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A Phase I Clinical Trial of Guadecitabine and Carboplatin in Platinum-Resistant, Recurrent Ovarian Cancer: Clinical, Pharmacokinetic, and Pharmacodynamic Analyses.

ABSTRACT: Purpose: Epigenetic changes are implicated in acquired resistance to platinum. Guadecitabine is a next-generation hypomethylating agent (HMA). Here, we report the clinical results, along with pharmacokinetic (PK) and pharmacodynamic analyses of the phase I study of guadecitabine and carboplatin in patients with recurrent, platinum-resistant high-grade serous ovarian cancer, primary peritoneal carcinoma (PPC), or fallopian tube cancer (FTC).Experimental Design: Guadecitabine was administered once daily on days 1 to 5 followed by carboplatin i.v. on day 8 of a 28-day cycle. Patients had either measurable or detectable disease. Safety assessments used CTCAE v4.Results: Twenty patients were enrolled and treated. Median age was 56 years (38-72 years). The median number of prior regimens was 7 (1-14). In the first cohort (N = 6), the starting doses were guadecitabine 45 mg/m2 and carboplatin AUC5. Four patients experienced dose-limiting toxicity (DLT; neutropenia and thrombocytopenia), leading to dose deescalation of guadecitabine to 30 mg/m2 and of carboplatin to AUC4. No DLTs were observed in the subsequent 14 patients. Grade ?3 adverse events ?10% were neutropenia, leukopenia, anemia, nausea, vomiting, ascites, constipation, hypokalemia, pulmonary embolism, small-intestinal obstruction, and thrombocytopenia. Three patients had a partial response (PR), and 6 patients had stable disease (SD) >3 months, for an overall response rate (ORR) and clinical benefit rate of 15% and 45%, respectively. LINE-1 demethylation in PBMCs and promoter demethylation/gene reexpression in paired tumor biopsies/ascites were recorded.Conclusions: Guadecitabine and carboplatin were tolerated and induced clinical responses in a heavily pretreated platinum-resistant ovarian cancer population, supporting a subsequent randomized phase II trial. Clin Cancer Res; 24(10); 2285-93. ©2018 AACR.

SUBMITTER: Matei D

PROVIDER: S-EPMC5955794 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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A Phase I Clinical Trial of Guadecitabine and Carboplatin in Platinum-Resistant, Recurrent Ovarian Cancer: Clinical, Pharmacokinetic, and Pharmacodynamic Analyses.

Matei Daniela D Ghamande Sharad S Roman Lynda L Alvarez Secord Angeles A Nemunaitis John J Markham Merry Jennifer MJ Nephew Kenneth P KP Jueliger Simone S Oganesian Aram A Naim Sue S Su Xiang Yao XY Keer Harold H Azab Mohammad M Fleming Gini F GF

Clinical cancer research : an official journal of the American Association for Cancer Research 20180302 10

<b>Purpose:</b> Epigenetic changes are implicated in acquired resistance to platinum. Guadecitabine is a next-generation hypomethylating agent (HMA). Here, we report the clinical results, along with pharmacokinetic (PK) and pharmacodynamic analyses of the phase I study of guadecitabine and carboplatin in patients with recurrent, platinum-resistant high-grade serous ovarian cancer, primary peritoneal carcinoma (PPC), or fallopian tube cancer (FTC).<b>Experimental Design:</b> Guadecitabine was adm ...[more]

PMID: 29500276

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Project description:OBJECTIVE:Plasma miRNAs represent potential minimally invasive biomarkers to monitor and predict outcomes from chemotherapy. The primary goal of the current study-consisting of patients with recurrent, platinum-resistant ovarian cancer-was to identify the changes in circulating miRNA concentrations associated with decitabine followed by carboplatin chemotherapy treatment. A secondary goal was to associate clinical response with changes in circulating miRNA concentration. METHODS:We measured miRNA concentrations in plasma samples from 14 patients with platinum-resistant, recurrent ovarian cancer enrolled in a phase II clinical trial that were treated with a low dose of the hypomethylating agent (HMA) decitabine for 5 days followed by carboplatin on day 8. The primary endpoint was to determine chemotherapy-associated changes in plasma miRNA concentrations. The secondary endpoint was to correlate miRNA changes with clinical response as measured by progression free survival (PFS). RESULTS:Seventy-eight miRNA plasma concentrations were measured at baseline (before treatment) and at the end of the first cycle of treatment (day 29). Of these, 10 miRNAs (miR-193a-5p, miR-375, miR-339-3p, miR-340-5p, miR-532-3p, miR-133a-3p, miR-25-3p, miR-10a-5p, miR-616-5p, and miR-148b-5p) displayed fold changes in concentration ranging from -2.9 to 4 (p<0.05), in recurrent platinum resistant ovarian cancer patients, that were associated with response to decitabine followed by carboplatin chemotherapy. Furthermore, lower concentrations of miR-148b-5p after this chemotherapy regimen were associated (P<0.05) with the PFS. CONCLUSIONS:This is the first report demonstrating altered circulating miRNA concentrations following a combination platinum plus HMA chemotherapy regiment. In addition, circulating miR-148b-5p concentrations were associated with PFS and may represent a novel biomarker of therapeutic response, with this chemotherapy regimen, in women with recurrent, drug-resistant ovarian cancer.

