Sargramostim (GM-CSF) and lenalidomide in castration-resistant prostate cancer (CRPC): Results from a phase I-II clinical trial

Background: Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a pleiotropic cytokine that stimulates dendritic cells (DCs) and promotes uptake of tumor antigens by DCs leading to T-cell cross-priming. Lenalidomide (Revlimid) is an immunomodulatory analog of thalidomide with significant T-cell stimulatory and antiangiogenic properties. GM-CSF in combination with thalidomide induces prostate-specific antigen (PSA) responses in 20% to 25% of patients with castration-resistant prostate cancer (CRPC). In an effort to further evaluate the clinical and immune activity of GM-CSF and lenalidomide, we conducted a phase I-II trial in patients with CRPC. Methods: Asymptomatic patients with CRPC were enrolled. Prior immunotherapy or chemotherapy was not allowed. All the patients received 250 mu g of GM-CSF administered subcutaneously 3 times weekly along with 25 mg/d of lenalidomide administered orally on days 1 to 21 of a 28-day cycle. The primary end points were objective. PSA response, and safety. Exploratory end points included activation of circulating DCs. regulatory T cells, and Th1 cytokine production. Results: Thirty-two patients were enrolled in the study. No dose-limiting toxicities occured in the phase I portion of the study. Although 81% of the patients achieved a decline in the levels of PSA while on therapy, only 4 achieved a PSA level decline of >= 50%. The overall response rate among 11 patients with response evaluation criteria in solid tumors-defined measurable disease was 18%. Overall toxicity was G1 and G2 in nature and included fatigue observed in 69% of the patients, nausea/vomiting in 34%, and diarrhea in 28% of the patients. Grade 3 or 4 toxicities occurred in 22% of the patients and were primarily thrombocytopenia (9%) or neutropenia (19%) or both. Conclusions: Administration of GM-CSF and lenalidomide in patients with CRPC is safe with modest evidence of antitumor activity and no immune changes observed. (C) 2014 Elsevier Inc. All rights reserved.