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

Alternate Title

ABT-888 in Patients With Refractory Solid Tumors or Hematologic Cancer

Basic Trial Information

Phase Type Status Age Sponsor Protocol IDs Phase I Biomarker/Laboratory analysis, Treatment Completed 18 and over NCI NCI-06-C-0172 NCI-P6890, 7675, NCT00387608

Objectives

Primary

1. Determine the dose-range at which ABT-888 inhibits poly (ADP-ribose) polymerase (PARP) in tumor samples and in peripheral blood mononuclear cells (PBMCs) in patients with refractory solid tumors or lymphoid malignancies.
2. Determine the pharmacokinetics of ABT-888.
3. Determine the time course of PARP inhibition in PBMCs by ABT-888.

Secondary

1. Determine the safety of administering 1 dose of ABT-888 in these patients.

Entry Criteria

Disease Characteristics:

• Histologically confirmed malignancy, meeting 1 of the following criteria:
  • Solid tumor that is refractory to ≥ 1 line of standard treatment OR for which no standard therapy is available
    • Must have ≥ 1 lesion amenable to percutaneous biopsy (for solid tumor patients enrolled after the initial phase of the study)
  • Chronic lymphocytic leukemia (CLL) or follicular lymphoma with no current indication for standard therapy OR disease that has failed ≥ 1 line of standard therapy



• No disease-associated symptoms requiring immediate therapy or other interventions



• Must be willing to undergo tumor biopsies* after the initial phase of the study

   [Note: *Patients with CLL undergo peripheral blood collection instead of biopsy]




• No primary brain tumors, brain metastases, or leptomeningeal disease

Prior/Concurrent Therapy:

• At least 2 weeks since prior radiation therapy or surgery and recovered
• At least 2 weeks since other prior therapy and recovered
• No concurrent antiretroviral therapy for HIV-positive patients
• No concurrent lung, liver, or mediastinal lymph node biopsies
• No other concurrent investigational agents

Patient Characteristics:

• ECOG performance status (PS) 0-2 or Karnofsky PS 60-100%
• Life expectancy ≥ 3 months
• Absolute neutrophil count ≥ 1,500/mm³
• Platelet count ≥ 100,000/mm³
• Hemoglobin ≥ 9 g/dL
• Bilirubin < 1.5 times upper limit of normal (ULN)
• AST and ALT ≤ 2.5 times ULN
• Creatinine < 1.5 times ULN OR creatinine clearance ≥ 60 mL/min
• INR ≤ 1.4
• PTT ≤ 36 seconds
• Calcium (corrected) normal
• Magnesium < 1.5 times ULN
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception during and for 30 days after study completion
• No history of seizures
• No evidence of bleeding diathesis
• No uncontrolled intercurrent illness including, but not limited to, any of the following:
  • Ongoing or active infection
  • Symptomatic congestive heart failure
  • Unstable angina pectoris
  • Cardiac arrhythmias
• No psychiatric illness or social situations that would limit study compliance

Expected Enrollment

A total of 23 patients will be accrued for this study.

Outcomes

Change in tumor poly (ADP-ribose) (PAR) levels from baseline to 3-6 hours after ABT-888 administration
Pharmacokinetics

Safety of administering 1 dose of ABT-888
Changes in PAR levels in peripheral blood mononuclear cells from baseline to after ABT-888 administration

Outline

This is a dose-finding study.

Patients receive oral ABT-888 once on day 1.

Cohorts of 3 patients receive escalating doses of ABT-888 until significant tumor poly (ADP-ribose) polymerase (PARP) inhibition is observed in 3 of 3 patients at 2 dose levels. Significant PARP inhibition is defined as ≥ 0.69 reduction on the log scale in poly (ADP-ribose) level from baseline to 3-6 hours after ABT-888 administration (with 90% confidence that it is not due to chance variation).

Patients undergo peripheral blood collection at baseline and periodically after ABT-888 administration for PARP inhibition, pharmacokinetic, and pharmacodynamic studies. Once significant PARP inhibition is observed in 1 of 3 patients, subsequently enrolled patients also undergo tumor biopsy* at baseline and 3-6 hours or 21-27 hours after ABT-888 administration to determine PARP inhibition in tumor tissue.

 [Note: *Patients with chronic lymphocytic leukemia undergo peripheral blood collection instead of biopsy.]

After completion of ABT-888 administration, patients are followed for 7 days.

Kummar S, Kinders R, Gutierrez M, et al.: Inhibition of poly (ADP-ribose) polymerase (PARP) by ABT-888 in patients with advanced malignancies: results of a phase 0 trial. [Abstract] J Clin Oncol 25 (Suppl 18): A-3518, 2007.

Trial Contact Information

Trial Lead Organizations

NCI - Center for Cancer Research

Shivaani Kummar, MD, Principal investigator		Ph: 301-435-5402 Email: kummars@exchange.nih.gov

Registry Information
Official Title		A Phase 0 Pharmacokinetic, Pharmacodynamic Study of ABT-888, an Inhibitor of Poly (ADP-ribose) Polymerase (PARP), in Refractory Solid Tumors and Lymphoid Malignancies
Trial Start Date		2006-06-27
Trial Completion Date		2008-06-13
Registered in ClinicalTrials.gov		NCT00387608
Date Submitted to PDQ		2006-05-26
Information Last Verified		2008-01-09