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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.

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



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.


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.


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.


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.

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