A randomized phase II trial of interleukin-2 in combination with four different doses of bryostatin-1 in patients with renal cell carcinoma

Purpose: Bryostatin-1 is a PKC modulator with direct anti-tumor activity and immunomodulatory properties. We combined different doses of Bryostatin-1 with IL-2 to determine effects on clinical response rate and T cell phenotype in patients with advanced kidney cancer. Experimental Design: IL-2 naive patients were given 11×106 IU subcutaneously of IL-2 on days 1–4, 8–11, and 15–18 of every 28-day cycle. Twenty four patients were randomized to treatment cohorts of 5, 15 or 25 mcg/m2 of Bryostatin-1 on days 1, 8 and 15, starting in the second cycle. An additional nine, non-randomized patients were given 35 mcg/m2. Lymphocytes were analyzed for number, activation status, and production of IL-2, IL-4 and IFN-γ. Response evaluation was performed every 3 cycles. Results: Common grade 3 toxicities included fatigue (5), nausea/vomiting (5), myopathy (3), dyspnea (3), and syncope (3). Four patients, in the two highest dose cohorts, demonstrated evidence of tumor shrinkage, although there was only 1 objective PR. The median time to progression was 104 days (95% CI 88–120) and the median survival was 452 days (95% CI = 424–480). There was no significant boosting effect of Bryostatin-1 on lymphocytes. Conclusions: The addition of Bryostatin-1 to IL-2 was well tolerated, but the overall response rate was low (3.2%), indicating that further studies with this combination are not warranted.