Alternate Title
Basic Trial Information
Objectives
Entry Criteria
Expected Enrollment
Outcomes
Outline
Trial Contact Information
Registry Information

Alternate Title

Vorinostat and Idarubicin in Treating Patients With Relapsed or Refractory Leukemia or Myelodysplastic Syndromes

Basic Trial Information

Phase	Type	Status	Age	Sponsor	Protocol IDs
Phase I	Biomarker/Laboratory analysis, Treatment	Temporarily closed	18 and over	NCI	MDA-2005-0031 6892, NCI-6892, NCT00331513

Objectives

1. Determine the maximum tolerated dose and dose-limiting toxicities of vorinostat (SAHA) in combination with standard-dose idarubicin in patients with relapsed or refractory acute myeloid leukemia, acute lymphocytic leukemia, myelodysplastic syndromes, acute promyelocytic leukemia, or chronic myelogenous leukemia in blastic phase.
2. Describe the clinical activity of this regimen in these patients.
3. Determine the in vivo molecular effects of this regimen, including the effects on DNA topoisomerase IIα mRNA expression and on the induction of γH2AX, histone H3 and H4 acetylation, as well as changes in the gene expression profile.
4. Determine the pharmacokinetic characteristics of this regimen in these patients.

Entry Criteria

Disease Characteristics:

• Histologically or cytologically confirmed diagnosis of 1 of the following hematologic malignancies:
  • Acute myeloid leukemia
    • Patients with acute promyelocytic leukemia should have received prior treatment with tretinoin and arsenic trioxide
  • Acute lymphocytic leukemia
  • Myelodysplastic syndromes requiring treatment
    • Previously treated with either azacytidine or decitabine, unless it was contraindicated
  • Blastic phase chronic myelogenous leukemia
    • Failed prior imatinib mesylate-based therapy
• Relapsed or refractory disease
• No known CNS disease
• Considered ineligible for or refused potentially curative therapy, including allogeneic stem cell transplantation, with or without standard induction therapy

Prior/Concurrent Therapy:

• See Disease Characteristics
• At least 2 weeks since prior chemotherapy and recovered, unless there is evidence of rapidly progressive disease
  • At least 24 hours since prior hydroxyurea for rapidly proliferating disease
• At least 2 weeks since prior imatinib mesylate
• At least 2 weeks since prior histone deacetylase inhibitors, including valproic acid
• Maximum cumulative dose of prior idarubicin or equivalent anthracycline drug ≤ 290 mg/m²
• No other concurrent investigational agents
• No other concurrent anticancer agents or therapies
• No concurrent combination antiretroviral therapy for HIV-positive patients
• No concurrent epoetin alfa or hematopoietic colony-stimulating factors during the first course of study therapy
• No concurrent prophylactic hematopoietic colony-stimulating factors

Patient Characteristics:

• ECOG performance status (PS) 0-2 OR Karnofsky PS 60-100%
• Total bilirubin ≤ 2 mg/dL
• AST and ALT ≤ 2.5 times upper limit of normal
• Creatinine ≤ 2 mg/dL
• LVEF ≥ 50%
• Not nursing or pregnant
• Negative pregnancy test
• Fertile patients must use effective contraception
• No history of allergic reaction attributed to compounds of similar chemical or biological composition to vorinostat (SAHA) or other agents used in this study
• No ongoing or active infection
• No symptomatic congestive heart failure
• No unstable angina pectoris
• No cardiac arrhythmia
• No other uncontrolled illness
• No psychiatric illness or social situation that would preclude study compliance

Expected Enrollment

A total of 40 patients will be accrued for this study.

Outcomes

Maximum tolerated dose of vorinostat (SAHA) as measured by NCI CTCAE v.30
Dose-limiting toxicities of vorinostat (SAHA) as measured by NCI CTCAE v.30
Clinical activity
In vivo molecular effects on DNA topoisomerase IIα messenger ribonucleic acid (mRNA) expression as measured by real-time polymerase chain reaction assays
In vivo molecular effects on induction of γH2AX as measured by immunocytochemistry analysis of bone marrow aspirates at baseline and on days 14 and 21 in course 1 and by Western blot analysis at baseline and on days 0, 1, 3, 14, and 21 in course 1
In vivo molecular effects on histone H3 and H4 acetylation as measured by Western blot analysis using peripheral blood mononuclear cells or by enzyme-linked immunosorbent assay (ELISA) at baseline and on days 0, 1, 3, 14, and 21 in course 1
Changes in the gene expression profile as measured by microarrays or other standard methods
Pharmacokinetics

Outline

This is a randomized, dose-escalation study of vorinostat (SAHA). Patients are randomized to 1 of 2 treatment arms.

• Arm I: Patients receive oral SAHA three times daily on days 1-14 and idarubicin IV over 15 minutes once daily on days 1-3. Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity.*
• Arm II: Patients receive oral SAHA three times daily and idarubicin IV over 15 minutes once daily on days 1-3. Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity.*

   [Note: *Patients completing 6 courses of therapy or who reach the maximum cumulative dose of idarubicin or an equivalent anthracycline and achieve clinical benefit may continue treatment with SAHA alone 3 times daily on days 1-14 of each course, in the absence of disease progression or unacceptable toxicity.]

Cohorts of 3-6 patients receive escalating doses of SAHA until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience a dose-limiting toxicity. An additional 10 patients are treated at the MTD.

Patients undergo blood collection and bone marrow biopsies periodically during the study for pharmacologic, biomarker, and genetic studies.

After completion of study treatment, patients are followed at 4 weeks and then periodically thereafter.

Trial Contact Information

Trial Lead Organizations

M. D. Anderson Cancer Center at University of Texas

Guillermo Garcia-Manero, MD, Protocol chair		Ph: 713-745-3428; 800-392-1611

Registry Information
Official Title		A Phase I Study of Suberoylanilide Hydroxamic Acid (Vorinostat, SAHA) in Combination with Idarubicin in Relapsed or Refractory Leukemia
Trial Start Date		2006-03-07
Trial Completion Date		2007-10-28 (estimated)
Registered in ClinicalTrials.gov		NCT00331513
Date Submitted to PDQ		2006-02-27
Information Last Verified		2007-10-23
NCI Grant/Contract Number		CA16672, CA62461

Back to Top