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Clin Cancer Res. 2015 Dec 1;21(23):5235-44. doi: 10.1158/1078-0432.CCR-15-0180. Epub 2015 Jul 17.

A Phase I Trial of Combined Ridaforolimus and MK-2206 in Patients with Advanced Malignancies.

Author information

1
H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida. Shilpa.Gupta@moffitt.org.
2
Vall d'Hebron University Hospital and Vall d'Hebron Institute of Oncology, Barcelona, Spain.
3
UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, California.
4
DITEP, Gustave Roussy, Cancer Campus, Grand Paris, Villejuif, France.
5
Oslo University Hospital, Oslo, Norway.
6
Merck & Co., Inc., Kenilworth, New Jersey and North Wales, Pennsylvania.
7
The University of Texas MD Anderson Cancer Center, Houston, Texas.

Abstract

PURPOSE:

The PI3K/Akt/mTOR signaling pathway is aberrantly activated in many cancers. Combining ridaforolimus, an mTOR inhibitor, with MK-2206, an Akt inhibitor, may more completely block the PI3K pathway and inhibit tumor growth.

EXPERIMENTAL DESIGN:

This phase I study assessed dose-limiting toxicities (DLT) and maximum tolerated dose (MTD) for the combination of oral ridaforolimus plus oral MK-2206 in patients with advanced solid tumors. Efficacy was evaluated in patients with biomarker-identified estrogen receptor-positive breast cancer (low RAS gene signature and high Ki67 index) or castration-resistant prostate cancer (PTEN deficiency) with PI3K pathway addiction.

RESULTS:

Thirty-five patients were enrolled: 11 patients in part A (three breast cancer) and 24 biomarker-eligible patients in part B (16 breast cancer, eight prostate cancer). One patient with breast cancer from part A was also found to be biomarker-eligible when tested after she had clinical response. The MTD was 10 mg/d ridaforolimus 5 d/wk + 90 mg/wk MK-2206; 1 of 17 patients experienced DLT (grade 3 rash) at this dose. The most common adverse events at MTD were rash (44.4%), stomatitis (38.9%), diarrhea (27.8%), and decreased appetite (27.8%). By investigator assessment, 2 of 16 (12.5%) evaluable patients with breast cancer had partial response; by central assessment, 2 of 14 (14.3%) evaluable patients had complete response. Two patients had durable stable disease (SD) for 416 and 285 days, respectively. No patients with prostate cancer responded; one patient had SD for ≥ 6 months.

CONCLUSIONS:

Combination ridaforolimus and MK-2206 showed promising activity and good tolerability in heavily pretreated patients with hormone-positive and -negative breast cancer exhibiting PI3K pathway dependence.

PMID:
26187616
DOI:
10.1158/1078-0432.CCR-15-0180
[Indexed for MEDLINE]
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