Reference Detail

Ref Type

Journal Article

PMID

(32669374)

Authors

Pishvaian MJ, Wang H, He AR, Hwang JJ, Smaglo BG, Kim SS, Weinberg BA, Weiner LM, Marshall JL, Brody JR

Title

A Phase I/II Study of Veliparib (ABT-888) in Combination with 5-Fluorouracil and Oxaliplatin in Patients with Metastatic Pancreatic Cancer.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Clinical cancer research : an official journal of the American Association for Cancer Research			2020 Jul 15	5092-5101	Clin Cancer Res

URL

Abstract Text

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.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.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%.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.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
ATM R3008C	pancreatic ductal adenocarcinoma	no benefit	Fluorouracil + Oxaliplatin + Veliparib	Case Reports/Case Series	Actionable	In a Phase I/II trial, Veliparib (ABT-888) in combination with Adrucil (fluorouracil) and Eloxatin (oxaliplatin) did not result in a clinical response in a patient with metastatic pancreatic ductal adenocarcinoma harboring ATM R3008C (PMID: 32669374; NCT01489865).	32669374
ATM T2333Nfs*40	pancreatic ductal adenocarcinoma	no benefit	Fluorouracil + Oxaliplatin + Veliparib	Case Reports/Case Series	Actionable	In a Phase I/II trial, Veliparib (ABT-888) in combination with Adrucil (fluorouracil) and Eloxatin (oxaliplatin) did not result in a clinical response in a patient with metastatic pancreatic ductal adenocarcinoma harboring ATM T2333Nfs*40 (reported as c.6997dupA) (PMID: 32669374; NCT01489865).	32669374