Clinical Trials /

Veliparib and Irinotecan Hydrochloride in Treating Patients With Cancer That Is Metastatic or Cannot Be Removed by Surgery

NCT00576654

Description:

This phase I trial studies the side effects and best dose of veliparib when given together with irinotecan hydrochloride in treating patients with cancer that has spread to other parts of the body or that cannot be removed by surgery. Irinotecan hydrochloride can kill cancer cells by damaging the deoxyribonucleic acid (DNA) that is needed for cancer cell survival and growth. Veliparib may block proteins that repair the damaged DNA and may help irinotecan hydrochloride to kill more tumor cells. Giving irinotecan hydrochloride together with veliparib may kill more cancer cells.

Related Conditions:
  • Breast Carcinoma
  • Lymphoma
  • Malignant Solid Tumor
Recruiting Status:

Active, not recruiting

Phase:

Phase 1

Trial Eligibility

Document

<span class="go-doc-concept go-doc-intervention">Irinotecan Hydrochloride</span> and <span class="go-doc-concept go-doc-intervention">Veliparib</span> in Treating Patients With <span class="go-doc-concept go-doc-disease">Cancer</span> That Is Metastatic or Cannot Be Removed by Surgery

Title

  • Brief Title: Irinotecan Hydrochloride and Veliparib in Treating Patients With Cancer That Is Metastatic or Cannot Be Removed by Surgery
  • Official Title: A Phase I Dose-Escalation Study of Oral ABT-888 (NSC #737664) Plus Intravenous Irinotecan (CPT-11, NSC#616348) Administered in Patients With Advanced Solid Tumors
  • Clinical Trial IDs

    NCT ID: NCT00576654

    ORG ID: NCI-2009-01057

    NCI ID: NCI-2009-01057

    Trial Conditions

    Adult Hodgkin Lymphoma

    Adult Non-Hodgkin Lymphoma

    BRCA1 Mutation Carrier

    BRCA2 Mutation Carrier

    Breast Carcinoma

    Estrogen Receptor Negative

    HER2/Neu Negative

    Malignant Neoplasm

    Progesterone Receptor Negative

    Trial Interventions

    Drug Synonyms Arms
    Irinotecan Hydrochloride Campto, Camptosar, Camptothecin 11, Camptothecin-11, CPT 11, CPT-11, U-101440E Dose escalation (irinotecan hydrochloride and veliparib), Expansion portion (irinotecan hydrochloride and veliparib), BRCA-mutant intermittent dose escalation (irinotecan, ABT-888)
    Veliparib ABT-888, PARP-1 inhibitor ABT-888 Dose escalation (irinotecan hydrochloride and veliparib), Expansion portion (irinotecan hydrochloride and veliparib), BRCA-mutant intermittent dose escalation (irinotecan, ABT-888)

    Trial Purpose

    This phase I trial studies the side effects and best dose of veliparib when given together
    with irinotecan hydrochloride in treating patients with cancer that has spread to other
    parts of the body or that cannot be removed by surgery. Irinotecan hydrochloride can kill
    cancer cells by damaging the deoxyribonucleic acid (DNA) that is needed for cancer cell
    survival and growth. Veliparib may block proteins that repair the damaged DNA and may help
    irinotecan hydrochloride to kill more tumor cells. Giving irinotecan hydrochloride together
    with veliparib may kill more cancer cells.

    Detailed Description

    PRIMARY OBJECTIVES:

    I. To determine the optimal biologic dose (OBD) for poly (adenosine diphosphate
    [ADP]-ribose) polymerase (PARP) inhibition using irinotecan (irinotecan hydrochloride) (once
    weekly intravenously in 2 of 3 weeks), in combination with ABT-888 (veliparib) (twice daily
    orally for 2 of 3 weeks).

    II. To determine the recommended phase II dose (RP2D) for irinotecan (once weekly
    intravenously in 2 of 3 weeks), in combination with ABT-888 (twice daily orally for 2 of 3
    weeks), determined by evaluating the feasibility, safety, dose limiting toxicities and the
    maximally tolerated dose.

    III. To determine the safety profile of irinotecan in combination with ABT-888: the
    incidence of adverse events (AEs) and clinically significant changes in laboratory tests,
    electrocardiograms (ECGs), and vital signs.

    IV. To determine the safety profile of irinotecan in combination with ABT-888 at the
    recommended phase II dose: the incidence of adverse events (AEs) and clinically significant
    changes in laboratory tests, ECGs, and vital signs.

