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A Phase I/II Study of Vorinostat [Suberoylanilide Hydroxamic Acid (SAHA)] in Combination With Azacitidine in Patients With the Myelodysplastic Syndrome (MDS)


Phase 1/Phase 2
18 Years
N/A
Not Enrolling
Both
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

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Trial Information

A Phase I/II Study of Vorinostat [Suberoylanilide Hydroxamic Acid (SAHA)] in Combination With Azacitidine in Patients With the Myelodysplastic Syndrome (MDS)


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.


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

Type of Study:

Interventional

Study Design:

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

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)

Outcome Description:

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

Outcome Time Frame:

Up to 1 month post-treatment

Safety Issue:

Yes

Principal Investigator

Lewis Silverman

Investigator Role:

Principal Investigator

Investigator Affiliation:

Montefiore Medical Center

Authority:

United States: Food and Drug Administration

Study ID:

NCI-2009-01050

NCT ID:

NCT00392353

Start Date:

November 2006

Completion Date:

Related Keywords:

  • 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
  • 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

Name

Location

Albert Einstein College of MedicineBronx, New York  10461
Weill Medical College of Cornell UniversityNew York, New York  10021
Mount Sinai Medical CenterNew York, New York  10029
Montefiore Medical CenterBronx, New York  10467-2490
University of Maryland Greenebaum Cancer CenterBaltimore, Maryland  21201