Vorinostat, Azacitidine, and Gemtuzumab Ozogamicin for Older Patients With Relapsed or Refractory AML

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT00895934
Recruitment Status : Completed
First Posted : May 8, 2009
Results First Posted : February 6, 2015
Last Update Posted : February 6, 2015
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Brief Summary:
The purpose of this study is to test the safety of vorinostat (Zolinza) and azacitidine (Vidaza) when combined with gemtuzumab ozogamicin (GO) at different dose levels. These drugs increase the effect of GO against leukemia cells in the test tube, but we don't know yet whether they also increase the anti-leukemia effect of GO in people.

Condition or disease Intervention/treatment Phase
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(16;16)(p13;q22) Adult Acute Myeloid Leukemia With t(8;21)(q22;q22) Adult Acute Myelomonocytic Leukemia (M4) Adult Erythroleukemia (M6a) Adult Pure Erythroid Leukemia (M6b) Recurrent Adult Acute Myeloid Leukemia Drug: vorinostat Drug: gemtuzumab ozogamicin Drug: azacitidine Phase 1 Phase 2

Detailed Description:


I. Determine the vorinostat dose with the most favorable efficacy and toxicity when combined with azacitidine and GO.


I. Describe the complete response (CR)/ CR with inadequate recovery (CRi) rate after a total of 6 cycles of therapy.

II. Describe the disease-free survival of patients that achieve CR/CRi. III. Determine whether acute myeloid leukemia (AML) characteristics associated with preclinical GO efficacy predict for clinical benefit, and assess whether differentiation-inducing agents modulate these characteristics and lower the apoptotic threshold for calicheamicin-gamma1-induced cytotoxicity (in vitro correlative and mechanistic studies).

OUTLINE: This is phase I, dose-escalation study of vorinostat followed by a phase II study.

Patients receive vorinostat orally (PO) on days 1-9, azacitidine subcutaneously (SC) or intravenously (IV) over 10-40 minutes on days 1-7, and gemtuzumab ozogamicin IV over 2 hours on day 4 and 8. Treatment repeats every 21 days for up to 12 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 3 years.

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 53 participants
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 1/2 Study of Vorinostat (Zolinza®) in Combination With Gemtuzumab Ozogamicin (Mylotarg®) and Azacitidine (Vidaza®) in Patients 50 Years of Age and Older With Relapsed/Refractory Non-APL Acute Myeloid Leukemia (AML)
Study Start Date : May 2009
Actual Primary Completion Date : July 2013
Actual Study Completion Date : September 2013

Arm Intervention/treatment
Experimental: Phase 1 - Dose Finding
Varying schedules and dose levels of vorinostat, azacitidine and gemtuzumab ozogamicin. Includes cohorts 1-3.
Drug: vorinostat
Given orally
Other Names:
  • L-001079038
  • SAHA
  • suberoylanilide hydroxamic acid
  • Zolinza

Drug: gemtuzumab ozogamicin
Given intravenously (IV)
Other Names:
  • Calicheamicin
  • CDP-771
  • CMA-676
  • Mylotarg

Drug: azacitidine
Given IV or subcutaneously (SC)
Other Names:
  • 5-AC
  • 5-azacytidine
  • azacytidine
  • Vidaza

Experimental: Phase 2 - Treatment at Selected Dose
Vorinostat 400 mg/day on days 1-9, azacitidine 75 mg/m2/day on days 1-7, gemtuzumab ozogamicin 3 mg/m2/day on days 4 and 8.
Drug: vorinostat
Given orally
Other Names:
  • L-001079038
  • SAHA
  • suberoylanilide hydroxamic acid
  • Zolinza

Drug: gemtuzumab ozogamicin
Given intravenously (IV)
Other Names:
  • Calicheamicin
  • CDP-771
  • CMA-676
  • Mylotarg

Drug: azacitidine
Given IV or subcutaneously (SC)
Other Names:
  • 5-AC
  • 5-azacytidine
  • azacytidine
  • Vidaza

Primary Outcome Measures :
  1. Dose-limiting Toxicity and Maximum Tolerated Dose of Vorinostat (Phase I) [ Time Frame: 42 days ]
  2. Efficacy Defined as Best Response Achieved During Study Treatment Measured by Complete Remission (CR) Rate [ Time Frame: Up to 3 years ]

Secondary Outcome Measures :
  1. Relapse-free Survival (RFS) [ Time Frame: Up to 3 years ]
    Estimated using Kaplan-Meier method. Logistic regression will be used as a tool to assess the association of various factors with the probability of response, recognizing that the power to detect statistically significant associations will be limited due to the sample size (and expected number of responses). The impact of remission and post-remission therapy on RFS will be assessed using Cox regression with remission and therapy treated as time-dependent covariates.

