Irinotecan and Veliparib in Treating Patients With Metastatic or Unresectable Cancer

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT00576654
First received: December 18, 2007
Last updated: April 18, 2014
Last verified: February 2014

December 18, 2007
April 18, 2014
December 2007
January 2015   (final data collection date for primary outcome measure)
  • 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 ]
  • Optimal biological dose of study drugs
  • Maximum administered dose of study drugs
  • Maximum tolerated dose of study drugs
  • Recommend phase II dose of study drugs
Complete list of historical versions of study NCT00576654 on ClinicalTrials.gov Archive Site
  • 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 y-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).
  • Toxicity
  • PAR levels
  • Pharmacological studies
  • PAR activity inhibition
  • Polymorphisms in UGT1A1, CYP2C9, CYP2C19, and ABCG2
Not Provided
Not Provided
 
Irinotecan and Veliparib in Treating Patients With Metastatic or Unresectable Cancer
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

This phase I trial studies the side effects and best dose of irinotecan when given together with veliparib in treating patients with metastatic or unresectable cancer. Drugs used in chemotherapy, such as irinotecan, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Veliparib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving irinotecan together with veliparib may kill more cancer cells.

PRIMARY OBJECTIVES:

I. To determine the optimal biologic dose (OBD) for poly (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.

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).

TERTIARY OBJECTIVES:

I. Pharmacodynamic (PD) biomarker response: PARP inhibition in peripheral blood mononuclear cells (PBMC) by measurement of PAR levels. (Dose escalation portion) II. Deoxyribonucleic acid (DNA) damaging effects of irinotecan and the combination of irinotecan with ABT-888: levels of gamma H2A histone family, member X (γ-H2AX) and Rad51 formation in tumor tissue. (Dose escalation portion) III. Relevance of cytochrome P450 family 2, subfamily C, polypeptide 9 (CYP2C9) and 2C19 polymorphisms, 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 γ-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 γH2AX response of CTCs to plasma drug by 4-6 hrs after CPT-11 administration. (Expansion portion) VI. To explore whether PARP inhibition increases γ-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 γ-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)

OUTLINE: This is a dose-escalation study of veliparib.

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.

