Alternate Title
Basic Trial Information
Objectives
Entry Criteria
Expected Enrollment
Outcomes
Outline
Trial Contact Information
Registry Information

Alternate Title

Irinotecan and ABT-888 in Treating Patients With Metastatic or Unresectable Cancer

Basic Trial Information

Phase Type Status Age Sponsor Protocol IDs Phase I Biomarker/Laboratory analysis, Treatment Active Over 18 NCI WSU-2007-014 2007-014, 7977, NCT00576654

Objectives

Primary

1. To determine the optimal biologic dose for poly (ADP-ribose) polymerase (PARP) inhibition using irinotecan hydrochloride in combination with ABT-888 in patients with metastatic or unresectable malignancies.
2. To determine the recommended phase II dose for irinotecan hydrochloride in combination with ABT-888, by evaluating the feasibility, safety, dose-limiting toxicities and the maximum tolerated dose.
3. To determine the safety profile of this regimen (incidence of adverse events and clinically significant changes in laboratory tests, ECGs, and vital signs).
4. To determine the safety profile of this regimen at the recommended phase II dose (incidence of adverse events and clinically significant changes in laboratory tests, ECGs, and vital signs).

Secondary

1. To determine the pharmacokinetic (PK) profile of ABT-888.
2. To determine the PK profile of irinotecan hydrochloride both as a single agent and in combination with ABT-888.
3. To determine the tumor response as assessed by RECIST.

Tertiary

1. To determine the pharmacodynamic biomarker response (PARP inhibition in tumor cells and peripheral blood mononuclear cells) by measurement of PAR levels.
2. To determine the DNA damaging effects of irinotecan hydrochloride and the combination of irinotecan hydrochloride with ABT-888 (levels of γ-H2AX and Rad51 formation in tumor tissue).
3. To determine the relevance of CYP2C9 and 2C19 polymorphisms, UGT1A1 polymorphism, and ABCG2 polymorphism to the pharmacokinetics of irinotecan hydrochloride and/or ABT-888.

Entry Criteria

Disease Characteristics:

• Histologically or cytologically confirmed metastatic or unresectable malignancy meeting 1 of the following criteria:
  • Standard curative or palliative measures do not exist or are no longer effective
  • Irinotecan hydrochloride is considered to be a viable therapy regimen



• Patients with solid hematologic malignancies (Hodgkin or non-Hodgkin lymphoma) are eligible provided a bone marrow has been performed within 6 weeks of treatment



• Measurable disease per 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)



• Patients must be negative for carrying the UGT1A1*28 allele (also called (TA)7)



• Archival tissue block or paraffin sample from archival tissue block (approximately 10 sections) for use in pharmacodynamic correlative studies must be available



• No known active brain metastases
  • Patients with previously treated brain metastases are eligible, provided they are not accompanied by seizures and a baseline brain MRI scan demonstrates no current evidence of brain metastases

Prior/Concurrent Therapy:

• See Disease Characteristics
• More than 4 weeks since prior chemotherapy (6 weeks for nitrosoureas or mitomycin C) and recovered
• More than 3 weeks since prior minimal radiotherapy (i.e., ≤ 5% of total marrow volume)
• More than 4 weeks since prior radiotherapy (i.e., > 5% of total marrow volume)
• No prior radiotherapy to ≥ 50% of total marrow volume
• More than 4 weeks since prior experimental (i.e., non-FDA approved) therapy or immunotherapy and recovered
• Males receiving treatment for prostate cancer must be maintained at castrate levels of testosterone by continuation of luteinizing-releasing hormone agonists
• No cytochrome P450 CYP3A4 isoform-inducing drugs (e.g. phenytoin, phenobarbital, carbamazepine, rifampin, rifabutin, ketoconazole, St. John’s Wort)
• No other investigational agents within 4 weeks of study entry
• No chronic growth factor support (e.g., filgrastim [G-CSF], pegfilgrastim) for maintenance of white blood cell counts or granulocyte counts
• No other concurrent anticancer therapy (cytotoxic, biologic, radiation, or hormonal other than for replacement) except medications for supportive care that may potentially have an anticancer effect (i.e., megestrol acetate, bisphosphonates) started 1 month prior to study

Patient Characteristics:

• ECOG performance status (PS) 0-2 OR Karnofsky PS 60-100%
• Life expectancy > 12 weeks
• Absolute neutrophil count ≥ 1,500/mm³
• Platelet count ≥ 100,000/mm³
• AST and ALT ≤ 2.5 times upper limit of normal (ULN) (≤ 5 times ULN if liver metastases are present)
• Alkaline phosphatase ≤ 2.0 times ULN (≤ 5 times ULN if bone or liver metastases are present)
• Bilirubin ≤ 1.5 times ULN
• Creatinine ≤ 1.5 times ULN OR creatinine clearance ≥ 60 mL/min
• Ability to understand and the willingness to sign a written informed consent document
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception prior to, during, and for 3 months after completion of study treatment
• Must be able to reliably tolerate and/or receive oral medications
• No 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)
  • No prior history of seizures
• No 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

Expected Enrollment

Outcomes

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

Toxicity
PAR levels
Pharmacological studies
PAR activity inhibition
Polymorphisms in UGT1A1, CYP2C9, CYP2C19, and ABCG2

Outline

This is a multicenter, dose-escalation of ABT-888 study.

Patients receive irinotecan hydrochloride IV over 90 minutes on days 1 and 8 and oral ABT-888 twice daily on days 0-14 (days 3-14 of course 1 only). Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Patients undergo blood sample collection for pharmacokinetic and pharmacodynamic sampling periodically during courses 1 and 2. Samples are analyzed for topoisomerase I expression, polymorphism of ERCC1, PAR concentration by immunoassay, plasma concentrations of irinotecan hydrochloride and its metabolites by high performance liquid chromatography, and pharmacogenomics assessing polymorphisms in UGT1A1, CYP2C9, CYP2C19, and ABCG2. Patients also undergo tumor tissue biopsies periodically and samples are also analyzed for research studies.

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

Trial Contact Information

Trial Lead Organizations

Barbara Ann Karmanos Cancer Institute

Patricia LoRusso, DO, Protocol chair		Ph: 313-576-8716; 800-527-6266

Registry Information
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
Trial Start Date		2007-12-05
Trial Completion Date		2008-10-01 (estimated)
Registered in ClinicalTrials.gov		NCT00576654
Date Submitted to PDQ		2007-11-29
Information Last Verified		2008-07-30
NCI Grant/Contract Number		CA62487, CA22453