Gemcitabine Hydrochloride and Cisplatin With or Without Veliparib or Veliparib Alone in Treating Patients With Locally Advanced or Metastatic Pancreatic Cancer

Official Title

A Randomized Phase II Study of Gemcitabine, Cisplatin +/- Veliparib in Patients With Pancreas Adenocarcinoma and a Known BRCA/ PALB2 Mutation (Part I) and a Phase II Single Arm Study of Single-Agent Veliparib in Previously Treated Pancreas Adenocarcinoma (Part II)

Summary:

This randomized phase II trial studies how well veliparib together with gemcitabine hydrochloride and cisplatin works compared to gemcitabine hydrochloride and cisplatin alone in treating patients with pancreatic cancer that has spread from where it started to nearby tissue or lymph nodes (locally advanced) or spread from the primary site (place where it started) to other places in the body (metastatic). Veliparib may stop the growth of tumour cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as gemcitabine hydrochloride and cisplatin, work in different ways to stop the growth of tumour cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. It is not yet known whether giving veliparib together with gemcitabine hydrochloride and cisplatin is an effective treatment for pancreatic cancer.

Trial Description

Primary Outcome:

  • Optimal dose of veliparib with gemcitabine hydrochloride and cisplatin (non-randomized part I)
  • Response rate of single-agent veliparib using RECIST criteria (Part II)
  • Response rate to gemcitabine hydrochloride and cisplatin with versus without veliparib as assessed by RECIST (randomized Part I)
Secondary Outcome:
  • Disease control rate (CR + PR + SD) and duration of response
  • Incidence of adverse events using the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0
  • Overall survival
  • Progression-free survival
PRIMARY OBJECTIVES:
I. To optimize the dose of veliparib combined with fixed doses of gemcitabine hydrochloride (gemcitabine) and cisplatin in a (non-randomized, lead-in portion of Part I). II. To evaluate the response rate (Response Evaluation Criteria in Solid Tumours [RECIST] criteria) of gemcitabine, cisplatin, and veliparib (Arm A) and gemcitabine, cisplatin (Arm B) in BRCA and PALB2 mutation carriers with advanced pancreas adenocarcinoma. (Part I) III. To evaluate the response rate (RECIST criteria) of single-agent veliparib (Arm C) in BRCA and PALB2 carriers with previously treated pancreas adenocarcinoma. (Part II) SECONDARY OBJECTIVES:
I. To evaluate the progression-free survival of patients in study Arm A and Arm B. (Part I) II. To describe the safety and tolerability of gemcitabine, cisplatin, and veliparib and gemcitabine and cisplatin in BRCA and PALB2 carriers with advanced pancreas adenocarcinoma. (Part I) III. To determine the disease control rate (complete response [CR] + partial response [PR] + stable disease [SD]) and duration of response in study Arm A and Arm B. (Part I) IV. To evaluate overall survival in study Arm A and Arm B. (Part I) V. To evaluate progression-free survival for single-agent veliparib in BRCA and PALB2 mutation carriers with previously treated pancreas adenocarcinoma (Arm C). (Part II) VI. To describe the safety and tolerability of single-agent veliparib in BRCA and PALB2 mutation carriers with previously treated pancreas adenocarcinoma. (Part II) VII. To determine the disease control rate (CR + PR + SD) and duration of response in Arm C. (Part II) VIII. To evaluate overall survival in Arm C. (Part II) TERTIARY OBJECTIVES:
I. To determine the genotype of BRCA1, BRCA2 and PALB2-mutated pancreas adenocarcinoma. II. To assess pre and post therapy biopsies for novel or persistent genetic alterations in genes identified in aim I. III. To quantify levels of PAR in peripheral blood mononuclear cells (PBMCs) and tumour tissues at sequential time points before and following therapy with veliparib. IV. To quantify levels of gammaH2AX and RAD51 foci in PBMCs and tumour tissue (where available) at sequential time points to assess for formation of double-stranded deoxyribonucleic acid (DNA) breaks, stalled/collapsed replication forks and evaluate homologous recombination competence. V. To correlate the results of genotyping with gene expression to provide functional information on mutations identified. (Exploratory) VI. An exploratory assessment of differential expression of genes involved in DNA repair pathways pre and post treatment to identify candidate genes predictive of response or resistance to therapy for further study in preclinical models of disease. (Exploratory) OUTLINE:

This is a dose-escalation study of veliparib followed by a randomized, open-label study. Patients receive veliparib orally (PO) twice daily (BID) on days 1-12 or 1-21. Patients also receive gemcitabine hydrochloride intravenously (IV) over 30 minutes and cisplatin IV over 30 minutes on days 3 and 10. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. (CLOSED AS OF 12/13/13) PART I: Once the maximum-tolerated dose of veliparib has been established, patients are randomized to 1 of 2 treatment arms. ARM A (no prior therapy or >= 6 months since adjuvant therapy): Patients receive veliparib PO BID on days 1-12 and gemcitabine hydrochloride IV over 30 minutes and cisplatin IV over 30 minutes on days 3 and 10. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. ARM B (no prior therapy or >= 6 months since adjuvant therapy): Patients receive gemcitabine hydrochloride IV and cisplatin IV as patients in arm A. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. PART II: Patients who are eligible receive treatment in Arm C. ARM C (prior therapy): Patients receive veliparib PO BID on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up at 30 days and then every 3 months thereafter.

View this trial on ClinicalTrials.gov

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