Bryostatin and Cisplatin in Advanced Cancer--Phase I

Georgetown University, Washington DC

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Abstract

Significant advances in cancer therapy have been made in the past few decades yet despite these advances, the treatment of patients with common solid tumors remains more often palliative than curative. We are approaching dose limiting toxicities of conventional chemotherapy in the autologous bone marrow/peripheral blood stem cell setting and are in the relative infancy in our understanding of immunomodulation. Therefore, new approaches which capitalize on our expanding understanding of the malignant process are being aggressively pursued. One such potential therapeutic target lies in interrupting the delicate balance of activation/inactivation of cellular functions via alteration(s) in gene expression, receptor presence/conformation or other downstream signaling events. Modulation of this intricate network of interacting pathways can lead to inhibition of both tumor growth and tumor metastasis. Cisplatin will be given first in cycle 1 to determine if bryostatin has an impact on CDDP clearance or toxicity. If clinical toxicity is as expected, the bryostatin will be administered before CDDP in cycle 2 and all subsequent cycles. Ten additional patients will be accrued once MTD has been determined to document safety of both infusion schedules. Initial dose levels will escalateCDDP to full treatment doses of 100mg/m2. The remaining dose levels will then escalate bryostatin. Preclinical data suggest a biphasic effect of bryostatin modulation of CDDP cytotoxicity (low doses more efficacious), therefore, bryostatin-1 dosing will begin below the recommended phase II dose (at 15mcg/m2/d). (As it is unknown if CDDP and bryostatin have a potentiating effect clinically, starting at lower doses of these agents in early cohorts seemed wise.) Further, PKC modulation and platination of PBLs will be assessed in all patients in an effort to assess whether this biphasic nature occurs in vivo; subsequent dose adjustments may occur based on this data. The purpose of this study is to determine the dose limiting toxicities (DLTs), maximum tolerated doses (MTDs) and pharmacokinetics of the combination of bryostatin (administered by continuous intravenous (IV) infusion for 24 hours) and CDDP (administered IV over two hours either prior to or immediately following bryostatin-1) every 3 weeks in patients with advanced, incurable malignancies. To measure PKC levels in peripheral blood lymphocytes (and tumor where available) of patients receiving bryostatin/CDDP as an indirect measure of drug activity and pharmacokinetics and to compare the effect of order of administration of said agents on these parameters. To measure levels of peripheral blood lymphocytes (PBL) platination and to compare these with order of drug administration, hematological toxicities and any objective antitumor response.