Phase 1 trial evaluating cisplatin, gemcitabine, and veliparib in 2 patient cohorts: Germline BRCA mutation carriers and wild-type BRCA pancreatic ductal adenocarcinoma Journal Article


Authors: O'Reilly, E. M.; Lee, J. W.; Lowery, M. A.; Capanu, M.; Stadler, Z. K.; Moore, M. J.; Dhani, N.; Kindler, H. L.; Estrella, H.; Maynard, H.; Golan, T.; Segal, A.; Salo-Mullen, E. E.; Yu, K. H.; Epstein, A. S.; Segal, M.; Brenner, R.; Do, R. K.; Chen, A. P.; Tang, L. H.; Kelsen, D. P.
Article Title: Phase 1 trial evaluating cisplatin, gemcitabine, and veliparib in 2 patient cohorts: Germline BRCA mutation carriers and wild-type BRCA pancreatic ductal adenocarcinoma
Abstract: BACKGROUND: A phase 1 trial was used to evaluate a combination of cisplatin, gemcitabine, and escalating doses of veliparib in patients with untreated advanced pancreatic ductal adenocarcinoma (PDAC) in 2 cohorts: a germline BRCA1/2-mutated (BRCA+) cohort and a wild-type BRCA (BRCA–) cohort. The aims were to determine the safety, dose-limiting toxicities (DLTs), maximum tolerated dose, and recommended phase 2 dose (RP2D) of veliparib combined with cisplatin and gemcitabine and to assess the antitumor efficacy (Response Evaluation Criteria in Solid Tumors, version 1.1) and overall survival. METHODS: Gemcitabine and cisplatin were dosed at 600 and 25 mg/m2, respectively, over 30 minutes on days 3 and 10 of a 21-day cycle. Four dose levels of veliparib were evaluated: 20 (dose level 0), 40 (dose level 1), and 80 mg (dose level 2) given orally twice daily on days 1 to 12 and 80 mg given twice daily on days 1 to 21 (dose level 2A [DL2A]). RESULTS: Seventeen patients were enrolled: 9 BRCA+ patients, 7 BRCA– patients, and 1 patient with an unknown status. DLTs were reached at DL2A (80 mg twice daily on days 1 to 21). Two of the 5 patients in this cohort (40%) experienced grade 4 neutropenia and thrombocytopenia. Two grade 5 events occurred on protocol. The objective response rate in the BRCA+ cohort was 7 of 9 (77.8%). The median overall survival for BRCA+ patients was 23.3 months (95% confidence interval [CI], 3.8-30.2 months). The median overall survival for BRCA– patients was 11 months (95% CI, 1.5-12.1 months). CONCLUSIONS: The RP2D of veliparib was 80 mg by mouth twice daily on days 1 to 12 in combination with cisplatin and gemcitabine; the DLT was myelosuppression. Substantial antitumor activity was seen in BRCA+ PDAC. A randomized phase 2 trial is currently evaluating cisplatin and gemcitabine with and without veliparib for BRCA+ PDAC (NCT01585805). Cancer 2018;124:1374-82. © 2018 American Cancer Society. © 2018 American Cancer Society
Keywords: cisplatin; germline; pancreatic cancer; brca; veliparib
Journal Title: Cancer
Volume: 124
Issue: 7
ISSN: 0008-543X
Publisher: Wiley Blackwell  
Date Published: 2018-04-01
Start Page: 1374
End Page: 1382
Language: English
DOI: 10.1002/cncr.31218
PROVIDER: scopus
PMCID: PMC5867226
PUBMED: 29338080
DOI/URL:
Notes: Article -- Export Date: 1 May 2018 -- Source: Scopus
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MSK Authors
  1. Zsofia Kinga Stadler
    144 Stadler
  2. Marinela Capanu
    206 Capanu
  3. Maeve Aine Lowery
    96 Lowery
  4. Kenneth Ho-Ming Yu
    58 Yu
  5. Kinh Gian Do
    112 Do
  6. Andrew Saul Epstein
    68 Epstein
  7. Laura Hong Tang
    320 Tang
  8. Eileen O'Reilly
    316 O'Reilly
  9. David P Kelsen
    332 Kelsen
  10. Michal F Segal
    9 Segal
  11. Jonathan Wennan Lee
    2 Lee