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

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT00392353
First received: October 25, 2006
Last updated: March 19, 2014
Last verified: March 2014
  Purpose

This phase I/II trial is studying the side effects and best dose of vorinostat and azacitidine in treating patients with myelodysplastic syndromes or acute myeloid leukemia. Vorinostat may stop the growth of cancer or abnormal cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as azacitidine, work in different ways to stop the growth of cancer or abnormal cells, either by killing the cells or by stopping them from dividing. Giving vorinostat together with azacitidine may kill more cancer or abnormal cells.


Condition Intervention Phase
Adult Acute Basophilic Leukemia
Adult Acute Eosinophilic Leukemia
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(15;17)(q22;q12)
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 Acute Promyelocytic Leukemia (M3)
Adult Erythroleukemia (M6a)
Adult Pure Erythroid Leukemia (M6b)
Chronic Myelomonocytic Leukemia
de Novo Myelodysplastic Syndromes
Previously Treated Myelodysplastic Syndromes
Recurrent Adult Acute Myeloid Leukemia
Refractory Anemia
Refractory Anemia With Excess Blasts
Refractory Anemia With Excess Blasts in Transformation
Refractory Anemia With Ringed Sideroblasts
Secondary Acute Myeloid Leukemia
Secondary Myelodysplastic Syndromes
Untreated Adult Acute Myeloid Leukemia
Drug: azacitidine
Drug: vorinostat
Other: laboratory biomarker analysis
Other: pharmacological study
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 I/II Study of Vorinostat [Suberoylanilide Hydroxamic Acid (SAHA)] in Combination With Azacitidine in Patients With the Myelodysplastic Syndrome (MDS)

Resource links provided by NLM:


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

Primary Outcome Measures:
  • Incidence of toxicities of vorinostat (SAHA) in combination with azacitidine graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v3.0 (Phase I) [ Time Frame: Up to 1 month post-treatment ] [ Designated as safety issue: Yes ]
    Exact 95% confidence intervals around the toxicity proportions will be calculated to assess the precision of the obtained estimates.

  • Objective overall response proportion (complete response [CR] + CR with incomplete blood count [Cri] + partial response [PR]) (Phase II) [ Time Frame: Up to day 168 ] [ Designated as safety issue: No ]
    Ninety-five percent confidence intervals will be estimated for the response proportion in all three treatment groups via binomial proportions.

  • Distribution of toxicities in the 12th treatment arm (Phase II) [ Time Frame: Up to 1 month post-treatment ] [ Designated as safety issue: Yes ]
    The frequency of subjects experiencing toxicities will be tabulated. Toxicities will be assessed and graded according to CTCAE v. 3.0 terminology. Exact 95% confidence intervals around the toxicity proportions will be calculated to assess the precision of the obtained estimates.


Secondary Outcome Measures:
  • Time to response [ Time Frame: Up to day 84 ] [ Designated as safety issue: No ]
  • Time to leukemic transformation [ Time Frame: Up to day 84 ] [ Designated as safety issue: No ]
  • Frequency of leukemic transformation [ Time Frame: Up to day 84 ] [ Designated as safety issue: No ]
  • Progression-free survival (PFS) [ Time Frame: Time from first treatment day until objective or symptomatic progression, assessed up to 8 years ] [ Designated as safety issue: No ]
    Assessed by Kaplan-Meier survival analysis and 95% confidence intervals will be calculated using Greenwood's formulae.

  • Overall survival (OS) [ Time Frame: Time from first treatment day until death, assessed up to 8 years ] [ Designated as safety issue: No ]
    Assessed by Kaplan-Meier survival analysis and 95% confidence intervals will be calculated using Greenwood's formulae.


Estimated Enrollment: 168
Study Start Date: November 2006
Estimated Primary Completion Date: November 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Treatment (azacitidine, vorinostat)

PHASE I: Patients receive azacitidine SC once daily on days 1-7 and vorinostat (SAHA) PO 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 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.

Drug: azacitidine
Given SC
Other Names:
  • 5-AC
  • 5-azacytidine
  • azacytidine
  • Vidaza
Drug: vorinostat
Given PO
Other Names:
  • L-001079038
  • SAHA
  • suberoylanilide hydroxamic acid
  • Zolinza
Other: laboratory biomarker analysis
Correlative studies
Other: pharmacological study
Correlative studies
Other Name: pharmacological studies

Detailed Description:

PRIMARY OBJECTIVES:

I. To evaluate the safety and toxicity of vorinostat in combination with azacitidine in patients with MDS and some select patients with AML (step 1).

II. To identify doses of both vorinostat and Azacitidine for safe combination of the 2 agents that can be administered in repetitive cycles over time for use in phase II studies.

III. To determine the response rate of patients treated with the combination of SAHA and azacitidine at the doses established as safe and effective in Step 1 in an expanded cohort of patients with MDS.

IV. To obtain preliminary data on the effects of treatment with the combination of VORINOSTAT and Aza C in patients with MDS on a series of biologic surrogate markers including: DNA methylation of specific genes (e.g. p15); histone acetylation; hematopoietic progenitor growth and differentiation; the fate of the MDS clone and changes in gene expression by array profiling.

SECONDARY OBJECTIVES:

I. Determine effect of treatment with the combination on time to response, time to leukemic transformation and frequency of transformation to leukemia in patients with MDS during the phase II segment of the study.

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 (PO) 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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • 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
  • MDS cannot be due to leukemic relapse
  • No advanced hepatic tumors
  • No CNS involvement
  • No history of leukemia (phase II)
  • 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
  • No other concurrent anticancer agents or therapies
  • 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
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT00392353

Locations
United States, Maryland
University of Maryland Greenebaum Cancer Center
Baltimore, Maryland, United States, 21201-1595
United States, New York
Albert Einstein College of Medicine
Bronx, New York, United States, 10461
Montefiore Medical Center
Bronx, New York, United States, 10467-2490
Mount Sinai Medical Center
New York, New York, United States, 10029
Weill Medical College of Cornell University
New York, New York, United States, 10065
Sponsors and Collaborators
Investigators
Principal Investigator: Lewis Silverman Montefiore Medical Center
  More Information

No publications provided

Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT00392353     History of Changes
Other Study ID Numbers: NCI-2009-01050, NCI-2009-01050, CDR0000511887, NYCC-6898, NCI-6898, 6898, 6898, P30CA013330, N01CM62204
Study First Received: October 25, 2006
Last Updated: March 19, 2014
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Congenital Abnormalities
Anemia
Anemia, Refractory
Anemia, Refractory, with Excess of Blasts
Leukemia
Leukemia, Basophilic, Acute
Leukemia, Eosinophilic, Acute
Leukemia, Erythroblastic, Acute
Leukemia, Megakaryoblastic, Acute
Leukemia, Monocytic, Acute
Leukemia, Myeloid, Acute
Leukemia, Myeloid
Leukemia, Myelomonocytic, Acute
Leukemia, Myelomonocytic, Chronic
Leukemia, Promyelocytic, Acute
Myelodysplastic Syndromes
Preleukemia
Hypereosinophilic Syndrome
Anemia, Aplastic
Hematologic Diseases
Bone Marrow Diseases
Neoplasms by Histologic Type
Neoplasms
Myeloproliferative Disorders
Myelodysplastic-Myeloproliferative Diseases
Precancerous Conditions
Eosinophilia
Leukocyte Disorders
Azacitidine
Vorinostat

ClinicalTrials.gov processed this record on April 16, 2014