The objectives of this protocol are to establish the qualitative and quantitative toxicity of bryostatin 1 when administered to children whose cancer is refractory to standard therapy. We would like to determine the acute dose-limiting toxicities (DLT) and times to recovery as well as determine whether there is cumulative toxicity when multiple courses are given. In addition, establish a maximum tolerated dose (MTD) of bryostatin 1 that results in tolerable toxicity which is predictable and reversible. Finally, determine the pharmacodynamics of bryostatin 1 in order to obtain information about the plasma concentration and the duration of effective concentrations that are present at various dose escalations. Bryostatin will be administered as a one hour intravenous infusion every week x 3 via an indwelling central venous catheter, with no therapy on week 4. A course will consist of three weekly treatments and the week off therapy. Patients should remain hospitalized for 24 hours following drug infusion for the first course. Subsequent courses may be given on an outpatient basis. Doses will be escalated by 30% in cohorts of at least three patients until the MTD is reached. The starting dose will be 20ug/m2/dose q week x 3. Bryostatin 1 is a macrocyclic lactone derived from the marine animal Bugula neritina of the phylum Bryozoa. Bryostatin 1 was identified and isolated as a result of the National Cancer Institute's natural products screening program. Studies have shown that this drug is a potent stimulator of the cellular enzyme protein kinase-C. It also stimulates production of cytokines in experimental animals, bone marrow progenitor cells and activates neutrophils. Bryostatin 1 has demonstrated anticancer activity against human tumors such as leukemia, lymphoma, sarcoma, ovarian and lung carcinoma, renal cell and melanoma cell lines. There have been two European Phase I trials of bryostatin 1 in 54 adult patients with refractory solid tumors. When patients were given bryostatin 1 as a one hour infusion every two weeks the MTD was 50ug/m2. Myalgia was the dose limiting toxicity. Flu like symptoms, hypotension, slight and transient decreased in platelets and neutrophils were observed. In a separate phase I study, bryostatin 1 was given as a one hour infusion use one of three different dosing regimens. The dose limiting toxicity was Myalgia. Myalgia developed within 48-72 hours of treated and lasted for 3-5 days. Headache, phlebitis and transient fall in platelets were also observed. The recommended dosage for phase II studies was 25 ug/m2 as a one hour infusion q week x three with week four off. Phase I studies in the U.S. with bryostatin 1 are ongoing. While the MTD has not been reached using a 72 hour infusion of drug, myalgia, cellulitis, fatigue and rash have been observed. No hematologic toxicity has been seen. Depending upon the results of this study, either further Phase I testing will be attempted, or a Phase II trial will be initiated.
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