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

Interventional
Phase 1
Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
  • Adult Grade III Lymphomatoid Granulomatosis
  • Adult Nasal Type Extranodal NK/T-cell Lymphoma
  • Angioimmunoblastic T-cell Lymphoma
  • Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue
  • Nodal Marginal Zone B-cell Lymphoma
  • Recurrent Adult Burkitt Lymphoma
  • Recurrent Adult Diffuse Large Cell Lymphoma
  • Recurrent Adult Diffuse Mixed Cell Lymphoma
  • Recurrent Adult Diffuse Small Cleaved Cell Lymphoma
  • Recurrent Adult Grade III Lymphomatoid Granulomatosis
  • Recurrent Adult Hodgkin Lymphoma
  • Recurrent Adult Immunoblastic Large Cell Lymphoma
  • Recurrent Adult Lymphoblastic Lymphoma
  • Recurrent Adult Non-Hodgkin Lymphoma
  • Recurrent Adult T-cell Leukemia/Lymphoma
  • Recurrent Cutaneous T-cell Non-Hodgkin Lymphoma
  • Recurrent Grade 1 Follicular Lymphoma
  • Recurrent Grade 2 Follicular Lymphoma
  • Recurrent Grade 3 Follicular Lymphoma
  • Recurrent Mantle Cell Lymphoma
  • Recurrent Marginal Zone Lymphoma
  • Recurrent Mycosis Fungoides/Sezary Syndrome
  • Recurrent Small Lymphocytic Lymphoma
  • Splenic Marginal Zone Lymphoma
  • Stage III Adult Burkitt Lymphoma
  • Stage III Adult Diffuse Large Cell Lymphoma
  • Stage III Adult Diffuse Mixed Cell Lymphoma
  • Stage III Adult Diffuse Small Cleaved Cell Lymphoma
  • Stage III Adult Hodgkin Lymphoma
  • Stage III Adult Immunoblastic Large Cell Lymphoma
  • Stage III Adult Lymphoblastic Lymphoma
  • Stage III Adult Non-Hodgkin Lymphoma
  • Stage III Adult T-cell Leukemia/Lymphoma
  • Stage III Cutaneous T-cell Non-Hodgkin Lymphoma
  • Stage III Grade 1 Follicular Lymphoma
  • Stage III Grade 2 Follicular Lymphoma
  • Stage III Grade 3 Follicular Lymphoma
  • Stage III Mantle Cell Lymphoma
  • Stage III Marginal Zone Lymphoma
  • Stage III Small Lymphocytic Lymphoma
  • Stage IIIA Mycosis Fungoides/Sezary Syndrome
  • Stage IIIB Mycosis Fungoides/Sezary Syndrome
  • Stage IV Adult Burkitt Lymphoma
  • Stage IV Adult Diffuse Large Cell Lymphoma
  • Stage IV Adult Diffuse Mixed Cell Lymphoma
  • Stage IV Adult Diffuse Small Cleaved Cell Lymphoma
  • Stage IV Adult Hodgkin Lymphoma
  • Stage IV Adult Immunoblastic Large Cell Lymphoma
  • Stage IV Adult Lymphoblastic Lymphoma
  • Stage IV Adult Non-Hodgkin Lymphoma
  • Stage IV Adult T-cell Leukemia/Lymphoma
  • Stage IV Cutaneous T-cell Non-Hodgkin Lymphoma
  • Stage IV Grade 1 Follicular Lymphoma
  • Stage IV Grade 2 Follicular Lymphoma
  • Stage IV Grade 3 Follicular Lymphoma
  • Stage IV Mantle Cell Lymphoma
  • Stage IV Marginal Zone Lymphoma
  • Stage IV Small Lymphocytic Lymphoma
  • Stage IVA Mycosis Fungoides/Sezary Syndrome
  • Stage IVB Mycosis Fungoides/Sezary Syndrome
  • Testicular Lymphoma
  • Unspecified Adult Solid Tumor, Protocol Specific
  • Waldenström Macroglobulinemia
  • Drug: irinotecan hydrochloride
    Given IV
    Other Names:
    • Campto
    • Camptosar
    • CPT-11
    • irinotecan
    • U-101440E
  • Drug: veliparib
    Given PO
    Other Name: ABT-888
  • Other: laboratory biomarker analysis
    Correlative studies
  • Other: pharmacological study
    Correlative studies
    Other Name: pharmacological studies
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.
Interventions:
  • Drug: irinotecan hydrochloride
  • Drug: veliparib
  • Other: laboratory biomarker analysis
  • Other: pharmacological study
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Active, not recruiting
40
Not Provided
January 2015   (final data collection date for primary outcome measure)

Inclusion Criteria:

  • 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
  • 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, or 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 > 12 weeks
  • Absolute neutrophil count >= 1,500/mcL
  • Platelet count >= 100,000/mcL
  • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x upper limit of normal (ULN) (=< 5 times ULN if liver metastases are present)
  • 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 hydrochloride, irinotecan hydrochloride, or exatecan mesylate)
    • Any ingredients contained within the liquid irinotecan hydrochloride 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 due to the reduction of the exposure of irinotecan. 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
Both
18 Years and older
No
Contact information is only displayed when the study is recruiting subjects
United States
 
NCT00576654
NCI-2009-01057, NCI-2009-01057, CDR0000579642, 2007-014, 7977, U01CA062490, P30CA022453, U01CA062487
Not Provided
National Cancer Institute (NCI)
National Cancer Institute (NCI)
Not Provided
Principal Investigator: Patricia LoRusso Wayne State University/Karmanos Cancer Institute
National Cancer Institute (NCI)
February 2014

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP