A phase I study of AT-101, a BH3 mimetic, in combination with paclitaxel and carboplatin in solid tumors

Mark N. Stein, Susan Goodin, Murugeson Gounder, Darlene Gibbon, Rebecca Moss, Daniella Portal, Diana Lindquist, Yujie Zhao, Naoko Takebe, Antoinette Tan, Joseph Aisner, Hongxia Lin, Neal Ready, Janice M. Mehnert

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

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/m2) and carboplatin (AUC 5) on day 1 of each cycle; DL2: paclitaxel (175 mg/m2) 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.

Original languageEnglish (US)
Pages (from-to)855-865
Number of pages11
JournalInvestigational New Drugs
Volume38
Issue number3
DOIs
StatePublished - Jun 1 2020

All Science Journal Classification (ASJC) codes

  • Oncology
  • Pharmacology
  • Pharmacology (medical)

Keywords

  • Apoptosis
  • BCL-2
  • Chemotherapy
  • Phase I
  • Prostate

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