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

Research output: Contribution to journalArticlepeer-review

35 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)295-302
Number of pages8
JournalInvestigational New Drugs
Volume32
Issue number2
DOIs
StatePublished - Apr 2014

Bibliographical note

Funding Information:
Acknowledgments This study was supported by NCI and the following grants - NCI UO1 CA062491, SAIC 25XS097, and 1ULRR025011.

Keywords

  • AT-101
  • Cisplatin
  • Etoposide
  • Extensive-stage small cell lung cancer
  • Phase I

ASJC Scopus subject areas

  • Oncology
  • Pharmacology
  • Pharmacology (medical)

Fingerprint

Dive into the research topics of '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'. Together they form a unique fingerprint.

Cite this