Clinical Trials /

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

NCT01585805

Description:

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.

Related Conditions:
  • Pancreatic Carcinoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 2

Trial Eligibility

Document

<span class="go-doc-concept go-doc-intervention">Gemcitabine Hydrochloride</span> and <span class="go-doc-concept go-doc-intervention">Cisplatin</span> With or Without <span class="go-doc-concept go-doc-intervention">Veliparib</span> or <span class="go-doc-concept go-doc-intervention">Veliparib</span> Alone in Patients With Locally Advanced or Metastatic <span class="go-doc-concept go-doc-disease">Pancreatic Cancer</span>

Title

  • Brief Title: Gemcitabine Hydrochloride and Cisplatin With or Without Veliparib or Veliparib Alone in 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)
  • Clinical Trial IDs

    NCT ID: NCT01585805

    ORG ID: NCI-2012-00864

    NCI ID: NCI-2012-00864

    Trial Conditions

    BRCA1 Mutation Carrier

    BRCA2 Mutation Carrier

    Pancreatic Adenocarcinoma

    Recurrent Pancreatic Carcinoma

    Stage III Pancreatic Cancer

    Stage IV Pancreatic Cancer

    Trial Interventions

    Drug Synonyms Arms
    Cisplatin Abiplatin, Blastolem, Briplatin, CDDP, Cis-diammine-dichloroplatinum, Cis-diamminedichloridoplatinum, Cis-diamminedichloro Platinum (II), Cis-diamminedichloroplatinum, Cis-dichloroammine Platinum (II), Cis-platinous Diamine Dichloride, Cis-platinum, Cis-platinum II, Cis-platinum II Diamine Dichloride, Cismaplat, Cisplatina, Cisplatinum, Cisplatyl, Citoplatino, Citosin, Cysplatyna, DDP, Lederplatin, Metaplatin, Neoplatin, Peyrone's Chloride, Peyrone's Salt, Placis, Plastistil, Platamine, Platiblastin, Platiblastin-S, Platinex, Platinol, Platinol- AQ, Platinol-AQ, Platinol-AQ VHA Plus, Platinoxan, Platinum, Platinum Diamminodichloride, Platiran, Platistin, Platosin Arm A (veliparib, gemcitabine hydrochloride, cisplatin), Arm B (gemcitabine hydrochloride, cisplatin)
    Gemcitabine Hydrochloride dFdCyd, Difluorodeoxycytidine Hydrochloride, Gemzar, LY-188011 Arm A (veliparib, gemcitabine hydrochloride, cisplatin), Arm B (gemcitabine hydrochloride, cisplatin)
    Veliparib ABT-888, PARP-1 inhibitor ABT-888 Arm A (veliparib, gemcitabine hydrochloride, cisplatin), Arm C (veliparib)

    Trial Purpose

    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

    PRIMARY OBJECTIVES:

    I. To optimize the dose of veliparib combined with fixed doses of gemcitabine (gemcitabine
    hydrochloride) 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 single-agent gemcitabine, cisplatin, and veliparib (Arm A) and gemcitabine,
    cisplatin (Arm B) in breast cancer, early onset (BRCA) and partner and localizer of BRCA2
    (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 B. (Part I)
    IV. To evaluate overall survival of patients in study arm A and 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) treated with single-agent veliparib.
    (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.

    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.

    III. To quantify levels of poly(adenosine diphosphate [ADP]-ribose) (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 gamma H2A histone family, member X (yH2AX) and RAD51 recombinase
    (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.

    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 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.

    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 every 3 months.

    Trial Arms

    Name Type Description Interventions
    Arm A (veliparib, gemcitabine hydrochloride, cisplatin) Experimental Patients receive veliparib PO BID on days 1-12 or 1-21. Patients also receive 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. Cisplatin, Gemcitabine Hydrochloride, Veliparib
    Arm B (gemcitabine hydrochloride, cisplatin) Active Comparator 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. Cisplatin, Gemcitabine Hydrochloride
    Arm C (veliparib) Experimental Patients receive veliparib PO BID on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Veliparib

    Eligibility Criteria

    Inclusion Criteria:

    - 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 (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 study therapy

    - 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

    - Hemoglobin >= 9.0 g/dL

    - Platelets >= 100,000/mcL

    - Total bilirubin =< 2 times institutional upper limit of normal (ULN)

    - Aspartate aminotransferase/serum glutamic oxaloacetic transaminase (AST/SGOT) and
    alanine aminotransferase/serum glutamate pyruvate transaminase (ALT/SGPT) =< 2.5 x
    institutional ULN unless there is evidence of liver metastases in which case the AST
    (SGOT)/ALT (SGPT) must be =< 5 times institutional ULN

    - Creatinine =< 1.5 x ULN

    - Measurable disease by RECIST criteria

    - For the lead-in, non-randomized portion of Part I, either measurable or
    evaluable disease is acceptable

    - For Part I, randomized portion, measurable disease is required

    - If a woman is of child-bearing potential a negative serum or urine pregnancy test is
    required; 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

    - Ability to understand and the willingness to sign a written informed consent document

    Exclusion Criteria:

    - Patients who have had chemotherapy or radiotherapy within 3 weeks (6 weeks for
    nitrosoureas or mitomycin C) prior to entering the study or those who have not
    recovered from adverse events due to agents administered more than 3 weeks earlier

    - 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

    - 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 may not be receiving any other investigational agents

    - History of allergic reactions attributed to compounds of similar chemical or biologic
    composition to veliparib or other agents used in study

    - For Part I: patients with known contraindications to platinum agents are excluded

    - 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

    - Pregnant women are excluded from this study; breastfeeding should be discontinued if
    the mother is treated with veliparib; this may also apply to other agents used in
    this study

    - Patients with an 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

    - Patients with active seizure or history of seizure are not eligible

    - 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

    - Patients with prior malignancy successfully treated who are currently stable and on
    no active treatment are eligible

    - Patients who are unable to swallow pills/capsules are ineligible

    Minimum Eligible Age: 19 Years

    Maximum Eligible Age: N/A

    Eligible Gender: Both

    Primary Outcome Measures

    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 Measures

    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

    Trial Keywords