Date: 2016-04-17
Type of information: Presentation of results at a congress
phase: 1
Announcement: presentation of results at the American Association for Cancer Research (AACR) Annual Meeting
Company: Medivation (USA - CA)
Product: talazoparib
Action
mechanism: enzyme inhibitor/poly ADP ribose polymerase PARP inhibitor/PARP inhibitor. Talazoparib is a potent and specific inhibitor of PARP 1 and 2 that is being developed by Medivation for the treatment of selected solid tumors. In pre-clinical studies, talazoparib has shown single-agent anti-tumor activity, as well as synergy in combination with lowered doses of DNA-damaging agents, due to its dual mechanisms of cytotoxicity, PARP trapping, and inhibition of PARP enzyme activity. Trapping of PARP on DNA impairs DNA replication resulting in tumor cell death.
Disease: heavily pre-treated non-BRCA-mutated ovarian cancer patients
Therapeutic area: Cancer - Oncology
Country:
Trial details:
Latest
news: * On April 17, 2016, Medivation announced that Phase I data from talazoparib was presented at the American Association for Cancer Research (AACR) Annual Meeting 2016 in New Orleans by the study's lead investigator Zev A. Wainberg, M.D., Associate Professor of Medicine at the University of California Los Angeles (UCLA) and Co-Director of the UCLA GI Oncology Program, during a Clinical Trials Mini-Symposium. The primary objective of the study was to determine the maximum tolerated dose (MTD) of talazoparib in combination with either low-dose temozolomide or low-dose irinotecan in heavily pretreated patients with advanced malignancies. The data from the 40 patient trial demonstrated that combination treatment with talazoparib and low-dose chemotherapy resulted in stable disease or an objective response in 23 of 40 heavily pretreated patients with a variety of advanced cancers (clinical benefit rate of 58%). Most notably, objective responses were seen in four of seven (57%) heavily pre-treated non-BRCA-mutated ovarian cancer patients when talazoparib was used in combination with either low-dose temozolomide or low-dose irinotecan. Six of seven individuals (86%) with non-BRCA ovarian cancer had clinical benefit (four partial responses and two stable disease) and had a reduction in CA 125 levels by 50% or greater. The overall study demonstrated responses to combination talazoparib/low-dose chemotherapy in patients with multiple tumor types in which specific deleterious mutations in certain DNA repair genes extended beyond BRCA deficiency, including one patient who did not meet the criteria of having homologous recombination deficiency (HRD). These effects may be mediated through PARP inhibition, as well as enhanced PARP trapping, which interferes with the tumor cell's ability to replicate DNA by locking PARP molecules onto the DNA strand. Talazoparib currently is in Phase III development for patients with locally advanced and/or metastatic breast cancer who harbor a germline BRCA1/2 mutation. It is also being studied in several investigator-sponsored trials across multiple tumor types. The Phase I investigator-sponsored study evaluated escalating doses of talazoparib (greater than or equal to 0.5 mg given orally once daily) with either temozolomide ( greater than or equal to 25 mg/m2 given orally on days 1-5; Arm A) or irinotecan (greater than or equal to 25 mg/m2 given by intravenous infusion every two weeks; Arm B) every 28 days in patients with advanced malignancies. Study participants ranged in age from 21 to 77 years (median: 57 years) and had received one to 15 prior chemotherapy regimens (median: 6). The primary endpoint of the study was the determination of the MTD. Secondary endpoints included pharmacokinetics, tumor response and biomarkers. A total of 40 patients received escalating doses of talazoparib (0.5-1.0 mg) and either temozolomide or irinotecan (18 patients in Arm A and 22 in Arm B). Results showed the MTD for talazoparib was 1.0 mg. and 37.5 mg/m2 for either temozolomide or irinotecan when combined with 1.0 mg talazoparib. Partial responses were seen in four of seven (57%) germline BRCA wild type ovarian cancer patients who were platinum-resistant. Additional responses were seen in one patient each with Ewing's Sarcoma, cervical adenocarcinoma, small cell lung cancer, and triple negative breast cancer. An association was observed between response and the presence of deleterious somatic mutations in DNA repair genes (PALB2 and RAD51D) distinct from BRCA mutations. The most common grade 3/4 adverse events (greater than or equal to 5%) observed in patients treated with talazoparib plus temozolomide were neutropenia (28%), anemia (33%), and thrombocytopenia (33%). Among those treated with talazoparib plus irinotecan, the most common adverse events were thrombocytopenia (13%), anemia (27%) and neutropenia (31%). No significant pharmacokinetic interactions were observed between talazoparib and either temozolomide or irinotecan.
