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

This study is ongoing, but not recruiting participants.
Information provided by (Responsible Party):
National Cancer Institute (NCI) Identifier:
First received: December 18, 2007
Last updated: November 25, 2014
Last verified: November 2014

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 the body 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.

Condition Intervention Phase
Malignant Neoplasm
Drug: Irinotecan Hydrochloride
Drug: Veliparib
Other: Laboratory Biomarker Analysis
Other: Pharmacological Study
Phase 1

Study Type: Interventional
Study Design: Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
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

Resource links provided by NLM:

Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:
  • Optimal biological dose of study drugs, defined as the maximal decrease in PAR [ Time Frame: Up to day 9 of course 1 ] [ Designated as safety issue: No ]
  • 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 [ Time Frame: Up to 21 days ] [ Designated as safety issue: Yes ]
  • 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 [ Time Frame: Up to 21 days ] [ Designated as safety issue: Yes ]
  • 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 [ Time Frame: Up to 21 days ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • Incidence of AEs, graded using the NCI CTCAE version 4.0 [ Time Frame: Up to 30 days ] [ Designated as safety issue: Yes ]
    Described by point estimates and exact 90% confidence intervals.

  • Tumor response, evaluated using RECIST version 1.1 [ Time Frame: Up to 30 days ] [ Designated as safety issue: No ]
  • Change in PARP levels in PBMCs [ Time Frame: Baseline to up to 10 days ] [ Designated as safety issue: No ]
    Summarized with standard descriptive statistics (N, median, mean, standard deviation, minimum, maximum, and 90% confidence interval for the mean).

  • PK profile of veliparib [ Time Frame: Baseline and at days 1, 2, and 3 of course 1 and days 1, 8, 9, and 10 of course 2 ] [ Designated as safety issue: No ]
    Summarized with standard descriptive statistics (N, median, mean, standard deviation, minimum, maximum, and 90% confidence interval for the mean).

  • PAR activity inhibition in peripheral blood mononuclear cells and tumor cells [ Time Frame: Up to 10 days ] [ Designated as safety issue: No ]
  • Change in gamma-H2AX foci and/or Rad51 levels [ Time Frame: Baseline to up to day 9 of course 1 ] [ Designated as safety issue: No ]
    Summarized with standard descriptive statistics (N, median, mean, standard deviation, minimum, maximum, and 90% confidence interval for the mean).

Estimated Enrollment: 40
Study Start Date: December 2007
Estimated Primary Completion Date: January 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Treatment (irinotecan hydrochloride and veliparib)
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.
Drug: Irinotecan Hydrochloride
Given IV
Drug: Veliparib
Given PO
Other Name: ABT-888
Other: Laboratory Biomarker Analysis
Correlative studies
Other: Pharmacological Study
Correlative studies
Other Name: pharmacological studies

  Show Detailed Description


Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No

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
  • 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

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its identifier: NCT00576654

United States, Connecticut
Yale University
New Haven, Connecticut, United States, 06520
United States, Massachusetts
Dana-Farber Cancer Institute
Boston, Massachusetts, United States, 02115
United States, Michigan
Wayne State University/Karmanos Cancer Institute
Detroit, Michigan, United States, 48201
Sponsors and Collaborators
Principal Investigator: Patricia LoRusso Yale University
  More Information

No publications provided

Responsible Party: National Cancer Institute (NCI) Identifier: NCT00576654     History of Changes
Other Study ID Numbers: NCI-2009-01057, NCI-2009-01057, CDR0000579642, 2007-014, 7977, UM1CA186689, U01CA062490, U01CA062487, P30CA016359
Study First Received: December 18, 2007
Last Updated: November 25, 2014
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Antineoplastic Agents
Antineoplastic Agents, Phytogenic
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Radiation-Sensitizing Agents
Therapeutic Uses
Topoisomerase I Inhibitors
Topoisomerase Inhibitors processed this record on November 25, 2014