Missing content? – Request curation!
Request curation for specific Genes, Variants, or PubMed publications.
Have questions, comments, or suggestions? - Let us know!
Email us at : ckbsupport@genomenon.com
Ref Type | Journal Article | ||||||||||||
PMID | (26187616) | ||||||||||||
Authors | Gupta S, Argilés G, Munster PN, Hollebecque A, Dajani O, Cheng JD, Wang R, Swift A, Tosolini A, Piha-Paul SA | ||||||||||||
Title | A Phase I Trial of Combined Ridaforolimus and MK-2206 in Patients with Advanced Malignancies. | ||||||||||||
|
|||||||||||||
URL | |||||||||||||
Abstract Text | 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. |