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

Alternate Title

Vorinostat, Cytarabine, and Etoposide in Treating Patients With Relapsed and/or Refractory Acute Leukemia or Myelodysplastic Syndromes or Myeloproliferative Disorders

Basic Trial Information

Phase	Type	Status	Age	Sponsor	Protocol IDs
Phase I	Biomarker/Laboratory analysis, Treatment	Active	18 and over	NCI	MSGCC-0447 6829, NCI-6829, MSGCC-H-27631, NCT00357305

Objectives

1. Determine the feasibility, tolerability, and toxicities, in terms of the maximum tolerated dose (MTD), of the sequential combination of vorinostat (SAHA) followed by cytarabine and etoposide in patients with relapsed and/or refractory acute leukemia or transforming myelodysplastic syndromes or myeloproliferative disorders.
2. Determine whether the addition of SAHA to cytarabine and etoposide chemotherapy improves outcome, in terms of complete response rate, duration of response, and overall survival, in these patients.
3. Determine the effects of SAHA on induction of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-death receptors DR4 and DR5 and other pro-apoptotic mediators in patient-derived cancer cells (leukemia blast cells) and somatic cells (buccal mucosa cells, using pre-SAHA and on SAHA treatment samples).
4. Determine the ability of SAHA to block leukemia blast cells in the G1 phase of the cell cycle (leukemia blast cells, using pre-SAHA and on SAHA treatment samples).
5. Determine the effects of SAHA on the expression of P-glycoprotein/MDR1/ABCB1, and the breast cancer resistance protein (BCRP/ABCG2), using functional and mRNA/protein assays for these transporters (leukemia blast cells, using pre-SAHA and on SAHA treatment samples).

Entry Criteria

Disease Characteristics:

• Histologically or cytologically confirmed diagnosis of 1 of the following:
  • Relapsed or refractory acute myeloid leukemia (AML)
    • Patients with acute promyelocytic leukemia t(15;17) must have failed prior tretinoin and arsenic trioxide-containing regimen
      • Must be refractory to both agents with absence of durable hematologic response OR relapsed after a complete response duration of < 6 months
  • Relapsed or refractory acute lymphoblastic leukemia
  • Chronic myelogenous leukemia in accelerated or blastic phase
    • Must be refractory to treatment with imatinib mesylate or dasatinib
      • Disease progression despite continued treatment with imatinib mesylate or dasatinib
    • Patients in accelerated or blastic phase are eligible if unable to tolerate imatinib mesylate provided their disease has progressed on dasatinib or if unable to tolerate dasatinib
  • AML arising in the setting of underlying myelodysplastic syndromes (MDS) and/or myeloproliferative disorders (MPD)
  • Secondary or therapy-related AML
• No active CNS leukemia
• Leukostasis OR leukemic blast count > 50,000/mm³ allowed provided patient is treated with emergency leukapheresis or hydroxyurea to reduce leukemic blast count to < 30,000/mm³

Prior/Concurrent Therapy:

• See Disease Characteristics
• Recovered from prior therapy
  • Persistent alopecia, fingernail discoloration, or hematologic abnormalities (primarily related to underlying disease) > 4 weeks after last course of chemotherapy or radiotherapy does not exclude patient
• At least 2 weeks since prior valproic acid or any other histone deacetylase inhibitor
• No more than 3 prior courses of induction/reinduction chemotherapy, including induction and consolidation therapy or induction therapy after any bone marrow transplantation or similar procedure
  • Prior low-dose azacitidine, growth factors, cytokines, thalidomide, interferon, or imatinib mesylate for treatment of preceding MDS/MPD do not count as prior induction/reinduction therapy
• At least 4 weeks since prior chemotherapy (6 weeks for nitrosoureas [e.g., carmustine] or mitomycin C) or radiotherapy
• At least 24 hours since prior hydroxyurea
• At least 2 weeks since prior imatinib mesylate, hematopoietic growth factors, and biological agents
• At least 4 weeks since prior autologous stem cell transplantation
• Prior allogeneic stem cell transplantation allowed if all of the following criteria are met:
  • At least 90 days since prior transplant
  • No evidence of graft-vs-host disease
  • At least 2 weeks since prior immunosuppressive therapy
• No other concurrent anticancer agents or therapies
• No other concurrent investigational agents
• Concurrent hydroxyurea or leukapheresis allowed on days 1-10 of study treatment to control rising leukemic blasts (blasts > 30,000/mm³) or leukostasis