    V. To determine the recommended phase II dose (RP2D) of each drug for irinotecan (once
    weekly intravenously in 2 of 3 weeks), in combination with ABT-888 (twice daily orally for
    intermittent dosing days -2 to 2 and days 6 to 9 of each cycle), determined by evaluating
    the feasibility, safety, dose limiting toxicities and the maximally tolerated dose (MTD).
    (breast cancer susceptibility gene [BRCA]-mutant dose escalation) VI. To determine the
    safety profile of irinotecan in combination with ABT-888: The incidence of adverse events
    (AEs) and clinically significant changes in laboratory tests, and vital signs. (BRCA-mutant
    dose escalation) VII. To determine the safety profile of irinotecan in combination with
    ABT-888 at the recommended phase II dose: The incidence of adverse events (AEs) and
    clinically significant changes in laboratory tests, and vital signs. (BRCA-mutant dose
    escalation)

    SECONDARY OBJECTIVES:

    I. To determine the pharmacokinetic (PK) profile of ABT-888. II. To determine the PK profile
    of irinotecan (CPT-11) both as a single agent and in combination with ABT-888.

    III. To determine the tumor response as assessed by the Response Evaluation Criteria in
    Solid Tumors (RECIST).

    IV. To determine the tumor response as assessed by the Response Evaluation Criteria in Solid
    Tumors (RECIST). (BRCA-mutant dose escalation) V. To determine response rate (RR) in
    patients with BRCA-mutant positive triple- negative breast cancer. (BRCA-mutant dose
    escalation)

    TERTIARY OBJECTIVES:

    I. Pharmacodynamic (PD) biomarker response: PARP inhibition in peripheral blood mononuclear
    cells (PBMC) by measurement of PAR levels. (Dose escalation portion) II. DNA damaging
    effects of irinotecan and the combination of irinotecan with ABT-888: levels of gamma H2A
    histone family, member X (gamma-H2AX) and RAD51 recombinase (Rad51) formation in tumor
    tissue. (Dose escalation portion) III. Relevance of cytochrome P450 family 2, subfamily C,
    polypeptide 9 (CYP2C9) and 2C19 polymorphisms, uridine 5'-diphosphosphate (UDP)
    glucuronosyltransferase 1 family, polypeptide A1 (UGT1A1) polymorphism, and ATP-binding
    cassette, sub-family G (WHITE), member 2 (ABCG2) polymorphism to the pharmacokinetics of
    irinotecan and/or ABT-888. (Dose escalation portion) IV. To explore whether a positive
    gamma-H2AX response in tumor tissue at 4-6 hrs is reflected in circulating tumor cells
    (CTCs) between 8-24 hrs but not at 4-6 hours (hrs), as predicted. (Expansion portion) V. To
    explore whether PARP inhibition increases gamma-H2AX response of CTCs to plasma drug by 4-6
    hrs after CPT-11 administration. (Expansion portion) VI. To explore whether PARP inhibition
    increases gamma-H2AX response of tumor cells to tissue drug level, as indicated by CTCs at
    8-24 hrs after CPT-11. (Expansion portion) VII. To explore when the gamma-H2AX response peak
    in CTCs occurs, indicating a response in tumor. (Expansion portion) VIII. To explore whether
    there is a tumor switch between gamma-H2AX and excision repair cross-complementation group 1
    (ERCC1)-mediated repair in the presence of PARP inhibition, (i.e., repeat initial PBMC and
    tumor findings). (Expansion portion) IX. To perform analysis of CTCs at day 15 to help guide
    alteration in ABT-888 drug administration schedule (continuous administration). (Expansion
    portion) X. To sequence the genome and transcriptome from both normal and tumor tissue from
    each study patient in the expansion cohort to evaluate point mutations, structural changes
    and copy number events. (Expansion portion) XI. To evaluate the damaging effects of
    irinotecan and the combination of irinotecan with ABT-888 by examining levels of Rad51
    formation in tumors. (Expansion portion) XII. To evaluate the percentage of breast cancer
    stem cells (BCSC) in serial breast tumor biopsies before and after irinotecan alone and
    after 1 cycle of treatment with the combination of irinotecan and ABT-888. (Expansion
    portion) XIII. To perform molecular profiling of the tumor cell and BCSC populations before
    and after irinotecan alone and after 1 cycle of treatment with the combination of irinotecan
    and ABT-888. (Expansion portion) XIV. To compare Rad51 foci in aldehyde
    dehydrogenase-positive (ALDH+) stem cell populations to the bulk tumor cells. (Expansion
    portion) XV. To sequence the genome and transcriptome from both normal and tumor tissue from
    each study patient in the expansion cohort to evaluate point mutations, structural changes
    and copy number events. (BRCA-mutant dose escalation) XVI. To develop assays to detect
    trapping of PARP1 and 2 in tumor biopsy tissue in response to treatment with irinotecan plus
    a PARP inhibitor, in this case ABT-888. (BRCA-mutant dose escalation) XVII. Additional
    exploratory assay to be named later. (BRCA-mutant dose escalation)

    OUTLINE: This is a dose-escalation study of veliparib. Patients are assigned to 1 of 3
    cohorts.

