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

• ClinicalTrials.gov Identifier: NCT00576654
• Recruitment Status: Active, not recruiting
• First Posted: December 19, 2007
• Last Update Posted: September 23, 2019
• Sponsor: National Cancer Institute (NCI)
• Information provided by (Responsible Party): National Cancer Institute (NCI)

Study Description

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; Hodgkin Lymphoma; Metastatic Malignant Neoplasm; Metastatic Malignant Solid Neoplasm; Non-Hodgkin Lymphoma; 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 Design

• 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: December 31, 2019

Arms and Interventions

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; Irinotecan Hydrochloride Trihydrate; Irinotecan Monohydrochloride Trihydrate; 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; Irinotecan Hydrochloride Trihydrate; Irinotecan Monohydrochloride Trihydrate; 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; Irinotecan Hydrochloride Trihydrate; Irinotecan Monohydrochloride Trihydrate; 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

Outcome Measures

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.

Eligibility Criteria

• 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

Contacts and Locations

Locations

United States, Connecticut

Yale University

New Haven, Connecticut, United States, 06520

United States, Maryland

University of Maryland/Greenebaum Cancer Center

Baltimore, Maryland, United States, 21201

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 M LoRusso; Yale University Cancer Center LAO

More Information

• 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) ); 1410014852; CDR0000579642; HIC 1410014852; 2007-014; HIC1410014852; 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
• Last Update Posted: September 23, 2019
• Last Verified: July 2019

Additional relevant MeSH terms:

Lymphoma; Breast Neoplasms; Lung Neoplasms; Pancreatic Neoplasms; Ovarian Neoplasms; Carcinoma, Ovarian Epithelial; Colonic Neoplasms; Triple Negative Breast Neoplasms; 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; Adnexal Diseases; Genital Diseases, Female; Genital Neoplasms, Female