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ABT-888) in Combination with 5-Fluorouracil and Oxaliplatin in Patients with Metastatic Pancreatic Cancer Michael J

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ABT-888) in Combination with 5-Fluorouracil and Oxaliplatin in Patients with Metastatic Pancreatic Cancer Michael J Published OnlineFirst July 15, 2020; DOI: 10.1158/1078-0432.CCR-20-1301 CLINICAL CANCER RESEARCH | CLINICAL TRIALS: TARGETED THERAPY A Phase I/II Study of Veliparib (ABT-888) in Combination with 5-Fluorouracil and Oxaliplatin in Patients with Metastatic Pancreatic Cancer Michael J. Pishvaian1, Hongkun Wang2, Aiwu Ruth He2, Jimmy J. Hwang3, Brandon G. Smaglo4, Sunnie S. Kim5, Benjamin A. Weinberg2, Louis M. Weiner2, John L. Marshall2, and Jonathan R. Brody6 ABSTRACT ◥ Purpose: Up to 17% of patients with pancreatic ductal adenocar- two parallel phase II trials to assess the objective response rate cinoma (PDAC) harbor pathogenic (germline or somatic) mutations (ORR) in untreated or in previously treated patients. If available, in a homologous recombination, DNA damage response and repair germline or somatic testing was collected to identify pathogenic (HR-DDR) gene, such as BRCA1/2,orPALB2.Platinum-basedche- HR-DDR mutations. motherapy, or treatment with PARP inhibitors are of particular benefit Results: The combination of veliparib and FOLFOX was toler- in these patients. However, there may be even greater benefitwhen able at a RP2D of veliparib of 200 mg twice a day. The primary platinums and PARP inhibitors are combined. endpoint for both phase II cohorts was met, and the ORR overall was Patients and Methods: We performed a single-arm, open-label, 26%. There was greater activity in platinum-na€ve patients, and phase I/II study of the PARP inhibitor, veliparib, with 5-fluorouracil those who harbored a pathogenic HR-DDR mutation. Specifically, (no 5FU bolus) and oxaliplatin (FOLFOX) for patients with met- the ORR of HR-DDR mutated, platinum-na€ve patients was 57%. astatic PDAC. Thirty-one patients were enrolled in a phase I dose Conclusions: The combination of veliparib and FOLFOX was escalation of veliparib (40 mg to 250 mg twice a day, days 1–7 of each safe for patients with metastatic PDAC and showed promising 14-day cycle), to identify the recommended phase II dose (RP2D) of activity particularly in patients with platinum-na€ve disease that veliparib for the combination. Another 33 patients were enrolled in harbors a pathogenic HR-DDR mutation. Introduction such as BRCA1/2 and PALB2 mutations, preliminary data suggest that treatment with platinum-based chemotherapy and/or PARP inhibi- Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease tors offers significant improvements in patient outcomes (8–14). In which, with a 5-year survival of only 10%, is poised to become the fact, based on the phase III POLO trial, PARP inhibitors are now an second leading cause of cancer-related death in the United States by FDA-approved standard treatment option as maintenance therapy for 2030 (1). Treatment for metastatic PDAC (mPDAC) has improved, patients with mPDAC who harbor pathogenic germline BRCA1/2 but the median overall survival (OS) remains less than 1 year (2, 3). mutations (15). PARP inhibitors have also been demonstrated to be However, for the subgroup of approximately 17% of patients with active in patients with PDAC whose tumors harbor pathogenic PALB2 PDAC whose tumors harbor defects in the homologous recombina- mutations (16). There is also evidence in other cancer types of the tion-DNA damage response and repair (HR-DDR) pathway (4–7), efficacy of PARP inhibitors in tumors with other (non-BRCA1/2/ PALB2) HR-DDR mutations (17). Moreover, there exists the potential for enhanced benefit when a 1Department of Oncology, Johns Hopkins University School of Medicine, SKCC, PARP inhibitor is combined with DNA damaging chemotherapy. Washington, DC. 2Lombardi Comprehensive Cancer Center, Georgetown Uni- PARP plays a critical role in facilitating the repair of both single- and 3 versity, Washington, DC. Levine Cancer Center, Carolinas Medical Center, double-stranded DNA breaks (18–20), and PARP inhibition results in Charlotte, North Carolina. 4Department of Gastrointestinal Medical Oncology, less efficient DNA repair. Thus, PARP inhibitors act as sensitizing University of Texas, MD Anderson Cancer Center, Houston, Texas. 5The Uni- versity of Colorado Cancer Center, Aurora, Colorado. 