Article ; Online: Preclinical and Clinical Trial Results Using Talazoparib and Low-Dose Chemotherapy.
Clinical cancer research : an official journal of the American Association for Cancer Research
2022 Volume 29, Issue 1, Page(s) 40–49
Abstract: Purpose: On the basis of preclinical data, we hypothesized that low doses of chemotherapy (10% of therapeutic doses) with full dose of a PARP inhibitor could have improved efficacy and tolerability.: Patients and methods: In this phase I dose- ... ...
| Abstract | Purpose: On the basis of preclinical data, we hypothesized that low doses of chemotherapy (10% of therapeutic doses) with full dose of a PARP inhibitor could have improved efficacy and tolerability. Patients and methods: In this phase I dose-escalation study, patients with BRCA-normal advanced malignancies were assigned to either talazoparib/temozolomide or talazoparib/irinotecan. Talazoparib was dose-escalated from 500 mcg to 1 mg daily before dose escalation of temozolomide/irinotecan. The starting dose of temozolomide was 25 mg/m2/day orally on days 1 to 5 and irinotecan was 25 mg/m2/day intravenously on days 1 and 15. The primary objectives of this trial were safety and tolerability, dose-limiting toxicities (DLT), and maximum tolerated dose (MTD). Results: Of 40 patients enrolled, 18 (mean: 7 prior therapies) were enrolled in talazoparib + temozolomide and 22 in talazoparib + irinotecan. DLTs were hematologic in both arms, but all hematologic adverse events resolved with either treatment interruption and/or dose reductions of talazoparib. The MTDs were talazoparib 1 mg + temozolomide 37.5 mg/m2 and talazoparib 1 mg + irinotecan 37.5 mg/m2. There were four partial responses in the talazoparib + temozolomide arm and five in the talazoparib + irinotecan arm for a response rate of 23% (9/40). The pharmacokinetic profiles of talazoparib + temozolomide/irinotecan were similar to that of talazoparib monotherapy. Responses were seen independent of homologous recombination (HR) status and HR deficiency score. Conclusions: These results show that talazoparib with low-dose temozolomide or irinotecan is reasonably well tolerated and demonstrates clinical activity in a wide range of cancers. Randomized trials of talazoparib with or without low-dose chemotherapy are ongoing in small cell lung cancer and ovarian cancer. |
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| MeSH term(s) | Female ; Humans ; Antineoplastic Combined Chemotherapy Protocols/administration & dosage ; Antineoplastic Combined Chemotherapy Protocols/adverse effects ; Irinotecan/administration & dosage ; Neoplasms/drug therapy ; Temozolomide/administration & dosage |
| Chemical Substances | Irinotecan (7673326042) ; talazoparib (9QHX048FRV) ; Temozolomide (YF1K15M17Y) |
| Language | English |
| Publishing date | 2022-09-22 |
| Publishing country | United States |
| Document type | Clinical Trial, Phase I ; Journal Article ; Research Support, Non-U.S. Gov't |
| ZDB-ID | 1225457-5 |
| ISSN | 1557-3265 ; 1078-0432 |
| ISSN (online) | 1557-3265 |
| ISSN | 1078-0432 |
| DOI | 10.1158/1078-0432.CCR-22-1553 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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