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

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ClinicalTrials.gov Identifier: NCT00576654
Recruitment Status : Active, not recruiting
First Posted : December 19, 2007
Last Update Posted : December 11, 2018
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Advanced Malignant Solid Neoplasm Estrogen Receptor Negative HER2/Neu Negative Hodgkin Lymphoma Metastatic Malignant Neoplasm Metastatic Malignant Solid Neoplasm Non-Hodgkin Lymphoma Progesterone Receptor Negative Stage III Breast Cancer AJCC v7 Stage III Colon Cancer AJCC v7 Stage III Lung Cancer AJCC v7 Stage III Ovarian Cancer AJCC v6 and v7 Stage III Pancreatic Cancer AJCC v6 and v7 Stage IIIA Breast Cancer AJCC v7 Stage IIIA Colon Cancer AJCC v7 Stage IIIA Ovarian Cancer AJCC v6 and v7 Stage IIIB Breast Cancer AJCC v7 Stage IIIB Colon Cancer AJCC v7 Stage IIIB Ovarian Cancer AJCC v6 and v7 Stage IIIC Breast Cancer AJCC v7 Stage IIIC Colon Cancer AJCC v7 Stage IIIC Ovarian Cancer AJCC v6 and v7 Stage IV Breast Cancer AJCC v6 and v7 Stage IV Colon Cancer AJCC v7 Stage IV Lung Cancer AJCC v7 Stage IV Ovarian Cancer AJCC v6 and v7 Stage IV Pancreatic Cancer AJCC v6 and v7 Stage IVA Colon Cancer AJCC v7 Stage IVB Colon Cancer AJCC v7 Triple-Negative Breast Carcinoma Unresectable Malignant Neoplasm Unresectable Solid Neoplasm Drug: Irinotecan Hydrochloride Other: Laboratory Biomarker Analysis Other: Pharmacological Study Drug: Veliparib Phase 1

  Show Detailed Description

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 36 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (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
Actual Study Start Date : December 5, 2007
Estimated Primary Completion Date : June 3, 2019


Arm Intervention/treatment
Experimental: Dose escalation (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
Other Names:
  • Campto
  • Camptosar
  • Camptothecin 11
  • Camptothecin-11
  • CPT 11
  • CPT-11
  • Irinomedac
  • U-101440E

Other: Laboratory Biomarker Analysis
Correlative studies

Other: Pharmacological Study
Correlative studies

Drug: Veliparib
Given PO
Other Names:
  • ABT-888
  • PARP-1 inhibitor ABT-888

Experimental: Expansion portion (irinotecan hydrochloride and veliparib)
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.
Drug: Irinotecan Hydrochloride
Given IV
Other Names:
  • Campto
  • Camptosar
  • Camptothecin 11
  • Camptothecin-11
  • CPT 11
  • CPT-11
  • Irinomedac
  • U-101440E

Other: Laboratory Biomarker Analysis
Correlative studies

Other: Pharmacological Study
Correlative studies

Drug: Veliparib
Given PO
Other Names:
  • ABT-888
  • PARP-1 inhibitor ABT-888

Experimental: Intermittent dose escalation (irinotecan, ABT-888)
Patients receive irinotecan hydrochloride IV over 90 minutes on days 3 and 10 and veliparib PO BID on days 1 to 4 and 8-11. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
Drug: Irinotecan Hydrochloride
Given IV
Other Names:
  • Campto
  • Camptosar
  • Camptothecin 11
  • Camptothecin-11
  • CPT 11
  • CPT-11
  • Irinomedac
  • U-101440E

Other: Laboratory Biomarker Analysis
Correlative studies

Other: Pharmacological Study
Correlative studies

Drug: Veliparib
Given PO
Other Names:
  • ABT-888
  • PARP-1 inhibitor ABT-888




Primary Outcome Measures :
  1. Optimal biologic dose (OBD) [ Time Frame: Up to day 9 of course 1 ]
    Defined as the dose level at which no greater inhibition of poly(ADP-ribose) (PAR) levels in tumor cells is identified, relative to the next lower dose.

  2. Maximum administered dose of study drugs [ Time Frame: Up to 21 days ]
    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 5.0.

  3. Maximally tolerated dose (MTD) of study drugs [ Time Frame: Up to 21 days ]
    Defined as the dose at which no more than 1 patient of 6 develops DLT as graded by the NCI CTCAE version 5.0.

