A phase I combination study of ABT-888 and topotecan hydrochloride in adults with refractory solid tumors and lymphomas
08.04.09
Category: Scientific News
Coadministration of the PARP purchase cialis potentiated the toxic effects of topotecan
Poly (ADP-ribose) polymerase (PARP) is an essential nuclear enzyme important for recognizing DNA damage and facilitating DNA repair. PARP inhibitors may prevent efficient repair of DNA damage induced by topoisomerase 1 inhibitors such as topotecan.
Dr S Kummar from the National Cancer institute, Bethesda, USA presented the study at the 7th International Symposium on Targeted Anticancer Therapies in Amsterdam, the Netherlands, on 23–25 March 2009. The objectives of the trial were to establish the safety, tolerability, and maximum tolerated dose of the combination of the oral PARP
cialis ABT-888 with topotecan, to evaluate the pharmacokinetics of each agent alone and in combination, and to determine drug effects on the level of PARP inhibition in peripheral blood mononuclear cells (PBMCs) and tumor samples.
Patients with histologically documented solid tumors and lymphoid malignancies whose disease had progressed following standard therapy were eligible. Treatment consisted of 21-day cycles of ABT-888 po and topotecan iv. PBMCs and optional biopsies were collected, and PARP activity was determined using a validated ELISA assay comparing pre- and post-treatment PAR levels.
Two of 6 patients developed dose-limiting toxicities (DLTs; grade 4 thrombocytopenia and grade 4 neutropenia) at the starting dose; myelosuppression was also observed at level 1. ABT-888 dosing was reduced to 5 days and the dose of topotecan lowered. However, significant myelosuppression was still seen at level 2. Six patients on study had stable disease for ≥ 2 cycles but 5 were removed due to toxicities. One patient with thyroid cancer on level 3 continued on study for > 6 months. PARP activity was inhibited in PBMCs in 14 of 18 patients. In 2 patients for whom paired tumor and PBMC data are available, there was a > 75% decrease in PAR levels 3-7 hours after treatment.
PARP inhibitors are being developed as chemopotentiating agents. However, coadministration of the PARP inhibitor ABT-888 potentiated the toxic effects of topotecan in this trial.
