Recruitment

Recruitment Status
Active, not recruiting
Estimated Enrollment
95

Inclusion Criteria

Platelets >= 100,000/mcL (measured within 14 days prior to administration of ABT-888)
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
Creatinine =< 1.5 x upper limit of normal (ULN) (measured within 14 days prior to administration of ABT-888)
...
Platelets >= 100,000/mcL (measured within 14 days prior to administration of ABT-888)
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
Creatinine =< 1.5 x upper limit of normal (ULN) (measured within 14 days prior to administration of ABT-888)
Ability to understand and the willingness to sign a written informed consent document
If a woman is of child-bearing potential a negative blood or urine pregnancy test is required; (the effects of veliparib on the developing human fetus are unknown; for this reason and because other therapeutic agents or modalities used in this trial are known to be teratogenic, women of child-bearing potential and men must agree to use adequate contraception [hormonal or barrier method of birth control; abstinence] prior to study entry and for the duration of study participation; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately)
Absolute neutrophil count >= 1,500/mcL (measured within 14 days prior to administration of ABT-888)
Aspartate aminotransferase(AST)/serum glutamic oxaloacetic transaminase (SGOT) and alanine aminotransferase(ALT)/serum glutamate pyruvate transaminase (SGPT) =< 2.5 x institutional upper limit of normal unless there is evidence of liver metastases in which case the AST (SGOT)/ALT (SGPT) must be =< 5 x institutional upper limit of normal (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)
For Part II (Arm C): 0-2 (Karnofsky >= 60%)
For Part I (Arm A, B): 0-1 (Karnofsky > 70%)
For Part I, randomized portion, measurable disease is required
Life expectancy of greater than 3 months
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 study therapy
For the lead-in, non-randomized portion of Part I, either measurable or evaluable disease is acceptable
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
Total bilirubin =< 2 x institutional upper limit of normal (measured within 14 days prior to administration of ABT-888)

Exclusion Criteria

Patients who are unable to swallow pills/capsules are ineligible
Patients with a known active infection, e.g., hepatitis B virus or hepatitis C virus; human immunodeficiency virus (HIV)-positive patients who are otherwise well and who do not have evidence of significant immune compromise are eligible
For Part II, no prior PARP inhibitor therapy is permitted; up to two prior treatment regimens are permitted as follows: 1 adjuvant and 1 metastatic; 1 locally advanced and 1 metastatic; or 2 metastatic, or a variation thereof
...
Patients who are unable to swallow pills/capsules are ineligible
Patients with a known active infection, e.g., hepatitis B virus or hepatitis C virus; human immunodeficiency virus (HIV)-positive patients who are otherwise well and who do not have evidence of significant immune compromise are eligible
For Part II, no prior PARP inhibitor therapy is permitted; up to two prior treatment regimens are permitted as follows: 1 adjuvant and 1 metastatic; 1 locally advanced and 1 metastatic; or 2 metastatic, or a variation thereof
History of allergic reactions attributed to compounds of similar chemical or biologic composition to veliparib or other agents used in study
Patients with uncontrolled central nervous system (CNS) metastasis are not eligible; patients with CNS metastases are to be stable for > 3 months after treatment and off steroid treatment prior to study enrollment
For Part I, prior adjuvant therapy with gemcitabine or a fluoropyrimidine therapy is permitted if completed > 6 months prior to recurrence; no prior PARP inhibitor therapy is allowed
Pregnant women are excluded from this study because veliparib is a PARP inhibitor with the potential for teratogenic or abortifacient effects; because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with veliparib, breastfeeding should be discontinued if the mother is treated with veliparib; these potential risks may also apply to other agents used in this study
Patients with prior malignancy successfully treated who are currently stable and on no active treatment are eligible
Patients with active seizure or history of seizure are not eligible
Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
Patients may not be receiving any other investigational agents
Patients with prior allogeneic bone marrow transplant or double umbilical cord blood transplantation are ineligible
For Part I: patients with known contraindications to platinum agents are excluded
Patients with treatment-related acute myeloid leukemia (AML) (t-AML)/myelodysplastic syndrome (MDS) or with features suggestive of AML/MDS are ineligible

Summary

Conditions
  • Metastatic Pancreatic Adenocarcinoma
  • Recurrent Pancreatic Carcinoma
  • Stage III Pancreatic Cancer AJCC v6 and v7
  • Stage IV Pancreatic Cancer AJCC v6 and v7
Type
Interventional
Phase
Phase 2
Design
  • Allocation: Randomized
  • Intervention Model: Parallel Assignment
  • Masking: None (Open Label)
  • Primary Purpose: Treatment

Participation Requirements

Age
Between 18 years and 125 years
Gender
Both males and females

Description

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 gemcitab...

