Phase II Study of Carfilzomib in Patients With Refractory Renal Cell Carcinoma

A von Hippel Lindau (VHL) mutation or functional inactivation occurs in a large proportion of patients with clear-cell renal cell carcinoma (ccRCC). Stabilizing VHL protein with proteasome inhibitors is one of the possible mechanism for treatment. We treated 9 patients with carfilzomib who had metastatic ccRCC with disease progression and at least 1 previous systemic therapy. Negative safety and efficacy results of this study do not favor the use of carfilzomib for the treatment of ccRCC. Background: A von Hippel Lindau (VHL) mutation or functional inactivation occurs in the a large proportion of patients with clear-cell renal cell carcinoma (ccRCC), which results in the dysregulation of a number of key cellular functions. A high throughput screen and candidate compound assessment revealed that agents with proteasome inhibition properties were able to stabilize point-mutated VHL and restore some of its functions. Patients and Methods: Nine patients with histologically confirmed metastatic ccRCC with disease progression during at least 1 previous systemic therapy were treated with carfilzomib at a dose of 20 mg/m(2) over 30 minutes via intravenous (I.V.) infusion on days 1 and 2 and a dose of 56 mg/m2 over 30 minutes via I.V. infusion on days 8, 9, 15, and 16 of each 4-week cycle. Results: The study was stopped after 9 patients were enrolled because of futility. Of the 9 patients treated in the study, all patients had disease progression within 4 months, with a median time of 1.8 months (95% confidence interval, 0.8-3.6 months). No patient showed a response according to Response Evaluation Criteria In Solid Tumors. Three patients showed a best response of stable disease. The most common side effects were musculoskeletal pain, elevated creatinine level, anemia, hyperkalemia, leukopenia, lymphopenia, and fatigue. Conclusion: Although the negative safety and efficacy results of this study do not favor the use of carfilzomib for the treatment of ccRCC, previous studies have shown selected patients achieved partial or complete response to this class of agent. Further preclinical investigations to evaluate the molecular characteristics of the patients who respond to proteasome inhibitors will better characterize the underlying mechanism of response, and might allow for the selection of an appropriate patient population in future studies. (C) 2019 Elsevier Inc. All rights reserved.