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

Alternate Title

ABT-888 and Cyclophosphamide in Treating Patients With Solid Tumors or Lymphoma That Did Not Respond to Previous Therapy

Basic Trial Information

Objectives

1. Establish the safety and tolerability of ABT-888 when administered in combination with metronomic cyclophosphamide in patients with refractory solid tumors or lymphoma.
2. Establish the maximum tolerated dose of ABT-888 when administered in combination with metronomic cyclophosphamide in these patients.
3. Evaluate the pharmacokinetics of ABT-888 when administered in combination with metronomic cyclophosphamide in these patients.
4. Evaluate the antitumor response in these patients.
5. Determine the effects of treatment on the level of PARP inhibition and γ-H2AX in blood and tumor samples from these patients.

Entry Criteria

Disease Characteristics:

• Histologically confirmed solid tumor or lymphoid (e.g., lymphoma or chronic lymphocytic leukemia) malignancies
  • Refractory to standard therapy or no acceptable standard treatment options exists
    • Patients with lymphoid malignancies must have disease progression after standard therapy AND have either refused stem cell transplantation (SCT) or SCT is not indicated

• No gliomas, symptomatic CNS metastases, or carcinomatous meningitis
  • Patients with a history of CNS metastases are eligible, at the discretion of the principal investigator, provided they have received treatment and their CNS metastatic disease status has remained stable for ≥ 3 months without requiring steroids or anti-seizure medications

Prior/Concurrent Therapy:

• See Disease Characteristics
• Recovered from prior therapy
• At least 4 weeks since prior chemotherapy (> 6 weeks for nitrosoureas or mitomycin C)
• At least 4 weeks since prior radiotherapy
• At least 2 weeks since prior investigational agents administered as part of a phase 0 study
• Prior ABT-888 as part of a single- or limited-dosing study (e.g., phase 0 study) allowed
• Prior cyclophosphamide allowed
• No concurrent protease inhibitors for HIV-positive patients
• No other concurrent chemotherapy
• No other concurrent investigational or commercial anticancer agents or therapies

Patient Characteristics:

• Karnofsky performance status 60-100%
• Life expectancy > 3 months
• Absolute neutrophil count ≥ 1,500/mm³
• Platelet count ≥ 100,000/mm³
• Total 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
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception during and for 3 months after completion of study treatment
• No concurrent uncontrolled illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situation that would preclude compliance with study requirements
• No history of seizures
• No gastrointestinal condition that may predispose patient to drug intolerability or poor drug absorption (e.g., inability to take oral medication or a requirement for IV alimentation, prior surgical procedures affecting absorption, malabsorption syndrome, or active peptic ulcer disease)
• No ulcerative colitis, inflammatory bowel disease, or partial or complete small bowel obstruction

Expected Enrollment

Outcomes

Maximum tolerated dose of ABT-888 when administered in combination with metronomic cyclophosphamide
Safety

Pharmacokinetics of ABT-888
Clinical response
Level of PARP inhibition
Amount of γ-H2AX induction

Outline

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

Patients receive oral ABT-888 once daily for 7-21 days and oral cyclophosphamide once daily for 14 or 21 days. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Plasma samples are collected periodically for pharmacodynamic and pharmacokinetic analysis. Samples are analyzed for PAR concentration by immunoassay, γ-H2AX levels by immunocytochemistry, quantification of the γ-H2AX marker and co-localization markers via quantitative immunofluorescence analysis, and ABT-888 concentration by liquid chromatography/mass spectrometry.

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

Trial Contact Information

Trial Lead Organizations

NCI - Center for Cancer Research

Shivaani Kummar, MD, Principal investigator		Ph: 301-435-5402

Registry Information
Official Title		A Phase I Study of ABT-888 in Combination with Metronomic Cyclophosphamide in Adults with Refractory Solid Tumors and Lymphomas
Trial Start Date		2008-12-10
Trial Completion Date		2012-03-14
Registered in ClinicalTrials.gov		NCT00810966
Date Submitted to PDQ		2008-12-05
Information Last Verified		2012-03-20