An Open-Label, Non-Randomized Phase I Study of the Protein Kinase C Inhibitor Bryostatin-1 Administered in Combination With Paclitaxel in Patients With Advanced Solid Tumors

OBJECTIVES: I. Determine the maximum tolerated dose of intravenous bryostatin 1 when administered in combination with a fixed dose of paclitaxel and cisplatin in patients with advanced solid tumors. II. Investigate the clinical pharmacokinetics of intravenous paclitaxel when administered in combination with bryostatin 1 in these patients. III. Obtain preliminary data on the therapeutic activity of this therapy in these patients and evaluate surrogate markers of activity. OUTLINE: This is an open label, dose escalation study. Patients receive paclitaxel IV over 1 hour on day 1. On day 2, patients receive bryostatin 1 IV over 1 hour immediately followed by cisplatin IV on day 2. Treatment is repeated weekly for 3 consecutive weeks followed by one week of rest for at least 2 courses. Treatment continues in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients are entered at escalating dose levels of bryostatin 1 and paclitaxel. If 2 of 6 patients experience dose limiting toxicity (DLT) at any given dose level, then the maximum tolerated dose (MTD) is declared to be the preceding dose level. Once the MTD of paclitaxel and bryostatin 1 has been established, escalations of weekly cisplatin will be added. Additional patient cohorts receive two escalating doses of paclitaxel and cisplatin with the fixed bryostatin 1 dose level, in the absence of DLT. Patients at a lower bryostatin 1 dose may be escalated to a higher bryostatin 1 dose, only if that higher dose has been proven to be safe in another cohort of patients. PROJECTED ACCRUAL: An anticipated 3 to 60 patients will be accrued for this study within 1-14 months.