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

Brief summary public domain (ClinicalTrials.gov)

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 tumor 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 tumor 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.

Detailed description public domain (ClinicalTrials.gov)

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 Tumors \[RECIST\] 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 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) CORRELATIVE SCIENCE 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 tumor tissues at sequential time points before and following therapy with veliparib. IV. To quantify levels of gammaH2AX and RAD51 foci in PBMCs and tumor 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. EXPLORATORY OBJECTIVES: I. To correlate the results of genotyping with gene expression to provide functional information on mutations …

Intervention public domain (ClinicalTrials.gov)

Procedure: Biopsy Procedure. Undergo biopsy

Intervention public domain (ClinicalTrials.gov)

Procedure: Biospecimen Collection. Undergo tumor tissue and blood sample collection

Intervention public domain (ClinicalTrials.gov)

Drug: Cisplatin. Given IV

Intervention public domain (ClinicalTrials.gov)

Procedure: Computed Tomography. Undergo CT

Intervention public domain (ClinicalTrials.gov)

Drug: Gemcitabine. Given IV

Intervention public domain (ClinicalTrials.gov)

Drug: Gemcitabine Hydrochloride. Given IV

Intervention public domain (ClinicalTrials.gov)

Procedure: Magnetic Resonance Imaging. Undergo MRI

Intervention public domain (ClinicalTrials.gov)

Drug: Veliparib. Given PO

Arm public domain (ClinicalTrials.gov)

Arm A (veliparib, gemcitabine hydrochloride, cisplatin) (experimental): Patients receive veliparib PO BID on days 1-12 or 1-21 of each cycle. Patients also receive gemcitabine hydrochloride IV over 30 minutes and cisplatin IV over 30 minutes on days 3 and 10 of each cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients also undergo CT or MRI throughout study. Patients also undergo tumor tissue and blood sample collection throughout the trial and undergo tumor biopsy during screening and on study.

Arm public domain (ClinicalTrials.gov)

Arm B (gemcitabine hydrochloride, cisplatin) (active comparator): Patients receive gemcitabine hydrochloride IV and cisplatin IV as patients in arm A. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients also undergo CT or MRI throughout study. Patients also undergo tumor tissue and blood sample collection throughout the trial and undergo tumor biopsy during screening and on study.

Arm public domain (ClinicalTrials.gov)

Arm C (veliparib) (experimental): Patients receive veliparib PO BID on days 1-28 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo CT or MRI throughout study. Patients also undergo tumor tissue and blood sample collection throughout the trial.

Arm public domain (ClinicalTrials.gov)

Part I (veliparib, gemcitabine, cisplatin) (experimental): There will be a small lead-in, non-randomized portion to Part I, where dose levels of veliparib 20 mg po BID (dose level 0), 40 mg po BID (dose level 1) and 80 mg po BID (dose level 2), will be evaluated on a day 1-12 schedule. The doses of gemcitabine 600 mg/m2 and cisplatin 25 mg/m2 are fixed. Three-6 patients will be evaluated per dose level starting with 20 mg po BID (dose level 0). If no dose-limiting toxicity (DLT), the dose of veliparib will be increased to 40 mg po BID (dose level 1) and subsequently to 80 mg po BID (dose level 2). If no DLT is observed at the veliparib dose of 80 mg BID day 1-12, then dose level 2A will examine veliparib at 80 mg po BID day 1-21, i.e., continuous dosing of veliparib. Subsequent cohorts will only examine continuous dosing of veliparib: dose level 3 (140mg po BID) and dose level 4 (200mg po BID). Approximately 6-24 patients total will be evaluated in this lead in portion of the study.

Primary outcome public domain (ClinicalTrials.gov)

Optimal Dose of Veliparib With Gemcitabine Hydrochloride and Cisplatin (Non-randomized Part I). There will be a small lead-in, non-randomized portion to Part I, where dose levels of veliparib 20 mg po BID (dose level 0), 40 mg po BID (dose level 1) and 80 mg po BID (dose level 2), will be evaluated on a day 1-12 schedule. The doses of gemcitabine 600 mg/m2 and cisplatin 25 mg/m2 are fixed. Three-6 patients will be evaluated per dose level starting with 20 mg po BID (dose level 0). If no dose-limiting toxicity (DLT), the dose of veliparib will be increased to 40 mg po BID (dose level 1) and subsequently to 80 mg po BID (dose level 2). If no DLT is observed at the veliparib dose of 80 mg BID day 1-12, then dose level 2A will examine veliparib at 80 mg po BID day 1-21, i.e., continuous dosing of veliparib. Time frame: 21 days.

