Vorinostat in Treating Patients With Acute Myeloid Leukemia

Phase 2

Completed

• Conditions: Adult Acute Minimally Differentiated Myeloid Leukemia (M0); Recurrent Adult Acute Myeloid Leukemia; Untreated Adult Acute Myeloid Leukemia; Adult Acute Erythroid Leukemia (M6); Adult Acute Megakaryoblastic Leukemia (M7); Adult Acute Myeloblastic Leukemia With Maturation (M2); Adult Acute Myeloblastic Leukemia Without Maturation (M1); Adult Acute Monoblastic Leukemia (M5a); Adult Acute Monocytic Leukemia (M5b); Refractory Cytopenia With Multilineage Dysplasia
• Interventions: Drug: vorinostat

• Registration Number: NCT00305773
• Lead Sponsor: National Cancer Institute (NCI)

Brief Summary

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

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.

Study Timeline

• Study Start: 2006-01
• Study First Submitted: 2006-03-21
• Study First Submitted QC: 2006-03-21
• Study First Posted: 2006-03-22
• Primary Completion: 2009-05
• Study Completion: 2010-01
• Status Verified: 2012-12
• Results First Submitted: 2013-03-28
• Results First Submitted QC: 2013-03-28
• Results First Posted: 2013-05-16
• Last Update Submitted: 2014-04-30
• Last Update Posted: 2014-05-19

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 37

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

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Exclusion Criteria

Not provided

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Arm II (thrice daily vorinostat)	vorinostat	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.
Arm I (once daily vorinostat)	vorinostat	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.

Primary Outcome Measures

Name	Time	Method
Confirmed Complete Response (CR) Rate	Up to 2 years	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.

Secondary Outcome Measures

Name	Time	Method
Time to Progression (TTP)	Duration of study (up to 2 years)	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
Overall Survival (OS)	Duration of study (up to 2 years)	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.
Number of Participants With Severe (Grade 3, 4 or 5) Adverse Events	Duration of study (up to 2 years)	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

Trial Locations

Locations (1)

Mayo Clinic; 🇺🇸 Rochester, Minnesota, United States