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

NCT00392353 | Active Not Recruiting Phase 1

• 9 other identifiers: NCI-2009-01050NYCC-689811-1773NCI-6898CDR00005118876898N01CM17103N01CM62204P30CA013330
• Study Type: interventional
• Target: 135
• Locations: 1 country
• Sites: 7

Brief Summary

This phase I/II trial studies the side effects and best dose of vorinostat and azacitidine and to see how well they work 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, by stopping them from dividing, or by stopping them from spreading. Giving vorinostat together with azacitidine may kill more cancer or abnormal cells.

Conditions

Acute Myeloid Leukemia Arising From Previous Myelodysplastic Syndrome; Acute Erythroid Leukemia; Acute Megakaryoblastic Leukemia; Chronic Myelomonocytic Leukemia; Myelodysplastic Syndrome; Myelodysplastic Syndrome With Excess Blasts; Myelodysplastic Syndrome With Ring Sideroblasts; Recurrent Adult Acute Myeloid Leukemia; Refractory Anemia

Outcome Measures

Primary Outcomes (3)

• Incidence of toxicities of vorinostat in combination with azacitidine graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version (v)5.0 (Phase I)

  Exact 95% confidence intervals around the toxicity proportions will be calculated to assess the precision of the obtained estimates.

  Up to 1 month post-treatment

• Objective overall response proportion (complete response [CR] + CR with incomplete blood count + partial response) (Phase II)

  Ninety-five percent confidence intervals will be estimated for the response proportion in all three treatment groups via binomial proportions.

  Up to day 168

• Distribution of toxicities in the 12th treatment arm (Phase II)

  The frequency of subjects experiencing toxicities will be tabulated. Toxicities will be assessed and graded according to CTCAE v. 5.0 terminology. Exact 95% confidence intervals around the toxicity proportions will be calculated to assess the precision of the obtained estimates.

  Up to 1 month post-treatment

Secondary Outcomes (5)

• Time to response

  Up to day 84

• Time to leukemic transformation

  Up to day 84

• Frequency of leukemic transformation

  Up to day 84

• Progression-free survival

  Time from first treatment day until objective or symptomatic progression, assessed up to 8 years

• Overall survival

  Time from first treatment day until death, assessed up to 8 years

Study Arms (1)

Treatment (azacitidine, vorinostat)

EXPERIMENTAL

Patients receive azacitidine SC QD on days 1-7 and vorinostat 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.

Drug: Azacitidine; Other: Laboratory Biomarker Analysis; Other: Pharmacological Study; Drug: Vorinostat

Interventions

Azacitidine DRUG

Given SC

Also known as: 5 AZC, 5-AC, 5-Azacitidine, 5-Azacytidine, 5-AZC, Azacytidine, Azacytidine, 5-, Ladakamycin, Mylosar, U-18496, Vidaza

Treatment (azacitidine, vorinostat)

Pharmacological Study OTHER

Correlative studies

Treatment (azacitidine, vorinostat)

Laboratory Biomarker Analysis OTHER

Correlative studies

Treatment (azacitidine, vorinostat)

Vorinostat DRUG

Given PO

Also known as: L-001079038, MSK-390, SAHA, Suberanilohydroxamic Acid, Suberoylanilide Hydroxamic Acid, Zolinza

