Phase I Study of Bryostatin 1 (NSC 339555) and High-Dose 1-Beta-D-Arabinofuranosylcytosine (HiDAC) in Patients With Refractory Leukemia
OBJECTIVES: I. Define the maximum tolerated dose (MTD) of bryostatin 1 administered before
and after high dose cytarabine in patients with refractory or relapsed acute myelocytic
leukemia or acute lymphocytic leukemia, chronic myelogenous leukemia, or refractory or
relapsed lymphoblastic lymphoma. II. Describe the toxic effects of bryostatin 1 and high
dose cytarabine in these patients. III. Describe the time course of bryostatin 1 induced
modulation of leukemic blast total protein kinase C (PKC) activity. IV. Describe bryostatin
1 pharmacokinetics. V. Correlate bryostatin 1 induced modulation of leukemic cell PKC
activity or leukemic cell maturation with high dose cytarabine mediated apoptosis.
OUTLINE: This is a dose escalation study. Patients receive bryostatin 1 by continuous
infusion over 24 hours on day 1. One hour after completion of bryostatin 1, patients receive
high dose cytarabine IV over 3 hours every 12 hours on days 2-4. Patients again receive
cytarabine over 3 hours every 12 hours on days 9-11, followed 1 hour later by bryostatin 1
by continuous infusion over 24 hours beginning on day 11. Patients achieving complete
remission may receive up to 4 courses of consolidation chemotherapy. Consolidation
chemotherapy is the same as induction chemotherapy except patients receive only 2 doses of
cytarabine after day 1 completion of bryostatin and only 2 doses of cytarabine prior to the
day 11 dose of bryostatin. Patients achieving partial remission may receive a second course
of induction chemotherapy. In the absence of dose limiting toxicity in the first 3 patients
treated, subsequent cohorts of 6 patients receive escalating doses of bryostatin 1 on the
same schedule. If dose limiting toxicity occurs in 2 of 6 patients at a given dose level,
then dose escalation ceases and the current dose is defined as the maximum tolerated dose.
Patients are followed every 6 months until death.
PROJECTED ACCRUAL: A total of 12-50 patients will be accrued for this study.
Allocation: Non-Randomized, Endpoint Classification: Safety Study, Intervention Model: Factorial Assignment, Masking: Open Label, Primary Purpose: Treatment
Steven Grant, MD
Massey Cancer Center
United States: Federal Government
|University of Texas - MD Anderson Cancer Center||Houston, Texas 77030-4009|
|New York Presbyterian Hospital - Cornell Campus||New York, New York 10021|
|Massey Cancer Center||Richmond, Virginia 23298-0037|