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Ages Eligible for Study:   50 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • Prior morphological diagnosis of acute myeloid leukemia (AML) other then acute promyelocytic leukemia (APL) according to the 2001 WHO criteria; patients with biphenotypic AML are eligible
  • Need for first salvage chemotherapy for persistent or relapsing disease, defined by standard criteria, after at least one course of conventional chemotherapy
  • A bone marrow biopsy is not required but should be obtained if the aspirate is dilute, hypocellular, or not aspirable; outside marrow exams performed within the stipulated time period are acceptable if the slides are reviewed at the study institution
  • Flow cytometric analysis of the marrow aspirate per institutional practice guidelines
  • Duration of first complete remission (CR1) < 12 months (or primary resistant disease)
  • Patients with prior autologous or allogeneic hematopoietic cell transplantation (HCT) if relapse occurs 6-12 months post-transplant
  • ECOG/WHO/Zubrod performance status of 0-3 within 14 days prior to registration
  • Off any active therapy for AML except hydroxyurea for at least 14 days prior to study registration, with resolution of all grade 3 and 4 non-hematological toxicities
  • Willingness to discontinue taking any medications known to cause a risk of Torsades de Pointes
  • Bilirubin =< 1.5 x Institutional Upper Limit of Normal (IULN) unless elevation is due to hepatic infiltration by AML, Gilbert's syndrome, or hemolysis (within 7 days prior to registration)
  • SGOT (AST) and SGPT (ALT) =< 1.5 x IULN unless elevation is due to hepatic infiltration by AML (within 7 days prior to registration)
  • Serum creatinine =< 1.5 x IULN (within 7 days prior to registration)
  • No clinical or radiographical evidence of heart failure
  • white blood cell (WBC) < 25,000/uL within 3 days prior to registration
  • Patients with symptoms/signs of hyperleukocytosis or WBC > 100,000/uL can be treated with leukapheresis prior to enrollment
  • Collection of bone marrow and peripheral blood specimens for correlative studies prior to study treatment is highly recommended; peripheral blood only is acceptable if the peripheral blast count is > 5,000/uL and > 50% of total WBC
  • Must agree to use adequate contraception prior to and during the study
  • Can understand and sign a written informed consent document; a legally authorized representative can provide consent if the patient is unable

Exclusion Criteria:

  • Remission or second or later relapse
  • Diagnosis of another malignancy, unless diagnosed at least 2 years earlier and disease-free for at least 6 months after completion of curative intent therapy except:

    • Treated non-melanoma skin cancer, in situ carcinoma, or cervical intraepithelial neoplasia, if definitive treatment has been completed
    • Organ-confined prostate cancer with no evidence of recurrent or progressive disease based on prostate-specific antigen (PSA) values if hormonal therapy has been initiated or a radical prostatectomy was performed
  • Refractory/relapsing blast crisis of chronic myeloid leukemia (CML)
  • Prior anti-AML treatment with GO, histone deacetylase (HDAC) inhibitor (including the use of valproic acid for control of seizure activity or other purposes), or demethylating agent
  • Known hypersensitivity to GO, vorinostat, azacitidine, or mannitol
  • Possible central nervous system (CNS) involvement with leukemia unless a lumbar puncture confirms no leukemic blasts in the cerebralspinal fluid (CSF)
  • HIV-positive patients with cluster of differentiation (CD)4 count is < 200 cells/uL or if AIDS-related complications
  • Pregnancy; breastfeeding should be discontinued if the mother is treated with vorinostat, azacitidine, and GO
  • Uncontrolled systemic infection, despite appropriate antibiotics or other treatment)
  • Receipt of any other investigational agents

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT00895934

United States, California
Stanford University Hospitals and Clinics
Stanford, California, United States, 94305
United States, Washington
Harrison HealthPartners Hematology and Oncology-Bremerton
Bremerton, Washington, United States, 98310
Fred Hutchinson Cancer Research Center
Seattle, Washington, United States, 98109
University of Washington Medical Center
Seattle, Washington, United States, 98195
Sponsors and Collaborators
National Cancer Institute (NCI)
Principal Investigator: Roland Walter Fred Hutchinson Cancer Research Center

Publications automatically indexed to this study by Identifier (NCT Number):
Responsible Party: National Cancer Institute (NCI) Identifier: NCT00895934     History of Changes
Other Study ID Numbers: NCI-2012-01147
NCI-2012-01147 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
IR-6921 ( Other Identifier: Fred Hutchinson Cancer Research Center )
CDR0000642213 ( Other Identifier: FDA Center for Drug Research )
2288.00 ( Other Identifier: Fred Hutchinson Cancer Research Center )
8297 ( Other Identifier: CTEP )
P30CA015704 ( U.S. NIH Grant/Contract )
First Posted: May 8, 2009    Key Record Dates
Results First Posted: February 6, 2015
Last Update Posted: February 6, 2015
Last Verified: July 2012

Additional relevant MeSH terms:
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Leukemia, Monocytic, Acute
Leukemia, Myelomonocytic, Acute
Leukemia, Megakaryoblastic, Acute
Leukemia, Erythroblastic, Acute
Neoplasms by Histologic Type
Myeloproliferative Disorders
Bone Marrow Diseases
Hematologic Diseases
Antimetabolites, Antineoplastic
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Enzyme Inhibitors
Histone Deacetylase Inhibitors