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

Hodgkin Lymphoma Clinical Trial

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

Status Active, not recruiting

Clinical Trial 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.

Clinical Trial 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). (ORIGINAL DOSE ESCALATION PORTION) 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. (ORIGINAL DOSE ESCALATION PORTION) 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. (ORIGINAL DOSE ESCALATION PORTION) 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. (ORIGINAL DOSE ESCALATION PORTION) 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 1 to 4 and days 8 to 11 of each cycle), determined by evaluating the feasibility, safety, dose limiting toxicities and the maximally tolerated dose (MTD). (DOSE ESCALATION FOR INTERMITTENT ABT-888 PORTION) 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. (DOSE ESCALATION FOR INTERMITTENT ABT-888 PORTION) 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. (DOSE ESCALATION FOR INTERMITTENT ABT-888 PORTION)

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). (DOSE ESCALATION FOR INTERMITTENT ABT-888 PORTION) V. To describe response rate (RR) in patients. (DOSE ESCALATION FOR INTERMITTENT ABT-888 PORTION)

TERTIARY OBJECTIVES:

I. Pharmacodynamic (PD) biomarker response: PARP inhibition in peripheral blood mononuclear cells (PBMC) by measurement of PAR levels. (ORIGINAL 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. (ORIGINAL 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. (ORIGINAL DOSE ESCALATION PORTION) IV. To explore whether a positive gamma-H2AX response in tumor tissue at 4-6 hours (hrs) is reflected in circulating tumor cells (CTCs) between 8-24 hrs but not at 4-6 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 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. (DOSE ESCALATION FOR INTERMITTENT ABT-888 PORTION) XVI. Additional exploratory assay to be named later. (DOSE ESCALATION FOR INTERMITTENT ABT-888 PORTION)

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.

INTERMITTENT DOSE ESCALATION: 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.

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

Related Conditions & MeSH terms

• Advanced Malignant Solid Neoplasm
• Breast Neoplasms
• Carcinoma, Ovarian Epithelial
• Colonic Neoplasms
• Hodgkin Lymphoma
• Lung Neoplasms
• Lymphoma
• Metastatic Malignant Neoplasm
• Metastatic Malignant Solid Neoplasm
• Neoplasms
• Non-Hodgkin Lymphoma
• Ovarian Neoplasms
• Pancreatic Neoplasms
• 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

• NCT number: NCT00576654
• Study type: Interventional
• Source: National Cancer Institute (NCI)
• Status: Active, not recruiting
• Phase: Phase 1
• Start date: December 5, 2007
• Completion date: June 30, 2023