6The Jefferson Pancreas, agents for DNA-damaging chemotherapies (21). Veliparib (ABT-888, Biliary and Related Cancer Center, Department of Surgery, and the Sidney Abbvie) is a PARP inhibitor that has proven in vivo activity (22), and Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania. increases tumor cell sensitivity to chemotherapy and radiation (23). In Note: Supplementary data for this article are available at Clinical Cancer humans, veliparib is safe and demonstrates inhibition of PARP activity Research Online (http://clincancerres.aacrjournals.org/). in tumor biopsies (22). In phase III trials, veliparib has been used in Prior presentation: Presented in part at the 2013 Gastrointestinal Cancers combination with platinum-based chemotherapy at a dose of 150 mg Symposium. orally twice a day; and at 400 mg twice a day as maintenance therapy without chemotherapy (24). ClinicalTrials.gov identifier: NCT01489865 (ABT-888 with Modified FOLFOX6 in Patients with Metastatic Pancreatic Cancer) We previously demonstrated in PDAC cells that genetically dis- rupting the DNA-binding domain of PARP1, or treating with veliparib Corresponding Author: Michael J. Pishvaian, Johns Hopkins University, – fi Washington, DC 20016. Phone: 202-660-6500; Fax: 202-660-6501; E-mail: synergizes with oxaliplatin (21), particularly in HR-DDR de cient cell [email protected] lines. Therefore, we designed a trial combining veliparib with FOL- FOX-based chemotherapy for patients with mPDAC. At the time of Clin Cancer Res 2020;XX:XX–XX study design, FOLFIRINOX was not yet standard-of-care, and may doi: 10.1158/1078-0432.CCR-20-1301 present toxicity challenges in combination with a PARP inhibitor due Ó2020 American Association for Cancer Research. to overlapping myelosuppression. Thus, herein, we present a phase I/ AACRJournals.org | OF1 Downloaded from clincancerres.aacrjournals.org on September 30, 2021. © 2020 American Association for Cancer Research. Published OnlineFirst July 15, 2020; DOI: 10.1158/1078-0432.CCR-20-1301 Pishvaian et al. (ii) the presence or absence of an FH (as defined previously); (iii) the Translational Relevance presence of a mutation in an HR-DDR gene; patients who were tested Platinum-based chemotherapies and PARP inhibitors have but did not harbor a pathogenic germline or somatic HR-DDR demonstrated promising activity in patients with metastatic pan- mutation were also identified and highlighted. The study protocol, creatic cancer who harbor pathogenic germline or somatic muta- amendments, and informed consent forms were approved by the tions in the homologous recombination, DNA damage response Institutional Review Board at Georgetown University (Washington, and repair (HR-DDR) genes, BRCA1/2,orPALB2. There is evi- DC). Investigators obtained written informed consent from each dence of benefit of PARP inhibitors for patients whose tumors participant or participant’s guardian prior to screening. The research harbor other HR-DDR gene mutations as well. However, there may was conducted in accordance with recognized ethical guidelines be even greater benefit when platinums and PARP inhibitors are including the Declaration of Helsinki, CIOMS, Belmont Report, and combined. To assess the safety and efficacy of such a combination, U.S. Common Rule, as described during training in Good Clinical we performed a phase I/II clinical trial of 64 patients, with the Practice guidelines (CITI Training). combination of the PARP inhibitor, veliparib, with chemotherapy, FOLFOX. The combination was safe and effective for patients with Study design and treatment schedule metastatic pancreatic cancer. The greatest activity, with an ORR of This was a single-center, phase I/II, open-label study. Initially, the 57%, was seen in patients whose disease had not progressed on dose and schedule for modified FOLFOX6 (27) were used (5FU bolus prior platinum, and who harbored germline or somatic HR-DDR 400 mg/m2, day 1; leucovorin 400 mg/m2, day 1; FOLFOX 85 mg/m2, mutations. day 1; and 5FU 2,400 mg/m2 continuous infusion over 46 hours, days 1–3). Each cycle was 14 days. However, the first 6 patients dosed at 40 mg of veliparib demonstrated prolonged grade 2 or 3 myelosup- pression. Thus, the 5FU bolus was dropped for all subsequent patients. II clinical trial of veliparib plus 5-fluorouracil (5FU) and oxaliplatin For the phase I portion, the dose of veliparib was escalated in a (FOLFOX) for patients with mPDAC. standard 3þ3 design from 40 to 60, 80, 100, 150, 200, and 250 mg twice a day, days 1–7 (Supplementary Table S1). As the primary endpoint of the phase I portion was to determine the recommended Patients and Methods phase II dose (RP2D) as well as the maximally tolerated dose Patients (MTD), dose-limiting toxicities (DLTs) were defined as any of the Patients with mPDAC with measurable disease [as per RECIST 1.1 following that were definitely, possibly, or probably related to therapy (25)] were eligible. Patients were ages ≥18 years, had an Eastern (veliparib þ FOLFOX) that occurred during the first cycle of therapy: Cooperative Oncology Group performance status score of ≤2, and had adequate organ and bone marrow function [hemoglobin ≥9.5 g/dL, (i) Grade 4 neutropenia lasting greater than 5 days or complicated absolute neutrophil count ≥1.5 Â 109/L, platelet count ≥75 Â 109/L, by fever or infection. serum creatinine level <1.5 mg/dL, bilirubin level ≤2.5 Â upper limit of (ii) Grade 4 anemia or thrombocytopenia. normal (ULN), and ALT/AST levels ≤3 Â ULN]. For the phase I (iii) Grade 3 thrombocytopenia associated with bleeding for which a portion of the study, patients were not selected on the basis of prior transfusion was required. therapy, family history (FH), nor germline or tumor HR-DDR (iv) Grade 3 or 4 nonhematologic toxicity not manageable with mutational status. routine supportive care (e.g., over-the-counter antidiarrheals For the phase II portion, there were two cohorts.
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