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|Ref Type||Journal Article|
|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||Clinical cancer research : an official journal of the American Association for Cancer Research|
|Date||2020 Jul 15|
|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.|
|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|
|Unknown unknown||pancreatic ductal adenocarcinoma||not applicable||Fluorouracil + Oxaliplatin + Veliparib||Phase Ib/II||Actionable||In a Phase I/II trial, Veliparib (ABT-888) in combination with Adrucil (fluorouracil) and Eloxatin (oxaliplatin) demonstrated safety, and resulted in an objective response rate of 26% (15/58, 4 complete responses, 11 partial responses), a disease control rate of 52%, a progression-free survival of 4.0 months, and an overall survival of 7.8 months in patients with metastatic pancreatic ductal adenocarcinoma (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|