Phase I/II trial of GM-CSF and lenalidomide in patients with hormone refractory prostate cancer (HRPC)

Abstract

15515 Background: Administration of GM-CSF in combination with thalidomide induces PSA responses in 20–25% of pts with HRPC. When administered in the neoadjuvant setting, this combination induces T cell and dendritic cell (DC) infiltration in prostate tumor tissue. Lenalidomide is an immunomodulatory analogue of thalidomide. In an effort to evaluate the clinical and immune activity of GM-CSF plus lenalidomide, we conducted a phase I/II trial in pts with HRPC. Methods: Pts had progressive asymptomatic HRPC by Consensus Criteria. Prior immunotherapy or chemotherapy was not permitted. A phase I safety phase followed by a phase II trial was undertaken. All pts received GM-CSF at 250 μg administered SC three times weekly along with lenalidomide 25 mg/day orally on days 1–21 of a 28-day cycle. Primary endpoints were safety and objective and PSA responses. Exploratory endpoints included activation of circulating DC, regulatory T cells (Treg) and cytokine production. Results: To date 19 of 34 planned pts are enrolled (13 with evidence of metastases; 6 with PSA-only disease). Seventeen pts are eligible for response (2 pts too early) Median age is 71 (49–80), median PSA is 19.1 (2.1–153.1). Median cycles of therapy is 4 (range: 1–14+). Overall, 13 of 17 pts (76%) experienced a reduction in PSA (<20% 2/17; 20–40% 7/17,>50% 4/17). Objective and PSA partial responses were observed in 2 and 4 of 17 pts respectively. Nine pts discontinued therapy (5 due to PD, 3 due to toxicity, and 1 withdrew consent). No pts on the phase I portion of the trial experienced a DLT. Grade (G) 1–2 toxicities for all 17 pts included neutropenia (20%), thrombocytopenia (13%), diarrhea (43%), dizziness, (25%), and fatigue (90%). Three pts developed G4 toxicities (PE, neutropenia, and emesis). The number of Treg cells decreased after 2 cycles of therapy. Similarly, Th1 cytokine and TNF-a production was increased after therapy. Although mean serum VEGF levels were decreased after therapy, changes in the mean serum levels of IL-8 and bFGF were not observed. Conclusions: The combination of GM-CSF and lenalidomide is relatively well tolerated with evidence of antitumor activity. Exploratory studies support the ability of this therapy to modulate immune cells. Accrual to this study is ongoing. [Table: see text]