Vorinostat in Treating Patients With Acute Myeloid Leukemia

Study Overview
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Brief Summary
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Vorinostat may stop the growth of cancer cells by blocking some of the enzymes needed for their growth. Giving the drug in different ways may kill more cancer cells. This randomized phase II trial is studying two different schedules of vorinostat to see how well they work in treating patients with acute myeloid leukemia.

Detailed Description
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PRIMARY OBJECTIVES: I. Determine the toxicity and the proportion of complete remissions associated with two different treatment schedules of vorinostat (SAHA) in patients with acute myeloid leukemia. SECONDARY OBJECTIVES: I. Determine the toxic effects of SAHA in this study population. II. Examine for preliminary evidence of re-expression of silenced genes in leukemic blasts in response to SAHA. OUTLINE: This is a multicenter, randomized study. Patients are stratified according to disease status (relapsed vs untreated). Patients are randomized to 1 of 2 treatment arms. ARM I: Patients receive oral vorinostat (SAHA) once a day on days 1-21. In both arms, treatment repeats every 21 days for up to 17 courses in the absence of disease progression or unacceptable toxicity. ARM II: Patients receive oral SAHA three times a day on days 1-14. In both arms, treatment repeats every 21 days for up to 17 courses in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed periodically for up to 2 years. PROJECTED ACCRUAL: A total of 44 patients will be accrued for this study.

Official Title
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A Phase 2 Study of Suberoylanilide Hydroxamic Acid (SAHA) in Acute Myeloid Leukemia (AML)

Conditions
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Adult Acute Erythroid Leukemia (M6), 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), Recurrent Adult Acute Myeloid Leukemia, Refractory Cytopenia With Multilineage Dysplasia, Secondary Acute Myeloid Leukemia, Untreated Adult Acute Myeloid Leukemia

Intervention / Treatment
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* Drug: vorinostat
* Drug: vorinostat


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of acute myeloid leukemia (AML), meeting 1 of the following criteria: Relapsed AML in the following categories: Good-risk cytogenetics [inv(16), t (8;21)] in second relapse or in first relapse following a remission of < 12 months Acute promyelocytic leukemia (M3) in second relapse or greater AND must have relapsed following both tretinoin-anthracycline-based therapy and arsenic trioxide-based therapy All other relapsed patients are eligible Untreated AML in the following categories: At least 65 years of age Myelodysplastic syndromes-AML (AML with trilineage dysplasia) AML with del5Q or monosomy 5, monosomy 7, or complex cytogenetics (≥ 3 cytogenetic abnormalities) Refused or ineligible for potentially curative options such as allogeneic stem cell transplantation No clinical evidence of CNS or pulmonary leukostasis, disseminated intravascular coagulation, or CNS leukemia ECOG performance status (PS) 0-2 or Karnofsky PS ≥ 60% Life expectancy ≥ 3 months Bilirubin normal unless attributed to hemolysis or Gilbert's disease in the opinion of the investigator AST/ALT ≤ 2.5 times upper limit of normal (ULN) Creatinine normal OR creatinine clearance ≥ 60 mL/min No history of allergic reactions attributed to compounds of similar chemical or biologic composition to vorinostat No uncontrolled intercurrent illness, including any of the following: Ongoing or active infection Symptomatic congestive heart failure Unstable angina pectoris Cardiac arrhythmia Psychiatric illness or social situation that would limit compliance with study requirements Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception No known HIV positivity More than 4 weeks since prior radiotherapy More than 2 weeks since prior valproic acid More than 3 weeks since other prior treatment for AML, including hematopoietic growth factors Hydroxyurea for WBC > 30,000/mm^3 allowed Recovered from prior therapy No concurrent filgrastim (G-CSF), sargramostim (GM-CSF), epoetin alfa, or darbepoetin alfa No other concurrent investigational agents No other concurrent anticancer agents or therapies for this cancer

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: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I (once daily vorinostat)<br>Patients receive oral vorinostat (SAHA) once a day on days 1-21. In both arms, treatment repeats every 21 days for up to 17 courses in the absence of disease progression or unacceptable toxicity. | Drug: vorinostat<br>* Given orally once daily<br>* Other names: Zolinza;|
| Experimental: Arm II (thrice daily vorinostat)<br>Patients receive oral SAHA three times a day on days 1-14. In both arms, treatment repeats every 21 days for up to 17 courses in the absence of disease progression or unacceptable toxicity. | Drug: vorinostat<br>* Given orally three times daily<br>* Other names: Zolinza;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Confirmed Complete Response (CR) Rate | The confirmed complete response rate was estimated by the number of participants with CR divided by the total number of evaluable participants. According to the International Working Group (IWG) Criteria for response in AML, to be considered a CR, the following must be met for at least 4 weeks: ANC > 1500/mL, platelets > 100000/mL, no circulating blasts, bone marrow cellularity >20% (biopsy), trilineage maturation, < 5% bone marrow blasts, no auer rods and no extramedullary disease. | Up to 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Progression (TTP) | Time to Progression (TTP) for each patient will be calculated as the number of days from date of registration to either date when disease progression was documented or date of last evaluation without disease progression. The TTP distribution will be estimated using the method of Kaplan-Meier | Duration of study (up to 2 years) | 
| Overall Survival (OS) | Overall survival (OS) was defined as the time from registration to death of any cause. Surviving patients were censored at the date of last follow-up. The median OS with 95% CI was estimated using the Kaplan Meier method. | Duration of study (up to 2 years) | 
| Number of Participants With Severe (Grade 3, 4 or 5) Adverse Events | Adverse events were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 3. Description of Grades: Grade 1: Mild Grade 2: Moderate Grade 3: Severe Grade 4: Life-threatening Grade 5: Death | Duration of study (up to 2 years) |