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 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) 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 identified. II. 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. 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. Cycles 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. Cycles 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. Cycles 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. Cycles 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.

Inclusion Criteria

Platelets >= 100,000/mcL (measured within 14 days prior to administration of ABT-888)
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
Creatinine =< 1.5 x upper limit of normal (ULN) (measured within 14 days prior to administration of ABT-888)
...
Platelets >= 100,000/mcL (measured within 14 days prior to administration of ABT-888)
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
Creatinine =< 1.5 x upper limit of normal (ULN) (measured within 14 days prior to administration of ABT-888)
Ability to understand and the willingness to sign a written informed consent document
If a woman is of child-bearing potential a negative blood or urine pregnancy test is required; (the effects of veliparib on the developing human fetus are unknown; for this reason and because other therapeutic agents or modalities used in this trial are known to be teratogenic, women of child-bearing potential and men must agree to use adequate contraception [hormonal or barrier method of birth control; abstinence] prior to study entry and for the duration of study participation; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately)
Absolute neutrophil count >= 1,500/mcL (measured within 14 days prior to administration of ABT-888)
Aspartate aminotransferase(AST)/serum glutamic oxaloacetic transaminase (SGOT) and alanine aminotransferase(ALT)/serum glutamate pyruvate transaminase (SGPT) =< 2.5 x institutional upper limit of normal unless there is evidence of liver metastases in which case the AST (SGOT)/ALT (SGPT) must be =< 5 x institutional upper limit of normal (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)
For Part II (Arm C): 0-2 (Karnofsky >= 60%)
For Part I (Arm A, B): 0-1 (Karnofsky > 70%)
For Part I, randomized portion, measurable disease is required
Life expectancy of greater than 3 months
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 study therapy
For the lead-in, non-randomized portion of Part I, either measurable or evaluable disease is acceptable
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
Total bilirubin =< 2 x institutional upper limit of normal (measured within 14 days prior to administration of ABT-888)

Exclusion Criteria

Patients who are unable to swallow pills/capsules are ineligible
Patients with a known active infection, e.g., hepatitis B virus or hepatitis C virus; human immunodeficiency virus (HIV)-positive patients who are otherwise well and who do not have evidence of significant immune compromise are eligible
For Part II, no prior PARP inhibitor therapy is permitted; up to two prior treatment regimens are permitted as follows: 1 adjuvant and 1 metastatic; 1 locally advanced and 1 metastatic; or 2 metastatic, or a variation thereof
...
Patients who are unable to swallow pills/capsules are ineligible
Patients with a known active infection, e.g., hepatitis B virus or hepatitis C virus; human immunodeficiency virus (HIV)-positive patients who are otherwise well and who do not have evidence of significant immune compromise are eligible
For Part II, no prior PARP inhibitor therapy is permitted; up to two prior treatment regimens are permitted as follows: 1 adjuvant and 1 metastatic; 1 locally advanced and 1 metastatic; or 2 metastatic, or a variation thereof
History of allergic reactions attributed to compounds of similar chemical or biologic composition to veliparib or other agents used in study
Patients with uncontrolled central nervous system (CNS) metastasis are not eligible; patients with CNS metastases are to be stable for > 3 months after treatment and off steroid treatment prior to study enrollment
For Part I, prior adjuvant therapy with gemcitabine or a fluoropyrimidine therapy is permitted if completed > 6 months prior to recurrence; no prior PARP inhibitor therapy is allowed
Pregnant women are excluded from this study because veliparib is a PARP inhibitor with the potential for teratogenic or abortifacient effects; because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with veliparib, breastfeeding should be discontinued if the mother is treated with veliparib; these potential risks may also apply to other agents used in this study
Patients with prior malignancy successfully treated who are currently stable and on no active treatment are eligible
Patients with active seizure or history of seizure are not eligible
Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
Patients may not be receiving any other investigational agents
Patients with prior allogeneic bone marrow transplant or double umbilical cord blood transplantation are ineligible
For Part I: patients with known contraindications to platinum agents are excluded
Patients with treatment-related acute myeloid leukemia (AML) (t-AML)/myelodysplastic syndrome (MDS) or with features suggestive of AML/MDS are ineligible

Tracking Information

NCT #
NCT01585805
Collaborators
Not Provided
Investigators
  • Principal Investigator: Eileen M O'Reilly Memorial Sloan Kettering Cancer Center
  • Eileen M O'Reilly Memorial Sloan Kettering Cancer Center