A Phase I Trial of Combined Ridaforolimus and MK-2206 in Patients with Advanced Malignancies
| Autor: | Ann M. Swift, Shilpa Gupta, Pamela N. Munster, Jonathan D. Cheng, Olav Dajani, Ruixue Wang, Antoine Hollebecque, Guillem Argiles, Sarina Anne Piha-Paul, Alessandra Tosolini |
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| Rok vydání: | 2015 |
| Předmět: |
Oncology
Adult Male Cancer Research medicine.medical_specialty Ridaforolimus chemistry.chemical_compound Prostate cancer Young Adult Breast cancer Internal medicine Neoplasms Antineoplastic Combined Chemotherapy Protocols medicine Humans Adverse effect Protein Kinase Inhibitors PI3K/AKT/mTOR pathway Aged Neoplasm Staging Phosphoinositide-3 Kinase Inhibitors Aged 80 and over Sirolimus business.industry TOR Serine-Threonine Kinases Middle Aged medicine.disease Rash Surgery Treatment Outcome chemistry Tolerability MK-2206 Retreatment Female medicine.symptom business Heterocyclic Compounds 3-Ring Biomarkers Signal Transduction |
| Zdroj: | Clinical cancer research : an official journal of the American Association for Cancer Research. 21(23) |
| ISSN: | 1557-3265 |
| Popis: | 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. Clin Cancer Res; 21(23); 5235–44. ©2015 AACR. |
| Databáze: | OpenAIRE |
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