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A phase I study of AT-101, a BH3 mimetic, in combination with paclitaxel and carboplatin in solid tumors.
- Source :
- Investigational New Drugs; Jun2020, Vol. 38 Issue 3, p855-865, 11p
- Publication Year :
- 2020
-
Abstract
- Summary: Background AT-101 is a BH3 mimetic that inhibits the heterodimerization of Bcl-2, Bcl-xL, Bcl-W, and Mcl-1 with pro-apoptotic proteins, thereby lowering the threshold for apoptosis. This phase I trial investigated the MTD of AT-101 in combination with paclitaxel and carboplatin in patients with advanced solid tumors. Methods Patients were treated with AT-101 (40 mg) every 12 h on days 1, 2 and 3 of each cycle combined with varying dose levels (DL) of paclitaxel and carboplatin [DL1: paclitaxel (150 mg/m<superscript>2</superscript>) and carboplatin (AUC 5) on day 1 of each cycle; DL2: paclitaxel (175 mg/m<superscript>2</superscript>) and carboplatin (AUC 6) on day 1 of each cycle]. Secondary objectives included characterizing toxicity, efficacy, pharmacokinetics, and pharmacodynamics of the combination. Results Twenty-four patients were treated across two DLs with a planned expansion cohort. The most common tumor type was prostate (N = 11). Two patients experienced DLTs: grade 3 abdominal pain at DL1 and grade 3 ALT increase at DL2; however, the MTD was not determined. Moderate hematologic toxicity was observed. One CR was seen in a patient with esophageal cancer and 4 patients achieved PRs (1 NSCLC, 3 prostate). PD studies did not yield statistically significant decreases in Bcl-2 and caspase 3 protein levels, or increased apoptotic activity induced by AT-101. Conclusion The combination of AT-101 at 40 mg every 12 h on days 1, 2 and 3 combined with paclitaxel and carboplatin was safe and tolerable. Based on the modest clinical efficacy seen in this trial, this combination will not be further investigated. Clinical Trial Registration: NCT00891072, CTEP#: 8016. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 01676997
- Volume :
- 38
- Issue :
- 3
- Database :
- Complementary Index
- Journal :
- Investigational New Drugs
- Publication Type :
- Academic Journal
- Accession number :
- 143136719
- Full Text :
- https://doi.org/10.1007/s10637-019-00807-2