinum or the other agents are warranted.