  4. Recommended phase II dose (RP2D) of study drugs [ Time Frame: Up to 21 days ]
    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 5.0.


Secondary Outcome Measures :
  1. Incidence of adverse events (AEs), graded using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 [ Time Frame: Up to 30 days ]
    Described by point estimates and exact 90% confidence intervals.

  2. Tumor response [ Time Frame: Up to 30 days ]
    Evaluated using Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.


Other Outcome Measures:
  1. Change in poly(ADP-ribose) polymerase (PARP) levels in peripheral blood mononuclear cells (PBMCs) [ Time Frame: Baseline to up to 10 days ]
    Summarized with standard descriptive statistics (N, median, mean, standard deviation, minimum, maximum, and 90% confidence interval for the mean).

  2. Pharmacokinetic (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 ]
    Summarized with standard descriptive statistics (N, median, mean, standard deviation, minimum, maximum, and 90% confidence interval for the mean).

  3. Poly(ADP-ribose) (PAR) activity inhibition in peripheral blood mononuclear cells and tumor cells [ Time Frame: Up to 10 days ]
    Will be measured.

  4. Change in gamma-H2AX foci and/or Rad51 levels [ Time Frame: Baseline to up to day 9 of course 1 ]
    Summarized with standard descriptive statistics (N, median, mean, standard deviation, minimum, maximum, and 90% confidence interval for the mean).

  5. Pharmacodynamic (PD) parameters [ Time Frame: Up to 30 days ]
    Will be summarized descriptively, by dose level and overall and will be summarized with standard statistics (N, median, mean, standard deviation, minimum, maximum, and 90% confidence interval for the mean).

  6. Pharmacokinetic (PK) parameters of irinotecan hydrochloride [ Time Frame: Baseline, 5.5 hours after infusion, and 28 hours after infusion of day one of course 1 ]
    Will be summarized descriptively within each cytochrome p450, family 2, subfamily C, polypeptide 9 (CYP2C9) polymorphism category, by dose level and overall.

  7. Circulating tumor cell (CTC) counts [ Time Frame: Up to day 15 ]
    Will be measured.

  8. Excision repair cross-complementation group 1 (ERCC1) expression levels [ Time Frame: Up to day 8 ]
    Will be measured.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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 dose escalation for intermittent ABT-888 portion of the study must 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
  • 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)
  • 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 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) or
    • 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 uncontrolled seizures
  • 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 family 3, subfamily A, polypeptide 4 (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 or
    • 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00576654


Locations
United States, Connecticut
Yale University
New Haven, Connecticut, United States, 06520
United States, Massachusetts
Dana-Farber Cancer Institute
Boston, Massachusetts, United States, 02215
United States, Michigan
Wayne State University/Karmanos Cancer Institute
Detroit, Michigan, United States, 48201
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
Principal Investigator: Patricia LoRusso Yale University Cancer Center LAO

Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT00576654     History of Changes
Other Study ID Numbers: NCI-2009-01057
NCI-2009-01057 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
HIC 1410014852
1410014852
2007-014
HIC1410014852
CDR0000579642
7977 ( Other Identifier: Yale University Cancer Center LAO )
7977 ( Other Identifier: CTEP )
P30CA016359 ( U.S. NIH Grant/Contract )
R21CA135572 ( U.S. NIH Grant/Contract )
U01CA062487 ( U.S. NIH Grant/Contract )
U01CA062490 ( U.S. NIH Grant/Contract )
UM1CA186689 ( U.S. NIH Grant/Contract )
UM1CA186709 ( U.S. NIH Grant/Contract )
First Posted: December 19, 2007    Key Record Dates
Last Update Posted: December 11, 2018
Last Verified: December 2018

Additional relevant MeSH terms:
Lymphoma
Breast Neoplasms
Lung Neoplasms
Neoplasms
Pancreatic Neoplasms
Lymphoma, Non-Hodgkin
Ovarian Neoplasms
Neoplasms, Glandular and Epithelial
Hodgkin Disease
Colonic Neoplasms
Neoplasms, Second Primary
Triple Negative Breast Neoplasms
Neoplasms by Histologic Type
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Neoplasms by Site
Breast Diseases
Skin Diseases
Respiratory Tract Neoplasms
Thoracic Neoplasms
Lung Diseases
Respiratory Tract Diseases
Digestive System Neoplasms
Endocrine Gland Neoplasms
Digestive System Diseases
Pancreatic Diseases
Endocrine System Diseases
Ovarian Diseases