    DOSE ESCALATION: Patients receive irinotecan hydrochloride intravenously (IV) over 90
    minutes on days 1 and 8 and veliparib orally (PO) twice daily (BID) on days -1 to 14 (days
    3-14 of course 1 only). Courses repeat every 21 days in the absence of disease progression
    or unacceptable toxicity.

    EXPANSION PORTION: Patients receive irinotecan hydrochloride IV over 90 minutes on days 1
    and 8 and veliparib PO BID on days 1-15 (days 2-15 of course 1 only). Courses repeat every
    21 days in the absence of disease progression or unacceptable toxicity.

    BRCA-MUTANT INTERMITTENT DOSE ESCALATION: Patients receive irinotecan hydrochloride IV over
    90 minutes on days 1 and 8 and veliparib PO BID on days -2 to 2 and days 6-9. Courses repeat
    every 21 days in the absence of disease progression or unacceptable toxicity.

    After completion of study treatment, patients are followed up periodically for 30 days.

    Trial Arms

    Name Type Description Interventions
    BRCA-mutant intermittent dose escalation (irinotecan, ABT-888) Experimental Patients receive irinotecan hydrochloride IV over 90 minutes on days 1 and 8 and veliparib PO BID on days -2 to 2 and days 6-9. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Irinotecan Hydrochloride, Veliparib
    Dose escalation (irinotecan hydrochloride and veliparib) Experimental Patients receive irinotecan hydrochloride IV over 90 minutes on days 1 and 8 and veliparib PO BID on days -1 to 14 (days 3-14 of course 1 only). Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Irinotecan Hydrochloride, Veliparib
    Expansion portion (irinotecan hydrochloride and veliparib) Experimental Patients receive irinotecan hydrochloride IV over 90 minutes on days 1 and 8 and veliparib PO BID on days 1-15 (days 2-15 of course 1 only). Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Irinotecan Hydrochloride, Veliparib

    Eligibility Criteria

    Inclusion Criteria:

    - Patients must have histologically or cytologically confirmed diagnosis of malignancy
    that is metastatic or unresectable and for which standard curative or palliative
    measures do not exist or are no longer effective or for whom CPT-11 treatment would
    be a viable therapy regimen; patients with solid hematologic malignancies (Hodgkin's
    and non-Hodgkin's lymphomas) may be included as long as a bone marrow has been
    performed within 6 weeks of treatment

    - Patients enrolled on the expansion portion of the study will consist of two cohorts:
    those patients who are triple-negative, BRCA-mutant positive and those patients who
    have triple-negative, non-BRCA mutated breast cancer

    - Patients enrolled on the BRCA-mutant dose escalation for intermittent ABT-888 portion
    of the study MUST have a deleterious mutation in BRCA and have human epidermal growth
    factor receptor 2 (Her-2) negative, estrogen receptor (ER) negative (defined as less
    than 1% ER by immunohistochemistry [IHC]) and progesterone receptor (PR) negative
    breast cancer (defined as less than 1% PR staining by IHC)

    - Patient must have measurable disease per Response Evaluation Criteria In Solid Tumors
    (RECIST) guidelines

    - Patients must have tumors determined to be easily accessible for biopsy (e.g.
    pleural-based lesions, peripheral lymph nodes, soft tissue metastases, large liver
    metastases, etc)

    - Patients must not be homozygous for the UGT1A1*28 allele (also called [TA]7);
    individuals who are carriers for the UGT1A1*28 allele may be at increased risk for
    neutropenia following initiation of irinotecan treatment

    - Prior chemotherapy is allowed; patients must not have received chemotherapy for 4
    weeks prior to the initiation of study treatment and must have full recovery from any
    acute effects of any prior chemotherapy; patients must not have had nitrosoureas or
    mitomycin C for 6 weeks prior to the initiation of study treatment

    - Prior radiation therapy is allowed; patients must not have received minimal radiation
    therapy (=< 5% of their total marrow volume) within 3 weeks prior to the initiation
    of study treatment; otherwise, patients must not have received radiation therapy (>
    5% of their total marrow volume) within 4 weeks prior to the initiation of study
    treatment; patients who have received prior radiation to 50% or more of their total
    marrow volume will be excluded

    - Prior experimental (non-Food and Drug Administration [FDA] approved) therapies and
    immunotherapies are allowed; patients must not have received these therapies for 4
    weeks prior to the initiation of study treatment and must have full recovery from any
    acute effects of these therapies

    - Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)

    - Life expectancy of greater than 12 weeks

    - Absolute neutrophil count (ANC) >= 1,500/mcL

    - Platelets (PLT) >= 100,000/mcL

    - Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x upper
    limit of normal (ULN); if liver metastases are present, =< 5 x ULN

    - Bilirubin =< 1.5 x ULN

    - Creatinine =< 1.5 x ULN OR calculated or measured creatinine clearance >= 60
    mL/min/1.73 m^2 for patients with creatinine above institutional normal

    - 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, for
    the duration of study participation, and for three months following completion of
    study therapy; 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

    - All patients must provide archival tissue block or paraffin sample from archival
    tissue block (approximately 10 sections) for use in pharmacodynamic correlative
    studies (NOT required for patients enrolled on the BRCA-mutant dose escalation for
    intermittent ABT-888 portion of the study)

    Exclusion Criteria:

    - Patients who have had chemotherapy or radiotherapy within 4 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 4 weeks earlier;
    patients who have been administered ABT-888 as part of a single or limited dosing
    study, such as a phase 0 study, should not necessarily be excluded from participating
    in this study solely because of receiving prior ABT-888

    - Patients may not have received any other investigational agents within 4 weeks of
    study entry

    - History of allergic reactions attributed to the following:

    - Camptothecin derivatives (e.g., topotecan [topotecan hydrochloride], irinotecan,
    or exatecan [exatecan mesylate])

    - Any ingredients contained within the liquid irinotecan solution (e.g., sorbitol)

    - Any antiemetics or antidiarrheals appropriate for administration with study
    therapy (e.g., loperamide or dexamethasone)

    - Patients must not receive any other anti-cancer therapy (cytotoxic, biologic,
    radiation, or hormonal other than for replacement) while on this study except for
    medications that are prescribed for supportive care but may potentially have an
    anti-cancer effect (i.e. megestrol acetate, bisphosphonates); these medications must
    have been started 1 month prior to enrollment on this study; in addition, men
    receiving treatment for prostate cancer will be maintained at castrate levels of
    testosterone by continuation of luteinizing-releasing hormone agonists

    - Patients with active seizure or a history of seizure

    - Patients with known active brain metastases should be excluded from this clinical
    trial; patients with prior treated brain metastases are allowed, providing that they
    were not accompanied by seizures and that a baseline brain magnetic resonance imaging
    (MRI) scan prior to study entry demonstrates no current evidence of brain metastases;
    all patients with central nervous system (CNS) metastases must be stable for > 3
    months after treatment and off steroid treatment prior to study enrollment

    - Any patient requiring chronic maintenance of white blood cell counts or granulocyte
    counts through the use of growth factor support (e.g. Neulasta, Neupogen)

    - Any patient requiring cytochrome P450 CYP3A4 isoform-inducing drugs (e.g. phenytoin,
    phenobarbital, carbamazepine, rifampin, rifabutin, ketoconazole, St. John's wort)
    will be excluded; CYP3A4-inducing drugs should be discontinued at least 2 weeks prior
    to the first cycle of irinotecan

    - Uncontrolled intercurrent illness including, but not limited to:

    - Ongoing or active infection

    - Symptomatic congestive heart failure

    - Unstable angina pectoris

    - Cardiac arrhythmia

    - Psychiatric illness or 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 ABT-888

    - Patients who are unable to reliably tolerate and/or receive oral medications

    Minimum Eligible Age: 18 Years

    Maximum Eligible Age: N/A

    Eligible Gender: Both

    Primary Outcome Measures

    Maximum administered dose of study drugs, defined as the dose level at which at least 2 of 6 patients develop dose-limiting toxicity (DLT) as graded by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0

    Maximum tolerated dose of study drugs, defined as the dose at which no more than 1 patient of 6 develops DLT as graded by the NCI CTCAE version 4.0

    Optimal biological dose of study drugs, defined as the maximal decrease in PAR

    RP2D of study drugs, defined as the MTD if DLTs are observed before achieving the OBD, or the OBD if DLTs are not observed before reaching the OBD as graded by the NCI CTCAE version 4.0

    Secondary Outcome Measures

    Change in gamma-H2AX foci and/or Rad51 levels

    Change in PARP levels in PBMCs

    Incidence of AEs, graded using the NCI CTCAE version 4.0

    PAR activity inhibition in peripheral blood mononuclear cells and tumor cells

    PK profile of veliparib

    Tumor response, evaluated using RECIST version 1.1

    Trial Keywords