Investigational New Drugs

, Volume 32, Issue 2, pp 295–302

A phase I study of AT-101 with cisplatin and etoposide in patients with advanced solid tumors with an expanded cohort in extensive-stage small cell lung cancer

  • William R. Schelman
  • Tabraiz A. Mohammed
  • Anne M. Traynor
  • Jill M. Kolesar
  • Rebecca M. Marnocha
  • Jens Eickhoff
  • Michael Keppen
  • Dona B. Alberti
  • George Wilding
  • Naoko Takebe
  • Glenn Liu
PHASE I STUDIES

DOI: 10.1007/s10637-013-9999-7

Cite this article as:
Schelman, W.R., Mohammed, T.A., Traynor, A.M. et al. Invest New Drugs (2014) 32: 295. doi:10.1007/s10637-013-9999-7

Summary

Background. A phase I, dose-escalation study of AT-101 with cisplatin and etoposide was conducted to determine the maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D), safety and pharmacokinetics in patients with advanced solid tumors, with an expanded cohort in patients with extensive-stage small cell lung cancer (ES-SCLC) to assess preliminary activity. Methods. In the dose escalation portion, increasing doses of AT-101 were administered orally BID on days 1–3 along with cisplatin on day 1 and etoposide on days 1–3 of a 21 day cycle. At the RP2D, an additional 7 patients with untreated ES-SCLC were enrolled. Results. Twenty patients were enrolled in the dose-escalation cohort, and 7 patients with ES-SCLC were enrolled in the expanded cohort. The MTD/RP2D was established at AT-101 40 mg BID days 1–3 with cisplatin 60 mg/m2 and etoposide 120 mg/m2 on day 1 of a 21 day cycle with pegfilgrastim support. Two DLTs of neutropenic fever were seen at dose level 1. After the addition of pegfilgrastim, no additional DLTs were observed. Grade 3/4 treatment-related toxicities included: diarrhea, increased AST, neutropenia, hypophosphatemia, hyponatremia, myocardial infarction and pulmonary embolism. No apparent PK interactions were observed between the agents. Preliminary activity was observed with PRs in patients with ES-SCLC, high-grade neuroendocrine tumor, esophageal cancer and NSCLC. Conclusions. AT-101 with cisplatin and etoposide is well tolerated with growth factor support. Anti-tumor activity was observed in a variety of cancers including ES-SCLC, supporting further investigation with BH-3 mimetics in combination with standard chemotherapy for ES-SCLC.

Keywords

AT-101CisplatinEtoposidePhase IExtensive-stage small cell lung cancer

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • William R. Schelman
    • 1
  • Tabraiz A. Mohammed
    • 1
  • Anne M. Traynor
    • 1
  • Jill M. Kolesar
    • 1
  • Rebecca M. Marnocha
    • 1
  • Jens Eickhoff
    • 1
  • Michael Keppen
    • 2
  • Dona B. Alberti
    • 1
  • George Wilding
    • 1
  • Naoko Takebe
    • 3
  • Glenn Liu
    • 1
  1. 1.University of Wisconsin Carbone Cancer CenterMadisonUSA
  2. 2.Sanford Cancer CenterSioux FallsUSA
  3. 3.Cancer Therapy Evaluation Program (CTEP)National Cancer Institute (NCI)BethesdaUSA