Journal article
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
Investigational new drugs, Vol.32(2), pp.295-302
04/01/2014
DOI: 10.1007/s10637-013-9999-7
PMCID: PMC3895103
PMID: 23860642
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.
Details
- Title: Subtitle
- 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
- Creators
- William R. Schelman - University of Wisconsin Carbone Cancer CenterTabraiz A. Mohammed - University of Wisconsin Carbone Cancer CenterAnne M. Traynor - University of Wisconsin Carbone Cancer CenterJill M. Kolesar - University of Wisconsin Carbone Cancer CenterRebecca M. Marnocha - University of Wisconsin Carbone Cancer CenterJens Eickhoff - University of Wisconsin Carbone Cancer CenterMichael Keppen - Sanford Canc Ctr, Sioux Falls, SD USADona B. Alberti - University of Wisconsin Carbone Cancer CenterGeorge Wilding - University of Wisconsin Carbone Cancer CenterNaoko Takebe - National Cancer InstituteGlenn Liu - University of Wisconsin Carbone Cancer Center
- Resource Type
- Journal article
- Publication Details
- Investigational new drugs, Vol.32(2), pp.295-302
- Publisher
- Springer Nature
- DOI
- 10.1007/s10637-013-9999-7
- PMID
- 23860642
- PMCID
- PMC3895103
- ISSN
- 0167-6997
- eISSN
- 1573-0646
- Number of pages
- 8
- Grant note
- NCI; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI) U01CA062491 / NATIONAL CANCER INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI) UL1TR000427 / NATIONAL CENTER FOR ADVANCING TRANSLATIONAL SCIENCES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Center for Advancing Translational Sciences (NCATS)
- Language
- English
- Date published
- 04/01/2014
- Academic Unit
- Pharmacy; Pharmaceutical Sciences and Experimental Therapeutics
- Record Identifier
- 9984696552702771
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