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A Phase 1 Study of Suberoylanilide Hydroxamic Acid (Vorinostat, SAHA) in Combination With Idarubicin in Relapsed or Refractory Leukemia


Phase 1
18 Years
N/A
Not Enrolling
Both
Acute Myeloid Leukemia With Multilineage Dysplasia Following Myelodysplastic Syndrome, 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 Promyelocytic Leukemia (M3), Blastic Phase Chronic Myelogenous Leukemia, Myelodysplastic/Myeloproliferative Neoplasm, Unclassifiable, Previously Treated Myelodysplastic Syndromes, Recurrent Adult Acute Lymphoblastic Leukemia, Recurrent Adult Acute Myeloid Leukemia, Relapsing Chronic Myelogenous Leukemia, Secondary Acute Myeloid Leukemia, Secondary Myelodysplastic Syndromes

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Trial Information

A Phase 1 Study of Suberoylanilide Hydroxamic Acid (Vorinostat, SAHA) in Combination With Idarubicin in Relapsed or Refractory Leukemia


OBJECTIVES:

I. Determine the maximum tolerated dose and dose-limiting toxicities of vorinostat (SAHA) in
combination with standard-dose idarubicin in patients with relapsed or refractory acute
myeloid leukemia, acute lymphocytic leukemia, myelodysplastic syndromes, acute promyelocytic
leukemia, or chronic myelogenous leukemia in blastic phase.

II. Describe the clinical activity of this regimen in these patients. III. Determine the in
vivo molecular effects of this regimen, including the effects on DNA topoisomerase IIα mRNA
expression and on the induction of γH2AX, histone H3 and H4 acetylation, as well as changes
in the gene expression profile.

IV. Determine the pharmacokinetic characteristics of this regimen in these patients.

OUTLINE:

This is a randomized, dose-escalation study of vorinostat (SAHA). Patients are randomized to
1 of 2 treatment arms.

ARM I: Patients receive oral SAHA three times daily on days 1-14 and idarubicin IV over 15
minutes once daily on days 1-3. Treatment repeats every 21 days for 6 courses in the absence
of disease progression or unacceptable toxicity.*

ARM II: Patients receive oral SAHA three times daily and idarubicin IV over 15 minutes once
daily on days 1-3. Treatment repeats every 21 days for 6 courses in the absence of disease
progression or unacceptable toxicity.*

Note: *Patients completing 6 courses of therapy or who reach the maximum cumulative dose of
idarubicin or an equivalent anthracycline and achieve clinical benefit may continue
treatment with SAHA alone 3 times daily on days 1-14 of each course, in the absence of
disease progression or unacceptable toxicity.

Cohorts of 3-6 patients receive escalating doses of SAHA until the maximum tolerated dose
(MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6
patients experience a dose-limiting toxicity. An additional 10 patients are treated at the
MTD.

Patients undergo blood collection and bone marrow biopsies periodically during the study for
pharmacologic, biomarker, and genetic studies.

After completion of study treatment, patients are followed at 4 weeks and then periodically
thereafter.


Inclusion Criteria:



- Patients must have histologically or cytologically confirmed relapsed/refractory
acute myelogenous leukemia, acute lymphocytic leukemia, myelodysplastic syndrome or
blastic phase chronic myelogenous leukemia.

- Patients that have received cumulative doses (or its equivalent to other
anthracycline) of more than 290 mg/m^2 of idarubicin will be excluded from the study.
No other limitations in terms of number of prior therapies or type of therapies apply
to this study.

- ECOG performance status (PS) 0-2 OR Karnofsky PS 60-100%

- Total bilirubin ≤ 2 mg/dL

- AST and ALT ≤ 2.5 times upper limit of normal

- Creatinine ≤ 2 mg/dL

- LVEF ≥ 50%

- Not nursing or pregnant

- Negative pregnancy test

- Fertile patients must use effective contraception

- At least 2 weeks since prior chemotherapy and recovered, unless there is evidence of
rapidly progressive disease, at least 24 hours since prior hydroxyurea for rapidly
proliferating disease

- At least 2 weeks since prior imatinib mesylate

- At least 2 weeks since prior histone deacetylase inhibitors, including valproic acid

- Maximum cumulative dose of prior idarubicin or equivalent anthracycline drug ≤ 290
mg/m2

- No concurrent epoetin alfa or hematopoietic colony-stimulating factors during the
first course of study therapy

- No concurrent prophylactic hematopoietic colony-stimulating factors

- Myelodysplastic syndromes requiring treatment, previously treated with either
azacytidine or decitabine, unless it was contraindicated; blastic phase chronic
myelogenous leukemia; failed prior imatinib mesylate-based therapy

- Patients with MDS should have received therapy with either 5-azacytidine or
5-aza-2'-deoxycytidine, unless the patient had a contraindication to such therapy,
and should require therapy.

- Ability to understand and the willingness to sign a written informed consent
document.

Exclusion Criteria:

- Patients with clinical evidence of CNS disease should be excluded from this clinical
trial because of their poor prognosis and because they often develop progressive
neurologic dysfunction that would confound the evaluation of neurologic and other
adverse events.

- No unstable angina pectoris

- Considered ineligible for or refused potentially curative therapy, including
allogeneic stem cell transplantation, with or without standard induction therapy

- No history of allergic reaction attributed to compounds of similar chemical or
biological composition to vorinostat (SAHA) or other agents used in this study

- No ongoing or active infection

- No symptomatic congestive heart failure

- No cardiac arrhythmia

- No other uncontrolled illness

- No psychiatric illness or social situation that would preclude study compliance

- No other concurrent investigational agents

- No other concurrent anticancer agents or therapies

- No concurrent combination antiretroviral therapy for HIV-positive patients

Type of Study:

Interventional

Study Design:

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Maximum-tolerated dose (MTD) of vorinostat determined by dose-limiting toxicities (DLT) as measured by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v.3.0

Outcome Time Frame:

21 days

Safety Issue:

Yes

Principal Investigator

Guillermo Garcia-Manero

Investigator Role:

Principal Investigator

Investigator Affiliation:

M.D. Anderson Cancer Center

Authority:

United States: Food and Drug Administration

Study ID:

NCI-2009-00094

NCT ID:

NCT00331513

Start Date:

March 2006

Completion Date:

Related Keywords:

  • Acute Myeloid Leukemia With Multilineage Dysplasia Following Myelodysplastic Syndrome
  • 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 Promyelocytic Leukemia (M3)
  • Blastic Phase Chronic Myelogenous Leukemia
  • Myelodysplastic/Myeloproliferative Neoplasm, Unclassifiable
  • Previously Treated Myelodysplastic Syndromes
  • Recurrent Adult Acute Lymphoblastic Leukemia
  • Recurrent Adult Acute Myeloid Leukemia
  • Relapsing Chronic Myelogenous Leukemia
  • Secondary Acute Myeloid Leukemia
  • Secondary Myelodysplastic Syndromes
  • Congenital Abnormalities
  • Blast Crisis
  • Neoplasms
  • Leukemia
  • Leukemia, Lymphoid
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma
  • Leukemia, Myeloid, Acute
  • Leukemia, Myeloid
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive
  • Leukemia, Promyelocytic, Acute
  • Myelodysplastic Syndromes
  • Preleukemia
  • Myeloproliferative Disorders
  • Myelodysplastic-Myeloproliferative Diseases

Name

Location

M D Anderson Cancer CenterHouston, Texas  77030