Phase I trial of sargramostim and thalidomide for treatment of hormone-refractory prostate cancer

Abstract

4690 Background: Sargramostim (GM-CSF) has been given to hormone-refractory prostate cancer (HRPC) patients to activate immune/inflammatory responses in situ. PSA and clinical responses have been seen but the response rates have been variable. We have combined sargramostim (activates dendritic cells)with thalidomide (modulates T cell and NK function) in an attempt to increase anti-tumor activity in HRPC patients. Methods: Sargramostim was administered subQ daily x 14 days, then QOD x 3 months. Thalidomide was administered po daily, beginning on day 15 and continuing for 3 months. PSA, clinical, and radiographic responses were monitored during therapy. Lymphocyte and dendritic cell populations were also monitored during treatment. Results: Ten patients with HRPC were enrolled on the study. The initial cohort (3 patients) dose level was sargramostim 500mcg/dose and thalidomide 200mg/d. Because of substantial toxicity, subsequent cohorts were treated with reduced doses (cohort 2 = sargramostim 500mcg/dose and thalidomide 100mg/day, and cohort 3 = sargramostim 250mcg/dose and thalidomide 100mg/day). One patient received only one week of Rx and was not considered to be evaluable. 7/9 evaluable patients (78%)had rapid PSA responses. Average PSA decrease was 50.4%. One patient with a soft tissue mass also had a 60% decrease in measurable disease. Substantial toxicity was noted in the first two cohorts, with 7 grade III toxicities (fatigue 2, DVT (on ASA) 1, acute MI (on coumadin)1, pleural/pericardial effusions 1, peripheral neuropathy 1, neurogenic bladder 1). The MTD appeared to be sargramostim 250mcg/d plus thalidomide 100mg/d. Time for PSA level to return to the pretreatment value was inversely correlated with PSA magnitude (PSA under 50ng/mL = 26.4wks, PSA over 50ng/mL = 9.5wks). Conclusions: Treatment of HRPC with sargramostim and thalidomide produced a high level of PSA responses. In patients with modest pretreatment PSA levels, freedom from PSA progression was often prolonged. However substantial toxicity was noted, leading to moderate morbidity. Immunomodulation may be useful in delaying progression of minimal HRPC. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Celegene Corporation