Patient Characteristics:

• ECOG performance status (PS) 0-2 OR Karnofsky PS 60-100%
• Bilirubin ≤ 1.5 times upper limit of normal (ULN)
• AST and ALT ≤ 2.5 times ULN
• Creatinine ≤ 2.0 mg/dL
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• No history of cytarabine-related neurotoxicity
• No history of allergic reactions attributed to compounds of similar chemical or biologic composition to vorinostat (SAHA) or other agents used in the study
• No other uncontrolled illness, including, but not limited to, any of the following:
  • Symptomatic congestive heart failure
  • Unstable angina pectoris
  • Cardiac arrhythmia
  • Psychiatric illness or social situation that would preclude compliance with study requirements
• Infection allowed provided patient is receiving active treatment
• No HIV positivity

Expected Enrollment

A total of 25 patients will be accrued for this study.

Outcomes

Maximum tolerated dose (MTD) of vorinostat (SAHA) in combination with cytarabine and etoposide

Response rate
Progression-free survival
Disease-specific survival
One-year survival
Overall survival
Degree of upregulation of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-death receptors and proteins associated with apoptosis
Alterations in cell cycle phase
Expression of MDR proteins at MTD of SAHA

Outline

This is a dose-escalation study of vorinostat (SAHA).

Patients receive oral SAHA two or three times daily on days 1-7 and cytarabine IV over 3 hours twice daily and etoposide IV over 1 hour once daily on days 11-14. Treatment repeats approximately every 6-7 weeks for up to 3 courses in the absence of disease progression or unacceptable toxicity. Patients who achieve complete response after 1 course of therapy may receive 1 or 2 more courses of therapy. Patients who achieve partial response after 1 course of therapy may receive 1 more course of therapy.

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 1 of 3 or 2 of 6 patients experience dose-limiting toxicity. Once the MTD is determined, an additional 10 patients are treated at that dose.

Blood, buccal cells, and bone marrow samples are collected prior to and during treatment. Samples are used for pharmacokinetic and pharmacodynamic studies, protein expression studies, and gene expression profiling.

After completion of study treatment, patients are followed within 30 days.

Trial Contact Information

Trial Lead Organizations

Greenebaum Cancer Center at University of Maryland Medical Center

Douglas Ross, MD, PhD, Protocol chair		Ph: 410-328-8095 Email: dross@som.umaryland.edu

U.S.A.
Maryland
	Baltimore
	Greenebaum Cancer Center at University of Maryland Medical Center
		Clinical Trials Office - Greenebaum Cancer Center at University of Maryladn Medical Center	Ph:  800-888-8823
Pennsylvania
	Pittsburgh
	UPMC Cancer Centers
		Clinical Trials Office - UPMC Cancer Centers	Ph:  412-647-8073

Registry Information
Official Title		A Phase I Study of Vorinostat (Suberoylanilide Hydroxamic Acid, or SAHA) in Combination with Cytosine Arabinoside (ara-C) and Etoposide for Patients with Relapsed and/or Refractory Acute Leukemias, Myelodysplasias and Myeloproliferative Disorders
Trial Start Date		2006-05-19
Trial Completion Date		2010-08-12 (estimated)
Registered in ClinicalTrials.gov		NCT00357305
Date Submitted to PDQ		2006-05-23
Information Last Verified		2009-06-25

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