7-Hydroxystaurosporine and Perifosine in Treating Patients With Relapsed or Refractory Acute Leukemia, Chronic Myelogenous Leukemia or High Risk Myelodysplastic Syndromes

• Maximum tolerated dose of 7-hydroxystaurosporine administered after perifosine [ Time Frame: Course 1 (first 28 days) ] [ Designated as safety issue: Yes ]
  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.
  
  

• Response rate, determined by improvement of blast cell count, degree of marrow infiltration by tumor cells, and improvement in peripheral blood count [ Time Frame: Baseline, at the end of course 1 (day 21-28), and any time that disease progression is suspected ] [ Designated as safety issue: No ]
  For patients with acute leukemias we will use revised International Working Group (IWG) response criteria as published by Cheson et al. For patients with MDS we will use IWG response assessment for MDS. 90% confidence interval (CI) will be provided.
  
  
• Progression free survival [ Time Frame: The time between the study entry and the first date that relapse or progressive disease is objectively documented, or death from any cause occurs ] [ Designated as safety issue: No ]
  Estimated using the Kaplan-Meier method.
  
  
• Disease specific survival and survival Rate [ Time Frame: 1 year ] [ Designated as safety issue: No ]
  Estimated using the Kaplan-Meier method.
  
  
• Overall survival [ Time Frame: From time of enrollment onto this study to the time of death ] [ Designated as safety issue: No ]
  Estimated using the Kaplan-Meier method.
  
  
• Pharmacokinetics and pharmacodynamics of both perifosine and 7-hydroxystaurosporine [ Time Frame: Baseline and at weeks 1, 5, and 9 ] [ Designated as safety issue: No ]
  Descriptive statistics and confidence intervals will be provided for molecular endpoints of drugs action: total akt, phospho akt, total erk, phospho erk, p21 in peripheral blood and marrow. We will also dichotomize pharmacokinetic levels at the median, and estimate differences in response rates for high versus low levels, using Fisher's exact test at the one-sided 0.05 significance level.
  
  

PRIMARY OBJECTIVES:

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 disorders.

SECONDARY OBJECTIVES:

I. Evaluate the safety and toxicity of UCN-01 administered after perifosine in these patients.

II. Evaluate the safety and toxicity of perifosine administered after UCN-01 in these patients.

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 thereafter.