Primary outcome public domain (ClinicalTrials.gov)

Response Rate to Gemcitabine Hydrochloride and Cisplatin With Versus Without Veliparib (Randomized Part I). Will be assessed by Response Evaluation Criteria in Solid Tumors (RECIST). Simon's two-stage minimax design will be employed separately in each arm A and B. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR. Time frame: Up to 5 years.

Primary outcome public domain (ClinicalTrials.gov)

Response Rate of Single-agent Veliparib (Part II). Will be assessed by RECIST criteria. Simon's two-stage optimal design will be employed. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR. Time frame: Up to 5 years.

Secondary outcome public domain (ClinicalTrials.gov)

Progression-free Survival (Parts I and II). Time frame: From the date of study enrollment to documentation of clear-cut progression of disease or last follow-up, assessed up to 5 years.

Secondary outcome public domain (ClinicalTrials.gov)

Number of Participants With Adverse Events (Parts I and II). Time frame: Up to 5 years.

Secondary outcome public domain (ClinicalTrials.gov)

Disease Control Rate (Complete Response + Partial Response + Stable Disease) and Duration of Response (Parts I and II). Time frame: Up to 5 years.

Secondary outcome public domain (ClinicalTrials.gov)

Overall Survival (Parts I and II). Time frame: From the time of study enrollment to the date of death or last follow-up, assessed up to 5 years.

Eligibility public domain (ClinicalTrials.gov)

Inclusion Criteria: * Male or female patients with cytologically or histologically confirmed locally advanced or metastatic pancreas adenocarcinoma with a BRCA1 or 2 or PALB2 mutation confirmed by report from Myriad Genetics (United States of America \[USA\]); reports from other molecular diagnostic companies can be used to confirm mutations as well; BRCA 1 or 2 or PALB2 mutation can be confirmed locally for all international sites * For part I, non-randomized, lead-in portion, patients with a known BRCA 1 or 2 or PALB2 mutation are eligible along with patients who potentially may have a likelihood of having a BRCA mutation (e.g., personal or family history of breast, pancreas, ovary, endometrial, prostate or other likely related malignancy) * For part I, randomized portion, a known BRCA 1 or 2 or PALB2 mutation is required * For part I (arms A, B): Patients can have either locally advanced or metastatic pancreas adenocarcinoma for which no prior therapy has been administered for either locally advanced or metastatic disease; prior adjuvant therapy is permissible if gemcitabine or a fluoropyrimidine was administered with or without radiation and if disease recurrence has been documented at least 6 months after completion of adjuvant therapy * For part II (arm C): Patients can have either locally advanced or metastatic pancreas adenocarcinoma; up to two prior treatment regimens are permissible (excluding a prior PARP inhibitor) for either localized or metastatic pancreas adenocarcinoma; prior combined chemotherapy and radiotherapy is permissible provided the patient has measurable disease outside the radiation port; prior therapy must have been completed at least 3 weeks prior to starting therapy * Age \> 18 years. No dosing or adverse event data are currently available on the use of veliparib in patients \< 18 years of age, therefore children are excluded from this study * Eastern Cooperative Oncology Group (ECOG) performance status: * For part I (arm A, B): 0-1 (Karnofsky \> 70%) * For part II (arm C): 0-2 (Karnofsky \>= 60%) * Life expectancy of greater than 3 months * Absolute neutrophil count \>= 1,500/mcL (measured within 14 days prior to administration of ABT-888) * Hemoglobin \>= 9.0 g/dl (measured within 14 days prior to administration of ABT-888) * Platelets \>= 100,000/mcL (measured within 14 days prior to administration of ABT-888) * Total bilirubin =\< 2 x institutional upper limit of normal (measured within 14 days prior to administration of …

Enrollment public domain (ClinicalTrials.gov)

Enrollment: 83 participants (actual).