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Vorinostat, Azacitidine, and Gemtuzumab Ozogamicin in Treating Older Patients With Relapsed or Refractory Acute Myeloid Leukemia

This study has been completed.
Information provided by (Responsible Party):
National Cancer Institute (NCI) Identifier:
First received: May 7, 2009
Last updated: March 13, 2014
Last verified: July 2012

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 Intervention 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 Del(5q)
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
Other: laboratory biomarker analysis
Phase 1
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: 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)

Resource links provided by NLM:

Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:
  • Dose-limiting toxicity and maximum tolerated dose of vorinostat (Phase I) [ Time Frame: 42 days ] [ Designated as safety issue: Yes ]
  • Efficacy defined as best response achieved during study treatment measured by CR rate (Phase II) [ Time Frame: Up to 3 years ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Relapse-free survival (RFS) [ Time Frame: Up to 3 years ] [ Designated as safety issue: No ]
    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.

Enrollment: 53
Study Start Date: May 2009
Primary Completion Date: July 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Treatment (vorinostat, azacitidine, gemtuzumab ozogamicin)
Patients receive vorinostat PO on days 1-9, azacitidine SC or IV over 10-40 minutes on days 1-7, and gemtuzumab ozogamicin IV over 2 hours on day 8. Treatment repeats every 21 days for up to 12 courses in the absence of disease progression or unacceptable toxicity.
Drug: vorinostat
Given orally
Other Names:
  • L-001079038
  • SAHA
  • suberoylanilide hydroxamic acid
  • Zolinza
Drug: gemtuzumab ozogamicin
Given IV
Other Names:
  • Calicheamicin-Conjugated Humanized Anti-CD33 Monoclonal Antibody
  • CDP-771
  • CMA-676
  • Mylotarg
Drug: azacitidine
Given IV or SC
Other Names:
  • 5-AC
  • 5-azacytidine
  • azacytidine
  • Vidaza
Other: laboratory biomarker analysis
Correlative studies

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 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.


Ages Eligible for Study:   50 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • Prior morphological diagnosis of AML other then acute promyelocytic leukemia according to the 2001 World Health Organization (WHO) diagnostic criteria; patients with biphenotypic AML are eligible
  • Requiring first salvage chemotherapy for persistent or relapsing disease, as defined by standard criteria, after at least one course of conventional chemotherapy, e.g. with "7+3"
  • A bone marrow biopsy is not routinely required, but should be obtained if the aspirate is dilute, hypocellular, or inaspirable; outside bone marrow examinations performed within the stipulated time period are acceptable as long as the slides are reviewed at the study institution
  • Flow cytometric analysis of the bone marrow aspirate should be performed according to institutional practice guidelines
  • Duration of CR1 < 12 months (or primary resistant disease)
  • Patients with prior autologous or allogeneic hematopoietic cell transplantation (HCT) are eligible if relapse occurs 6-12 months post-transplant
  • Eastern Cooperative Oncology Group (ECOG)/WHO/Zubrod performance status of 0-3, assessed within 14 days prior to registration
  • Must be off any active therapy for AML with the exception of hydroxyurea for at least 14 days prior to study registration, and all grade 3 and 4 non-hematological toxicities must have resolved
  • Willingness to discontinue taking any medications that are generally accepted to have a risk causing Torsades de Pointes during the study
  • Bilirubin =< 1.5 x Institutional Upper Limit of Normal (IULN) unless elevation is thought to be due to hepatic infiltration by AML, Gilbert's syndrome, or hemolysis (assessed within 7 days prior to registration
  • Serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) and serum glutamic pyruvate transaminase (SPGT) (alanine aminotransferase [ALT]) =< 1.5 x IULN unless elevation is thought to be due to hepatic infiltration by AML (assessed within 7 days prior to registration)
  • Serum creatinine =< 1.5 x IULN (assessed within 7 days prior to registration)
  • No clinical or radiographical evidence of heart failure
  • White blood cell count (WBC) < 25,000/uL, assessed within 3 days prior to registration; patients with WBC >= 25,000/uL must undergo cytoreduction with hydroxyurea prior to enrollment and will not be treated if the WBC remains >= 25,000/ uL despite hydroxyurea treatment
  • 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; submission of peripheral blood only is acceptable as long as the peripheral blast count is > 5,000/uL and blast count > 50% of total WBC
  • Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately
  • Ability to understand and the willingness to sign a written informed consent document; the consent can be obtained from a legally authorized representative if the patient is unable to provide informed consent

Exclusion Criteria:

  • Patients in remission or with second or later relapse
  • Diagnosis of another malignancy, unless the patient was diagnosed at least 2 years earlier and has been disease-free for at least 6 months following the completion of curative intent therapy with the following exceptions:

    • Patients with treated non-melanoma skin cancer, in situ carcinoma, or cervical intraepithelial neoplasia, regardless of the disease-free duration, are eligible for this study if definitive treatment for the condition has been completed
    • Patients with organ-confined prostate cancer with no evidence of recurrent or progressive disease based on prostate-specific antigen (PSA) values are also eligible for this study if hormonal therapy has been initiated or a radical prostatectomy has been performed
  • Refractory/relapsing blast crisis of chronic myelogenous 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
  • Clinical evidence suggestive of central nervous system (CNS) involvement with leukemia unless a lumbar puncture confirms the absence of leukemic blasts in the cerebrospinal fluid (CSF)
  • Human immunodeficiency virus (HIV)-positive patients are excluded if their cluster of differentiation (CD)4 count is below 200 cells/uL or if they have active acquired immune deficiency syndrome (AIDS)-related complications, as these patients are at increased risk of lethal infections when treated with marrow-suppressive therapy
  • Pregnancy; women of child-bearing potential must undergo pregnancy test within 7 days prior to registration; breastfeeding should be discontinued if the mother is treated with vorinostat, azacitidine, and GO
  • Uncontrolled systemic fungal, bacterial, viral, or other infection (defined as exhibiting ongoing signs/symptoms related to the infection and without improvement, despite appropriate antibiotics or other treatment)
  • Patients may not be receiving any other investigational agents
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its identifier: 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
Principal Investigator: Roland Walter Fred Hutchinson Cancer Research Center
  More Information

No publications provided by National Cancer Institute (NCI)

Additional 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, IR-6921, CDR0000642213, 2288.00, 8297, P30CA015704
Study First Received: May 7, 2009
Last Updated: March 13, 2014
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Leukemia, Erythroblastic, Acute
Leukemia, Megakaryoblastic, Acute
Leukemia, Monocytic, Acute
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Leukemia, Myelomonocytic, Acute
Leukemia, Myelomonocytic, Chronic
Bone Marrow Diseases
Hematologic Diseases
Myelodysplastic-Myeloproliferative Diseases
Myeloproliferative Disorders
Neoplasms by Histologic Type
Antimetabolites, Antineoplastic
Antineoplastic Agents
Enzyme Inhibitors
Histone Deacetylase Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Therapeutic Uses processed this record on November 20, 2014