A Phase I Study of ABT-888 in Combination With Metronomic Cyclophosphamide in Adults With Refractory Solid Tumors and Lymphomas
- 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
- 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.
- 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
- Evaluate the pharmacokinetics of ABT-888 when administered combination with
- 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.
- 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
- 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.
Allocation: Non-Randomized, Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Establish the safety and tolerability of the combination of ABT-888 with metronomic cyclophosphamide in patients with refractory solid tumors and lymphomas. Establish the MTD of the combination of ABT-888 with metronomic cyclophosphamide.
Antonio T Fojo, M.D.
National Cancer Institute (NCI)
United States: Federal Government
|National Institutes of Health Clinical Center, 9000 Rockville Pike||Bethesda, Maryland 20892|
|University of Pittsburgh Cancer Institute||Pittsburgh, Pennsylvania 15213|
|City of Hope National Medical Center||Los Angeles, California 91010|
|City of Hope Medical Group||Pasadena, California 91105|
|USC Norris Cancer Center||Los Angeles, California 90033|
|University of California, Davis Cancer Center||Sacramento, California 95817|
|Penn State College of Medicine||Hershey, Pennsylvania 17033|