A Phase 1 Study of UCN-01 in Combination With Perifosine in Patients With Relapsed and Refractory Acute Leukemias and High Risk MDS
I. Define the maximum tolerated dose and recommended phase II dose of UCN-01
(7-hydroxystaurosporine) administered after perifosine in patients with relapsed or
refractory acute leukemia, chronic myelogenous leukemia, or high risk myelodysplastic
I. Evaluate the safety and toxicity of UCN-01 administered after perifosine in these
II. Evaluate the safety and toxicity of perifosine administered after UCN-01 in these
III. Document responses in patients treated with this regimen. IV. Observe the
pharmacokinetics of both perifosine and UCN-01 when administered in combination.
V. Study the pharmacodynamics of perifosine alone, UCN-01 alone, and in combination in
leukemic blast cells.
OUTLINE: This is a multicenter, dose-escalation study of 7-hydroxystaurosporine. The first
patients enrolled in the study are assigned to arm 1. Once the maximum tolerated dose (MTD)
is determined in arm 1, subsequent patients are enrolled in arm 2.
ARM 1: Patients receive a loading dose of oral perifosine every 6 hours on day 1 followed by
a maintenance dose once daily on days 2-28 of course 1 and then once daily on days 1-28 in
all subsequent courses. Patients also receive 7-hydroxystaurosporine intravenously (IV) over
3 hours on day 4. Cohorts of 3-6 patients receive escalating doses of 7-hydroxystaurosporine
until the MTD is determined. The MTD is defined as the dose preceding that at which 2 of 6
patients experience dose-limiting toxicity.
ARM 2: Patients receive 7-hydroxystaurosporine IV over 3 hours on day 1 at the MTD
determined in group I. Patients also receive oral perifosine as a loading dose every 6 hours
on day 4 followed by a maintenance dose once daily on days 5-28 of course 1 and then once
daily on days 1-28 in all subsequent courses. In both groups, treatment repeats every 28
days for ≥ 2 courses in the absence of disease progression or unacceptable toxicity.
Patients who achieve a complete remission (CR) or a CR with incomplete hematologic recovery
receive 4 additional courses beyond documentation of CR. Patients who achieve a partial
remission or hematologic improvement may continue treatment in the absence of disease
progression or unacceptable toxicity.
After completion of study treatment, patients are followed for 30 days and then periodically
Allocation: Non-Randomized, Endpoint Classification: Safety Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment
Maximum tolerated dose of 7-hydroxystaurosporine administered after perifosine
Evaluated according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. The highest dose with none or one DLT observed in six patients will be declared as MTD. To ensure the toxicity at the MTD is acceptable, additional 6 patients will be accrued at the MTD.
Course 1 (first 28 days)
University of Maryland Greenebaum Cancer Center
United States: Food and Drug Administration
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