Treatment (azacitidine, vorinostat)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Eligibility Criteria for the phase I portion (step 1); patients must have a diagnosis of either MDS according to French-American-British (FAB) and International Prognostic Scoring System (IPSS) criteria, or a diagnosis of AML according to FAB or World Health Organization (WHO) criteria
• MDS: All patients must have an established diagnosis of myelodysplastic syndrome confirmed by peripheral blood and bone marrow maturational abnormalities in the erythroid, megakaryocytic and granulocytic series, defined according to the French -American-British (F.A.B.) classification
• Refractory anemia (RA), defined as having anemia with =\< 1% blasts in the peripheral blood and dyserythropoiesis; neutropenia and thrombocytopenia may also be present but are less common; the bone marrow is usually normocellular or hypercellular with \< 5% blast cells
• Refractory anemia with ring sideroblasts (RARS), defined as refractory anemia above, but also including the presence of ringed sideroblasts comprising \>= 15% of all nucleated cells in the bone marrow
• Refractory anemia with excess blasts (RAEB), defined as having 5-20% myeloblasts in the bone marrow and less than 5% blasts in the peripheral blood, together with abnormalities in erythroid megakaryocytic and granulocytic maturation consistent with myelodysplasia
• Refractory anemia with excess blasts in transformation (RAEB-T), defined as 21-29% myeloblasts in the marrow, or more than 5% blasts in the peripheral blood, or Auer rods in granulocytic precursors in the marrow or blood (with \< 30% myeloblasts in the marrow)
• Chronic myelomonocytic leukemia (CMMoL) defined as an absolute monocytosis (\> 1 x 10\^9/liter) with \< 5% blasts in the peripheral blood and \< 20% blasts in the bone marrow; additional criteria include a white blood cell (WBC) =\< 13 x 10\^9/L
• For patients with refractory anemia or refractory anemia with ring sideroblasts and IPSS =\< 0.5, must also meet at least one of the following criteria to be eligible:
• Symptomatic anemia requiring packed red blood cell (PRBC) transfusions for at least 3 months prior to study entry (document), or
• Thrombocytopenia with platelet counts =\< 50,000/ml or significant clinical hemorrhage (e.g., gastrointestinal \[GI\], gastric ulcer \[GU\] or gynecologic \[GYN\] hemorrhage requiring platelet transfusion; petechiae alone do not constitute sufficient hemorrhage)
• Neutropenia with absolute neutrophil count \< 1000/ul with an infection requiring treatment with antibiotics
• Patients with MDS classified according to IPSS criteria with intermediate -1, intermediate -2 or high risk disease are eligible
• Patients with low risk MDS (IPSS Score \< 0.5) must additionally meet criteria as outlined for patients with refractory anemia or refractory anemia with ring sideroblasts above
• AML - phase 1 only; patients with AML are not eligible for phase II; patients with AML defined according to FAB or WHO criteria will be eligible for the phase I portion of this study (phase 1 only); additional selection criteria:
• De novo AML or AML evolving from MDS associated with intermediate or poor risk cytogenetics in patients who decline standard chemotherapy or who have failed or relapsed following one prior regimen

You may not qualify if:

• Patients who have had chemotherapy or radiotherapy within 12 months prior to entering the study or those with another malignancy who have had evidence of the malignancy during the 3 years prior to study entry
• Patients may not be receiving any other investigational agents
• Patients may not have central nervous system (CNS) involvement with MDS or AML
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to vorinostat or other agents used in study
• Pregnant women are excluded from this study; breastfeeding should be discontinued if the mother is treated with vorinostat
• Any other serious medical or psychiatric illness which would limit survival to \< 3 months or prevent the granting of informed consent
• Uncontrolled or severe congestive heart failure; (does not include patients with high output congestive heart failure \[CHF\] states secondary to anemia which can be controlled)
• \>= 30% myeloblasts in the bone marrow or M6 leukemia as defined by FAB criteria (phase II component of the study)
• Prior treatment with G-CSF, GM-CSF, or other hematopoietic growth factors, erythropoietin within one month prior to study; no interferon or retinoids within one month prior to study
• Known positive serology for human immunodeficiency virus (HIV); appropriate studies will be undertaken in patients receiving combination anti-retroviral therapy when indicated
• Active systemic bacterial, fungal of viral infection; infection should be fully treated and the patient afebrile for 7 days before study entry
• Prior history of leukemia (step 2 phase II component of the study only)
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, clinically significant cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
• Patients with advanced hepatic tumors are excluded

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (7)

University of Chicago Comprehensive Cancer Center

Chicago, Illinois, 60637, United States

Location

University of Maryland/Greenebaum Cancer Center

Baltimore, Maryland, 21201, United States

Location

North Shore University Hospital

Manhasset, New York, 11030, United States

Location

Mount Sinai Hospital

New York, New York, 10029, United States

Location

NYP/Weill Cornell Medical Center

New York, New York, 10065, United States

Location

Montefiore Medical Center-Weiler Hospital

The Bronx, New York, 10461, United States

Location

Montefiore Medical Center - Moses Campus

The Bronx, New York, 10467, United States

Location

MeSH Terms

Conditions

Leukemia, Erythroblastic, Acute; Leukemia, Megakaryoblastic, Acute; Leukemia, Myelomonocytic, Chronic; Myelodysplastic Syndromes; Anemia, Refractory, with Excess of Blasts; Leukemia, Myeloid, Acute; Anemia, Refractory

Interventions

Azacitidine; Vorinostat

Condition Hierarchy (Ancestors)

Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Myeloproliferative Disorders; Bone Marrow Diseases; Hematologic Diseases; Hemic and Lymphatic Diseases; Myelodysplastic-Myeloproliferative Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Anemia

Intervention Hierarchy (Ancestors)

Aza Compounds; Organic Chemicals; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Ribonucleosides; Anilides; Amides; Aniline Compounds; Amines; Hydroxamic Acids; Hydroxylamines; Hydroxy Acids; Carboxylic Acids

Study Officials

• Lewis R Silverman

  Montefiore Medical Center - Moses Campus

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 25, 2006
• First Posted: October 26, 2006
• Study Start: November 22, 2006
• Primary Completion (Estimated): December 31, 2026
• Study Completion (Estimated): December 31, 2026
• Last Updated: April 13, 2026

Record last verified: 2026-02

Locations

US (7)