Project description:BackgroundAnti-programmed death 1 (PD1)/programmed cell death ligand 1 (PD-L1) therapies have shown modest activity as monotherapy in recurrent ovarian cancer. Platinum chemotherapies induce T-cell proliferation and enhance tumor recognition. We assessed activity and safety of pembrolizumab with carboplatin in recurrent platinum-resistant ovarian cancer.Patients and methodsThis phase I/II, single-arm clinical trial studied concurrent carboplatin and pembrolizumab in recurrent platinum-resistant ovarian, fallopian tube, and primary peritoneal cancer. Primary platinum refractory patients were excluded. Patients were treated after progression on subsequent non-platinum systemic therapy after becoming platinum resistant or refractory. Pembrolizumab 200 mg was given on day 1 and carboplatin area under the curve 2 on days 8 and 15 of a 3-week cycle until progression. Imaging was assessed by blinded independent review. PD-L1 expression was assessed by immunohistochemistry. Flow cytometry on peripheral blood mononuclear cells was performed for CD3, CD4, CD8, PD1, CTLA4 and Ki67.ResultsThe most common treatment-related adverse events were lymphopenia (18%) and anemia (9%) with most being grade 1 or 2 (93%). Of 29 patients treated, 23 patients were evaluable for best objective response: 10.3% (95% CI 2.2 to 27.4) had partial response (PR), 51.7% (95% CI 32.5 to 70.6) had stable disease (SD). 56.5% of patients had decreases in target lesions from baseline. All PD-L1-positive patients achieved PR (3/7, 42.8%) or SD (4/7, 57.2%). Median progression-free survival was 4.63 months (95% CI 4.3 to 4.96). Median OS was 11.3 months (95% CI 6.094 to 16.506). Peripheral CD8+PD1+Ki67+ T cells expanded after 3 (p=0.0015) and 5 (p=0.0023) cycles. CTLA4+PD1+CD8+ T cells decreased through the course of treatment up to the 12th cycle (p=0.004). When stratified by ratio of peripheral CD8+PD1+Ki67+ T cells to tumor burden at baseline, patients with a ratio ≥0.0375 who had a significantly longer median OS of 18.37 months compared with those with a ratio <0.0375 who had a median OS of 8.72 months (p=0.0099). No survival advantage was seen with stratification by tumor burden alone (p=0.24) or by CD8+PD1+Ki67+ T cells alone (p=0.53).ConclusionsPembrolizumab with carboplatin was well-tolerated and active in recurrent platinum-resistant ovarian cancer. A ratio of peripheral T-cell exhaustion to radiographic tumor burden may identify patients more likely to benefit from this chemoimmunotherapy.Trial registration numberNCT03029598.

Project description:Patients diagnosed with epithelial ovarian cancers (EOCs) often suffer from disease relapse associated with the emergence of resistance to standard platinum‑based chemotherapy. Treatment of patients with chemo‑resistant disease remains a clinical challenge. One mechanism of chemoresistance includes overexpression of pro‑survival proteins called inhibitors of apoptosis (IAP) which enable cancer cells to evade apoptosis. Due to their anti‑apoptotic activity, association with poor prognosis, and correlation with therapy resistance in multiple malignancies, IAP proteins have become an attractive target for development of anticancer therapeutics. Second mitochondrial activator of caspase (SMAC) mimetics are the most widely used IAP antagonists currently being tested in clinical trials as a monotherapy and in combination with different chemotherapeutic drugs to target different types of cancer. In the present study, the antitumor efficacy of combination therapy with birinapant, a bivalent SMAC mimetic compound, and carboplatin to target platinum‑resistant EOC cells was investigated. A 3D organoid bioassay was utilized to test the efficacy of the combination therapy in a panel of 7 EOC cell lines and 10 platinum‑resistant primary patient tumor samples. Findings from the in vitro studies demonstrated that the birinapant and carboplatin combination was effective in targeting a subset of ovarian cancer cell lines and platinum‑resistant primary patient tumor samples. This combination therapy was also effective in vitro and in vivo in targeting a platinum‑resistant patient‑derived xenograft (PDX) model established from one of the patient tumors tested. Overall, our study demonstrated that birinapant and carboplatin combination could target a subset of platinum‑resistant ovarian cancers and also highlights the potential of the 3D organoid bioassay as a preclinical tool to assess the response to chemotherapy or targeted therapies in ovarian cancer.

Dataset Information

A Phase I Clinical Trial of Guadecitabine and Carboplatin in Platinum-Resistant, Recurrent Ovarian Cancer: Clinical, Pharmacokinetic, and Pharmacodynamic Analyses.

Publications

A Phase I Clinical Trial of Guadecitabine and Carboplatin in Platinum-Resistant, Recurrent Ovarian Cancer: Clinical, Pharmacokinetic, and Pharmacodynamic Analyses.

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