PARP Inhibitor and Metronomic Chemotherapy for Refractory Cancer
Name of the Trial
Phase I Study of ABT-888 and Metronomic Cyclophosphamide in Patients with Refractory Solid Tumors or Lymphoma (NCI-09-C-0048). See the protocol summary.
Dr. Shivaani Kummar, NCI Center for Cancer Research
Why This Trial Is Important
Many chemotherapy drugs kill cancer cells by causing damage to DNA. However, cells can employ a number of mechanisms to repair this damage. When cells experience drug-induced breaks in their DNA strands, proteins called PARPs bind to the DNA at the sites of the breaks and recruit other proteins involved in DNA repair. This process can allow cancer cells to continue to survive and grow despite the damage caused by chemotherapy treatment.
The oral drug ABT-888 blocks the activity of PARP proteins, thereby interfering with the ability of cancer cells to repair their DNA. Combining ABT-888 with a chemotherapy drug that causes DNA strand breaks, such as cyclophosphamide, may result in a greater antitumor effect.
In this clinical trial, patients with solid tumors or lymphomas that have not responded to previous treatment (refractory cancer), or for which no effective treatment exists, will receive ABT-888 and metronomic cyclophosphamide. The term metronomic refers to the administration of drugs at lower than normal doses more frequently than usual. Metronomic chemotherapy may work differently from treatment with the same drugs at higher doses. Metronomic cyclophosphamide still causes DNA damage, but also exhibits an antiangiogenic effect, is less toxic, and can be given in pill form daily, making it more convenient for patients than intravenous cyclophosphamide.
Doctors will assess the safety, tolerability, and pharmacokinetics of this combination, as well as establish the maximum tolerated dose of ABT-888 and examine the effects of treatment on molecular markers in blood and tumor samples.
"Our goal with this study is to come up with a regimen that is not only effective but also well tolerated and orally available," said Dr. Kummar.