ABT-888 Plus Metronomic Cyclophosphamide to Treat Cancer

Lymphoma Clinical Trial

Official title: A Phase I Study of ABT-888 in Combination With Metronomic Cyclophosphamide in Adults With Refractory Solid Tumors and Lymphomas

Status Completed

Clinical Trial Summary

Background:

• Cyclophosphamide (CP) is a drug approved by the Food and Drug Administration for the treatment of certain cancers. It works by causing DNA damage, resulting in cell death, including cancer cells.

• ABT-888 is an experimental drug that has been given to a small number of patients. It works by preventing DNA repair in tumor cells.

Objectives:

• To test the safety of the combination of ABT-888 and CP, and to determine the dose of each drug that can be given together to patients with cancer.

• To see how the body handles ABT-888 when given together with CP

• To evaluate the anti-tumor response of the drug combination.

Eligibility:

• Adults with solid tumors or lymphoid cancers (lymphoma and chronic lymphocytic leukemia) whose disease does not respond to standard treatments.

Design:

• Patients take ABT-888 by mouth once a day for 7, 14 or 21 days, depending on the dose level assigned to the individual patient.

• Patients take CP by mouth once a day every day in 21-day cycles. (Some patients take CP for 14 days only.)

• Patients undergo tests and procedures periodically during the study, including:

• Clinic visit and physical examination at the beginning of each cycle

• Blood and urine tests, electrocardiogram, measurement of vital signs

• CT scans, MRI scans or ultrasound tests to check the response of the tumor to treatment

• Tumor biopsies (optional)

• Bone marrow aspiration and biopsy

Clinical Trial Description

Background:

• The poly (ADP-ribose) polymerase (PARP) family of enzymes is characterized by the ability to poly-ADP-ribosylate protein substrates. PARP-1 and PARP-2 play a critical role in the maintenance of genomic stability by regulating a variety of DNA repair mechanisms.

• PARP activity has been shown to be important in base excision repair pathways. The inhibition of PARP could inhibit the repair of the DNA damage caused by alkylating agents such as cyclophosphamide. ABT-888 has been shown to potentiate the action of cyclophosphamide in xenografts models. ABT-888 is an orally delivered PARP inhibitor and cyclophosphamide can be delivered orally as an alkylating agent.

• Metronomic therapy with cyclophosphamide has demonstrated efficacy in multiple tumor types including, but not limited to, ovarian cancer, lymphoma, prostate cancer, and breast cancer. Its activity has been at least partially attributed to mediation of anti-angiogenic effects through induction of apoptosis in endothelial cells.

Objectives:

• Establish the safety and tolerability of the combination of ABT-888 with metronomic cyclophosphamide in patients with refractory solid tumors and lymphomas.

• Establish the maximum tolerated dose (MTD) of the combination of ABT-888 with metronomic cyclophosphamide.

• Evaluate the pharmacokinetics of ABT-888 when administered combination with cyclophosphamide.

• Evaluate for anti-tumor response.

• Determine the effects of the study treatment on the level of PARP inhibition and gamma-H2AX in PBMCs and tumor samples.

Eligibility:

• Patients with histologically documented solid tumors or lymphoid malignancies (lymphoma and CLL) whose disease has progressed following standard therapy or who have no acceptable standard treatment options.

• No major surgery, radiation or chemotherapy within four weeks prior to study enrollment, and recovered from toxicities of prior therapies to at least eligibility levels.

Study Design:

• ABT-888 will be administered orally once daily for 7 to 21 days, depending on the dose level (see below). Cyclophosphamide will be administered orally once daily in 50 mg or 100 mg doses continuously from days 1 to 21. Cycle length is 21 days.

• Dose escalation will proceed as outlined below. Once MTD is established, 6 additional patients will be enrolled at the MTD to evaluate that dose further and extend PD studies at that dose level. ;

Related Conditions & MeSH terms

• Lymphoma
• Neoplasms

• NCT number: NCT01445522
• Study type: Interventional
• Source: National Institutes of Health Clinical Center (CC)
• Status: Completed
• Phase: Phase 1
• Start date: December 3, 2008
• Completion date: July 3, 2012