Ganetespib, a novel Hsp90 inhibitor in patients with KRAS mutated and wild type, refractory metastatic colorectal cancer Journal Article
| Authors: | Cercek, A.; Shia, J.; Gollub, M.; Chou, J. F.; Capanu, M.; Raasch, P.; Reidy-Lagunes, D.; Proia, D. A.; Vakiani, E.; Solit, D. B.; Saltz, L. B. |
| Article Title: | Ganetespib, a novel Hsp90 inhibitor in patients with KRAS mutated and wild type, refractory metastatic colorectal cancer |
| Abstract: | Seventeen patients with refractory KRAS mutated and wild type metastatic colorectal adenocarcinoma received single agent ganetespib in a single institution phase II study. The drug was well tolerated but did not yield any responses, although two patients achieved durable stable disease. Background: Heat shock protein 90 (Hsp90) is a cellular chaperone that is required for the maturation and stability of a variety of proteins that play key roles in colon cancer initiation and progression. The primary objective of the current study was to define the safety and efficacy of ganetespib, a novel, selective small-molecule Hsp90 inhibitor, in patients with refractory metastatic colorectal cancer. Patients and Methods: The study was a single-arm, Simon 2-stage, phase II trial for patients with chemotherapy-refractory, metastatic colorectal cancer. Patients received ganetespib 200 mg/m2 intravenously. Tumor tissue was collected before treatment and 48 hours after treatment for changes in expression of Hsp90 client proteins and other potential pharmacodynamics markers. V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS), v-Raf murine sarcoma viral oncogene homolog B, and phosphatidylinositol-4, 5- bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA) mutational status was also determined. Results: Seventeen patients were treated (median age, 58; range, 44-79 years). No patients demonstrated objective regression of disease. Two patients had stable disease of 6.8 and 5.1 months duration. Serious adverse events that were potentially attributable to ganetespib included diarrhea (12%, n = 2), fatigue (17%, n = 3), and increased aspartate aminotransferase/alanine aminotransferase (12%, n = 2) and alkaline phosphatase (6%, n = 1) levels. Of the 17 evaluable patients, 9 (53%) including patients with stable disease as best response, had KRAS-mutant tumors. Conclusion: In this first phase II investigation of an Hsp90 inhibitor in colorectal cancer, ganetespib as a single agent did not demonstrate activity in chemotherapy-refractory metastatic colorectal cancer. However, on the basis of the drug's promising preclinical combination data and the relatively mild toxicity profile, further clinical investigation of this agent in combination with standard cytotoxic agents is planned. |
| Keywords: | adult; cancer chemotherapy; clinical article; human tissue; treatment response; aged; middle aged; gene mutation; disease course; drug tolerability; raf protein; diarrhea; drug efficacy; drug safety; side effect; cancer staging; anorexia; pharmacodynamics; phase 2 clinical trial; gene expression; nausea; vomiting; antineoplastic activity; wild type; drug hypersensitivity; alanine aminotransferase; alkaline phosphatase; aspartate aminotransferase; drug induced headache; clinical evaluation; brain metastasis; heat shock protein 90; cancer fatigue; disease duration; intestine obstruction; kras; k ras protein; allergic reaction; enzyme active site; metastatic colorectal cancer; virus oncogene; single agent; ganetespib; phosphatidylinositol 4,5 bisphosphate 3 kinase; human; male; female; article; hsp 90 |
| Journal Title: | Clinical Colorectal Cancer |
| Volume: | 13 |
| Issue: | 4 |
| ISSN: | 1533-0028 |
| Publisher: | Elsevier Inc. |
| Date Published: | 2014-12-01 |
| Start Page: | 207 |
| End Page: | 212 |
| Language: | English |
| DOI: | 10.1016/j.clcc.2014.09.001 |
| PROVIDER: | scopus |
| PUBMED: | 25444464 |
| PMCID: | PMC5489410 |
| DOI/URL: | |
| Notes: | Export Date: 2 March 2015 -- Source: Scopus |
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