TY - JOUR
T1 - A Phase I/II Study of Veliparib (ABT-888) in Combination with 5-Fluorouracil and Oxaliplatin in Patients with Metastatic Pancreatic Cancer
AU - Pishvaian, Michael J.
AU - Wang, Hongkun
AU - He, Aiwu Ruth
AU - Hwang, Jimmy J.
AU - Smaglo, Brandon G.
AU - Kim, Sunnie S.
AU - Weinberg, Benjamin A.
AU - Weiner, Louis M.
AU - Marshall, John L.
AU - Brody, Jonathan R.
N1 - Funding Information:
We would like to thank Meeta Jaiswal, PhD for scientific guidance throughout protocol development and implementation. This work was funded by the Otto J. Ruesch Center for the Cure of GI Cancers, Lombardi Comprehensive Cancer Center. Abbvie, Inc. has provided veliparib and partial research funding for the
Funding Information:
M.J. Pishvaian reports grants from AbbVie (institutional support only) during the conduct of the study; grants, personal fees, and nonfinancial support from Merck (consultant/advisor, institution), AstraZeneca/Medimmune (consultant/advisor, institution), Halozyme (consultant/advisor, institution); personal fees and nonfinancial support from Sirtex Medical (consultant/advisor, speaker), Caris Life Sciences (consultant/advisor, speaker); personal fees from Rafael (consultant/advisor), RenovoRx (consultant/advisor); personal fees, nonfinancial support, and other from Perthera (consultant/advisor/stock); grants from Bavarian Nordic (institutional support only), Celldex (institutional support only), Pfizer (institutional support only), Novartis (institutional support only), Boston Biomedical (institutional support only), Tesaro (institutional support only), Bristol-Myers Squibb (institutional support only), Genentech (institutional support only), ARMO Biosciences (institutional support only), Bayer (institutional support only), Calithera (institutional support only), Curegenix (institutional support only), Fibrogen (institutional support only), Gilead (institutional support only), GlaxoSmithKline (institutional support only), Karyopharm (institutional support only), Regeneron (institutional support only), Pharmacyclics (institutional support only); grants and personal fees from Celgene (consultant/advisor, institution); and personal fees from Foundation Medicine (consultant/advisor) outside the submitted work; and is listed as a coinventor on a pending patent regarding the use of FOLFOX + veliparib in pancreatic cancer. J.J. Hwang reports personal fees from Genentech/Roche (speaker bureau/consultant), Bristol-Myers Squibb (speaker bureau/consultant), Amgen (speaker bureau/ consultant), Ipsen (speaker bureau/consultant), Celgene (consultant), Deciphera (consultant), Eisai (consultant), Bayer (consultant), Taiho (consultant), and Caris (consultant) outside the submitted work. B.A. Weinberg reports personal fees from Lilly, Bayer, Sirtex, and Taiho outside the submitted work. L.M. Weiner reports personal fees from Celldex Therapeutics, Cytomx Therapeutics, Jounce Therapeutics, Immunome, Klus Pharmaceuticals, Tessa Therapeutics, and Samyang Biopharm USA; other from Targeted Diagnostics & Therapeutics (shareholder), grants from Bioexcel Therapeutics outside the submitted work; and performs occasional consulting on patent cases in areas unrelated to the subject of this paper. J.L. Marshall reports personal fees from Caris Life Sciences (interim CMO), Indivumed (interim CMO), Amgen, Taiho, Merck, and Bayer outside the submitted work. J.R. Brody is listed as a coinventor on a pending patent regarding methods of treating gastrointestinal cancers and tumors thereof using combination therapy. No potential conflicts of interest were disclosed by the other authors.
Funding Information:
We would like to thank Meeta Jaiswal, PhD for scientific guidance throughout protocol development and implementation. This work was funded by the Otto J. Ruesch Center for the Cure of GI Cancers, Lombardi Comprehensive Cancer Center. Abbvie, Inc. has provided veliparib and partial research funding for the correlative science. M.J. Pishvaian and J.R. Brody are supported by 1R01CA212600-01 (NCI, NIH); a 2015 Pancreatic Cancer Action Network American Association for Cancer Research Acceleration Network Grant (15-90-25-BROD); and M.J. Pishvaian and J.R. Brody are also supported in part by U01CA224012 (NCI, NIH). J.R. Brody was supported in part by the NCI of the NIH Award Number P30CA056036 SKCC Core Grant (Thomas Jefferson University). We also would like to acknowledge The Sarah Parvin Foundation for their generous support.
Funding Information:
correlative science. M.J. Pishvaian and J.R. Brody are supported by 1R01CA212600-01 (NCI, NIH); a 2015 Pancreatic Cancer Action Network American Association for Cancer Research Acceleration Network Grant (15-90-25-BROD); and M.J. Pishvaian and J.R. Brody are also supported in part by U01CA224012 (NCI, NIH). J.R. Brody was supported in part by the NCI of the NIH Award Number P30CA056036 SKCC Core Grant (Thomas Jefferson University). We also would like to acknowledge The Sarah Parvin Foundation for their generous support.
Publisher Copyright:
©2020 American Association for Cancer Research.
PY - 2020/10/1
Y1 - 2020/10/1
N2 - 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-nave patients, and those who harbored a pathogenic HR-DDR mutation. Specifically, the ORR of HR-DDR mutated, platinum-nave 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-nave disease that harbors a pathogenic HR-DDR mutation.
AB - 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-nave patients, and those who harbored a pathogenic HR-DDR mutation. Specifically, the ORR of HR-DDR mutated, platinum-nave 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-nave disease that harbors a pathogenic HR-DDR mutation.
UR - http://www.scopus.com/inward/record.url?scp=85099106075&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85099106075&partnerID=8YFLogxK
U2 - 10.1158/1078-0432.CCR-20-1301
DO - 10.1158/1078-0432.CCR-20-1301
M3 - Article
C2 - 32669374
AN - SCOPUS:85099106075
VL - 26
SP - 5092
EP - 5101
JO - Clinical Cancer Research
JF - Clinical Cancer Research
SN - 1078-0432
IS - 19
ER -