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

Alternate Title

Vorinostat and Azacitidine in Treating Patients With Myelodysplastic Syndromes or Acute Myeloid Leukemia

Basic Trial Information

Phase	Type	Status	Age	Sponsor	Protocol IDs
Phase II, Phase I	Treatment	Active	18 and over	NCI	NYCC-6898 6898, NCI-6898, NCT00392353

Objectives

Primary

1. Determine safe doses of vorinostat (SAHA) and azacitidine in patients with myelodysplastic syndromes (MDS) or acute myeloid leukemia. (Phase I)
2. Determine the safety and toxicity of this regimen in these patients. (Phase I)
3. Determine the response rate in patients with MDS treated with this regimen. (Phase II)

Secondary

1. Determine time to response in patients with MDS treated with this regimen. (Phase II)
2. Determine time to leukemic transformation in patients with MDS treated with this regimen. (Phase II)
3. Determine frequency of transformation to leukemia in patients with MDS treated with this regimen. (Phase II)

Entry Criteria

Disease Characteristics:

• Histologically confirmed diagnosis of 1 of the following:
  • Myelodysplastic syndromes (MDS) meeting the following criteria:
    • One of the following types by FAB classification:
      • Refractory anemia (RA)
      • RA with ringed sideroblasts (RARS)
      • RA with excess blasts (RAEB)
      • RAEB in transformation
      • Chronic myelomonocytic leukemia
    • Classified according to International Prognostic Scoring System (IPSS) criteria as intermediate-1, intermediate-2, or high-risk disease
    • Patients with RA or RARS and IPSS ≤ 0.5 or low-risk MDS (IPSS < 0.5) must meet ≥ 1 of the following criteria:
      • Symptomatic anemia requiring packed red blood cell transfusions for ≥ 3 months prior to study entry
      • Thrombocytopenia with platelet count ≤ 50,000/mm³ or significant clinical hemorrhage (e.g., gastrointestinal, genitourinary, or gynecologic hemorrhage requiring platelet transfusions; petechiae alone do not constitute sufficient hemorrhage)
      • Neutropenia with absolute neutrophil count < 1,000/mm³ and an infection requiring antibiotics
      • Less than 30% myeloblasts in the bone marrow (phase II)
      • No FAB M6 leukemia (phase II)

  • Acute myeloid leukemia (AML) meeting the following criteria*:
    • De novo AML or AML evolving from MDS associated with intermediate- or poor-risk cytogenetics and meeting 1 of the following criteria:
      • Declined standard chemotherapy
      • Failed or relapsed after 1 prior chemotherapy regimen
    • Stable disease, defined as WBC ≤ 25,000/mm³ and no requirement for hydroxyurea, chemotherapy, or leukapheresis within the past 4 weeks

     [Note: *Patients with AML are eligible only for the phase I portion of the study]

• MDS cannot be due to leukemic relapse
• No advanced hepatic tumors
• No CNS involvement
• No history of leukemia (phase II)

Prior/Concurrent Therapy:

• See Disease Characteristics
• More than 1 month since prior corticosteroids
• More than 1 month since prior interferon
• More than 1 month since prior retinoids
• More than 1 month since prior hematopoietic growth factors, including any of the following:
  • Filgrastim (G-CSF)
  • Sargramostim (GM-CSF)
  • Epoetin alfa
• At least 2 weeks since prior histone deacetylase inhibitor (e.g., valproic acid)
• More than 4 weeks since prior investigational agent and recovered
• More than 4 weeks since prior chemotherapy (6 weeks for nitrosoureas or mitomycin C) or radiotherapy for this cancer and recovered
• More than 12 months since prior radiotherapy for another cancer and recovered
• More than 12 months since prior chemotherapy for another cancer and recovered
• No prior antimetabolites, including the following:
  • Azacitidine
  • Decitabine
  • Vorinostat (SAHA)
• No other concurrent investigational agents
• No other concurrent anticancer agents or therapies

Patient Characteristics:

• Life expectancy > 2 months
• ECOG performance status (PS) 0-2 OR Karnofsky PS 60-100%
• AST and ALT ≤ 2.5 times upper limit of normal (ULN)
• Bilirubin ≤ 1.5 times ULN (unless active hemolysis present or elevation is secondary to ineffective erythropoiesis)
• Creatinine normal OR creatinine clearance ≥ 60 mL/min
• No other malignancy within the past 3 years
• No history of allergic reaction to compounds of similar chemical or biologic composition to vorinostat (SAHA) or other drugs used in this study
• No uncontrolled concurrent illness, including, but not limited to, the following:
  • Symptomatic congestive heart failure (CHF) except high-output CHF secondary to anemia
  • Unstable angina pectoris
  • Clinically significant cardiac arrhythmia
  • Ongoing or active systemic, bacterial, fungal, or viral infection (must be afebrile for more than 7 days prior to study entry)
  • Psychiatric illness or social situation that would preclude study participation
• No HIV positivity
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception during and for 3 months after completion of study treatment

Expected Enrollment

A total of 48 patients will be accrued for the phase I portion of this study. A total of 37 patients will be accrued for the phase II portion of this study.

Outcomes

Safety and tolerability of vorinostat (SAHA) in combination with azacitidine
Clinical efficacy
Effect of combination therapy on clinical and biologic response

Time to response
Time to leukemic transformation
Frequency of leukemic transformation

Outline

This is a multicenter, phase I, dose-escalation study followed by an open-label phase II study.

• Phase I: Patients receive azacitidine subcutaneously (SC) once daily on days 1-7 and vorinostat (SAHA) orally 2-3 times daily on days 3-5, 3-9, or 3-16. Treatment repeats every 28 days for at least 4 courses in the absence of disease progression or unacceptable toxicity.

  Cohorts of 3-6 patients receive escalating doses of azacitidine and vorinostat (SAHA) until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which at least 2 of 6 patients experience dose-limiting toxicity.

• Phase II: Patients receive azacitidine and vorinostat (SAHA) at the safe dose and duration determined in phase I.

After completion of study treatment, patients are followed monthly for 6 months and then every 2 months thereafter.

Trial Contact Information

Trial Lead Organizations

New York Cancer Consortium

Lewis Silverman, MD, Protocol chair		Ph: 212-241-5520 Email: lewis.silverman@mssm.edu

U.S.A.
New York
	Bronx
	Albert Einstein Cancer Center at Albert Einstein College of Medicine
		Samir Parekh, MD	Ph:  718-920-4826
			Email: sparekh@montefiore.org
	Manhasset
	Don Monti Comprehensive Cancer Center at North Shore University Hospital
		Clinical Trials Office - Don Monti Comprehensive Cancer Center at North Shore University Hospital	Ph:  516-734-8900
	New York
	Mount Sinai Medical Center
		Lewis Silverman, MD	Ph:  212-241-5520
			Email: lewis.silverman@mssm.edu
	New York Weill Cornell Cancer Center at Cornell University
		Clinical Trials Office - New York Weill Cornell Cancer Center at Cornell University	Ph:  212-746-1848

Registry Information
Official Title		A Phase I/II Study of Vorinostat [Suberoylanilide Hydroxamic Acid (SAHA)] in Combination with Azacitidine in Patients with the Myelodysplastic Syndrome (MDS)
Trial Start Date		2006-11-22
Trial Completion Date		2007-11-07 (estimated)
Registered in ClinicalTrials.gov		NCT00392353
Date Submitted to PDQ		2006-09-25
Information Last Verified		2008-12-21
NCI Grant/Contract Number		CM62204

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