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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. Pishvaian, Hongkun Wang, Aiwu Ruth He, Jimmy J. Hwang, Brandon G. Smaglo, Sunnie S. Kim, Benjamin A. Weinberg, Louis M. Weiner, John L. Marshall and Jonathan R. Brody
Michael J. Pishvaian
1Department of Oncology, Johns Hopkins University School of Medicine, SKCC, Washington, DC.
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  • For correspondence: mpishva1@jh.edu
Hongkun Wang
2Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC.
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Aiwu Ruth He
2Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC.
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Jimmy J. Hwang
3Levine Cancer Center, Carolinas Medical Center, Charlotte, North Carolina.
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Brandon G. Smaglo
4Department of Gastrointestinal Medical Oncology, University of Texas, MD Anderson Cancer Center, Houston, Texas.
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Sunnie S. Kim
5The University of Colorado Cancer Center, Aurora, Colorado.
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Benjamin A. Weinberg
2Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC.
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Louis M. Weiner
2Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC.
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John L. Marshall
2Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC.
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Jonathan R. Brody
6The Jefferson Pancreas, Biliary and Related Cancer Center, Department of Surgery, and the Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.
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DOI: 10.1158/1078-0432.CCR-20-1301 Published October 2020
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Abstract

Purpose: Up to 17% of patients with pancreatic ductal adenocarcinoma (PDAC) harbor pathogenic (germline or somatic) mutations in a homologous recombination, DNA damage response and repair (HR-DDR) gene, such as BRCA1/2, or PALB2. Platinum-based chemotherapy, or treatment with PARP inhibitors are of particular benefit in these patients. However, there may be even greater benefit when platinums and PARP inhibitors are combined.

Patients and Methods: We performed a single-arm, open-label, phase I/II study of the PARP inhibitor, veliparib, with 5-fluorouracil (no 5FU bolus) and oxaliplatin (FOLFOX) for patients with metastatic PDAC. Thirty-one patients were enrolled in a phase I dose escalation of veliparib (40 mg to 250 mg twice a day, days 1–7 of each 14-day cycle), to identify the recommended phase II dose (RP2D) of veliparib for the combination. Another 33 patients were enrolled in two parallel phase II trials to assess the objective response rate (ORR) in untreated or in previously treated patients. If available, germline or somatic testing was collected to identify pathogenic HR-DDR mutations.

Results: The combination of veliparib and FOLFOX was tolerable at a RP2D of veliparib of 200 mg twice a day. The primary endpoint for both phase II cohorts was met, and the ORR overall was 26%. There was greater activity in platinum-naïve patients, and those who harbored a pathogenic HR-DDR mutation. Specifically, the ORR of HR-DDR mutated, platinum-naïve patients was 57%.

Conclusions: The combination of veliparib and FOLFOX was safe for patients with metastatic PDAC and showed promising activity particularly in patients with platinum-naïve disease that harbors a pathogenic HR-DDR mutation.

This article is featured in Highlights of This Issue, p. 5053

Footnotes

  • Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/).

  • Prior presentation: Presented in part at the 2013 Gastrointestinal Cancers Symposium.

  • ClinicalTrials.gov identifier: NCT01489865 (ABT-888 with Modified FOLFOX6 in Patients with Metastatic Pancreatic Cancer)

  • Clin Cancer Res 2020;26:5092–101

  • Received April 7, 2020.
  • Revision received June 8, 2020.
  • Accepted July 13, 2020.
  • Published first July 15, 2020.
  • ©2020 American Association for Cancer Research.
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Clinical Cancer Research: 26 (19)
October 2020
Volume 26, Issue 19
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A Phase I/II Study of Veliparib (ABT-888) in Combination with 5-Fluorouracil and Oxaliplatin in Patients with Metastatic Pancreatic Cancer
Michael J. Pishvaian, Hongkun Wang, Aiwu Ruth He, Jimmy J. Hwang, Brandon G. Smaglo, Sunnie S. Kim, Benjamin A. Weinberg, Louis M. Weiner, John L. Marshall and Jonathan R. Brody
Clin Cancer Res October 1 2020 (26) (19) 5092-5101; DOI: 10.1158/1078-0432.CCR-20-1301

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A Phase I/II Study of Veliparib (ABT-888) in Combination with 5-Fluorouracil and Oxaliplatin in Patients with Metastatic Pancreatic Cancer
Michael J. Pishvaian, Hongkun Wang, Aiwu Ruth He, Jimmy J. Hwang, Brandon G. Smaglo, Sunnie S. Kim, Benjamin A. Weinberg, Louis M. Weiner, John L. Marshall and Jonathan R. Brody
Clin Cancer Res October 1 2020 (26) (19) 5092-5101; DOI: 10.1158/1078-0432.CCR-20-1301
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