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

Publication ,  Journal Article
Stein, MN; Goodin, S; Gounder, M; Gibbon, D; Moss, R; Portal, D; Lindquist, D; Zhao, Y; Takebe, N; Tan, A; Aisner, J; Lin, H; Ready, N; Mehnert, JM
Published in: Invest New Drugs
June 2020

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.

Duke Scholars

Published In

Invest New Drugs

DOI

EISSN

1573-0646

Publication Date

June 2020

Volume

38

Issue

3

Start / End Page

855 / 865

Location

United States

Related Subject Headings

  • Treatment Outcome
  • Proto-Oncogene Proteins c-bcl-2
  • Paclitaxel
  • Oncology & Carcinogenesis
  • Neoplasms
  • Middle Aged
  • Maximum Tolerated Dose
  • Male
  • Humans
  • Gossypol
 

Citation

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Stein, M. N., Goodin, S., Gounder, M., Gibbon, D., Moss, R., Portal, D., … Mehnert, J. M. (2020). A phase I study of AT-101, a BH3 mimetic, in combination with paclitaxel and carboplatin in solid tumors. Invest New Drugs, 38(3), 855–865. https://doi.org/10.1007/s10637-019-00807-2
Stein, Mark N., Susan Goodin, Murugeson Gounder, Darlene Gibbon, Rebecca Moss, Daniella Portal, Diana Lindquist, et al. “A phase I study of AT-101, a BH3 mimetic, in combination with paclitaxel and carboplatin in solid tumors.Invest New Drugs 38, no. 3 (June 2020): 855–65. https://doi.org/10.1007/s10637-019-00807-2.
Stein MN, Goodin S, Gounder M, Gibbon D, Moss R, Portal D, et al. A phase I study of AT-101, a BH3 mimetic, in combination with paclitaxel and carboplatin in solid tumors. Invest New Drugs. 2020 Jun;38(3):855–65.
Stein, Mark N., et al. “A phase I study of AT-101, a BH3 mimetic, in combination with paclitaxel and carboplatin in solid tumors.Invest New Drugs, vol. 38, no. 3, June 2020, pp. 855–65. Pubmed, doi:10.1007/s10637-019-00807-2.
Stein MN, Goodin S, Gounder M, Gibbon D, Moss R, Portal D, Lindquist D, Zhao Y, Takebe N, Tan A, Aisner J, Lin H, Ready N, Mehnert JM. A phase I study of AT-101, a BH3 mimetic, in combination with paclitaxel and carboplatin in solid tumors. Invest New Drugs. 2020 Jun;38(3):855–865.
Journal cover image

Published In

Invest New Drugs

DOI

EISSN

1573-0646

Publication Date

June 2020

Volume

38

Issue

3

Start / End Page

855 / 865

Location

United States

Related Subject Headings

  • Treatment Outcome
  • Proto-Oncogene Proteins c-bcl-2
  • Paclitaxel
  • Oncology & Carcinogenesis
  • Neoplasms
  • Middle Aged
  • Maximum Tolerated Dose
  • Male
  • Humans
  • Gossypol