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

Study Overview
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Brief Summary
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This phase I trial is studying the side effects and best dose of 7-hydroxystaurosporine when given together with perifosine in treating patients with relapsed or refractory acute leukemia, chronic myelogenous leukemia, or myelodysplastic syndromes. 7-Hydroxystaurosporine may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as perifosine, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving 7-hydroxystaurosporine together with perifosine may kill more cancer cells.

Detailed Description
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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.

Official Title
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A Phase 1 Study of UCN-01 in Combination With Perifosine in Patients With Relapsed and Refractory Acute Leukemias and High Risk MDS

Conditions
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Accelerated Phase Chronic Myelogenous Leukemia, Adult Acute Megakaryoblastic Leukemia (M7), Adult Acute Minimally Differentiated Myeloid Leukemia (M0), Adult Acute Monoblastic Leukemia (M5a), Adult Acute Monocytic Leukemia (M5b), Adult Acute Myeloblastic Leukemia With Maturation (M2), Adult Acute Myeloblastic Leukemia Without Maturation (M1), Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities, Adult Acute Myeloid Leukemia With Inv(16)(p13;q22), Adult Acute Myeloid Leukemia With t(15;17)(q22;q12), Adult Acute Myeloid Leukemia With t(16;16)(p13;q22), Adult Acute Myeloid Leukemia With t(8;21)(q22;q22), Adult Acute Myelomonocytic Leukemia (M4), Adult Acute Promyelocytic Leukemia (M3), Adult Erythroleukemia (M6a), Adult Pure Erythroid Leukemia (M6b), Blastic Phase Chronic Myelogenous Leukemia, Myelodysplastic/Myeloproliferative Neoplasms, Previously Treated Myelodysplastic Syndromes, Recurrent Adult Acute Lymphoblastic Leukemia, Recurrent Adult Acute Myeloid Leukemia, Relapsing Chronic Myelogenous Leukemia, Secondary Acute Myeloid Leukemia, T-cell Adult Acute Lymphoblastic Leukemia, Untreated Adult Acute Lymphoblastic Leukemia, Untreated Adult Acute Myeloid Leukemia

Intervention / Treatment
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* Drug: 7-hydroxystaurosporine
* Drug: perifosine
* Other: pharmacological study


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically or cytologically confirmed hematologic malignancy of 1 of the following types: Relapsed or refractory acute myelogenous leukemia (AML) Patients with acute promyelocytic leukemia t(15;17) are eligible provided they failed a prior tretinoin and arsenic-containing regimen Patients should be either refractory to both agents (absence of durable hematologic response) OR relapsed after a complete response duration of < 6 months Relapsed or refractory pre-B-cell or T-cell acute lymphoblastic leukemia (ALL) Chronic myelogenous leukemia (CML) in accelerated or blastic phase that is refractory to imatinib mesylate Must have evidence of disease progression despite continued treatment with imatinib mesylate AML arising in the setting of underlying myelodysplastic syndromes (MDS) and/or myeloproliferative disorders (MPD) Secondary or therapy-related AML De novo AML or pre-B-cell or T-cell ALL in adults > 60 years of age with poor-risk features, such as complex (≥ 3) or adverse cytogenetics The following are considered adverse cytogenetic abnormalities for AML: -5q 7q- 9q- 20q- abn12p +21 +8 t(6;9) t(6;11) t(11;19) -7 -5 inv3/t(3;3) abn11q23 abn17p abn21q t(9;22) refractory to imatinib mesylate The following are considered adverse cytogenetic abnormalities for ALL: t(9;22) refractory to imatinib mesylate Hypodiploidy t(4;11) t(1;19) Myelodysplastic Syndromes (MDS) meeting 1 of the following criteria: Intermediate and high risk (i.e., International Prognostic Scoring System [IPSS] ≥ 1.5) MDS that is refractory or has progressed after treatment with azacitidine and/or decitabine Intermediate and high risk (i.e., IPSS ≥ 1.5) MDS with a 5q- cytogenetic abnormality that is refractory or has progressed after treatment with lenalidomide, azacitidine, or decitabine Intermediate 2 and high risk MDS without 5q- cytogenetic abnormality that is refractory or has progressed after azacitidine or decitabine Original 5q must also be refractory to lenalidomide Received OR ineligible for established curative regimens, including stem cell transplantation No active CNS leukemia ECOG performance status (PS) 0-2 OR Karnofsky PS ≥ 60% Total or direct bilirubin ≤ 1.5 times upper limit of normal (ULN) AST/ALT ≤ 2.5 times ULN Creatinine ≤ 2 mg/dL Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception during and for 3 months after completion of study treatment No hyperleukocytosis (i.e., WBC > 30,000/mm^3) (recent treatment with hydroxyurea to prevent impending leukostasis allowed provided there has been no dose increase for ≥ 1 week) No history of allergic reactions attributed to compounds of similar chemical or biologic composition to UCN-01 or perifosine No intrinsic impaired organ function No active, uncontrolled infection Infection that is controlled with antibiotics allowed No symptomatic cardiac disease No active ischemia on EKG LVEF ≥ 40% by echocardiogram or MUGA Patients with a history of cardiac disease or mediastinal radiation should undergo testing of ventricular function No poorly controlled diabetes mellitus No psychiatric illness or social situation that would preclude giving informed consent or complying with study requirements No HIV positivity See Disease Characteristics At least 4 weeks since prior cytotoxic chemotherapy (6 weeks for carmustine or mitomycin C) and recovered At least 4 weeks since prior radiotherapy and recovered At least 4 weeks since prior autologous stem cell transplantation (SCT) At least 90 days since prior allogeneic SCT No evidence of graft vs host disease At least 2 weeks since prior immunosuppressive therapy No concurrent hematopoietic growth factors or biologic agents No other concurrent investigational agents, chemotherapy, radiotherapy, or immunotherapy No other concurrent anticancer therapy

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I (enzyme inhibitor, chemotherapy)<br>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 IV over 3 hours on day 4. Cohorts of 3-6 patients receive escalating doses of 7-hydroxystaurosporine until the MTD is determined. | Drug: 7-hydroxystaurosporine<br>* Given IV<br>* Other names: UCN-01;Drug: perifosine<br>* Given orally<br>* Other names: octadecylphosphopiperidine;Other: pharmacological study<br>* Correlative studies<br>* Other names: pharmacological studies;|
| Experimental: Arm 2 (enzyme inhibitor, chemotherapy)<br>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. | Drug: 7-hydroxystaurosporine<br>* Given IV<br>* Other names: UCN-01;Drug: perifosine<br>* Given orally<br>* Other names: octadecylphosphopiperidine;Other: pharmacological study<br>* Correlative studies<br>* Other names: pharmacological studies;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response rate, determined by improvement of blast cell count, degree of marrow infiltration by tumor cells, and improvement in peripheral blood count | 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. | Baseline, at the end of course 1 (day 21-28), and any time that disease progression is suspected | 
| Progression free survival | Estimated using the Kaplan-Meier method. | The time between the study entry and the first date that relapse or progressive disease is objectively documented, or death from any cause occurs | 
| Disease specific survival and survival Rate | Estimated using the Kaplan-Meier method. | 1 year | 
| Overall survival | Estimated using the Kaplan-Meier method. | From time of enrollment onto this study to the time of death | 
| Pharmacokinetics and pharmacodynamics of both perifosine and 7-hydroxystaurosporine | 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. | Baseline and at weeks 1, 5, and 9 |