Vorinostat and Idarubicin in Treating Patients With Relapsed or Refractory Leukemia or Myelodysplastic Syndromes - Full Text View

Sponsors and Collaborators:	M.D. Anderson Cancer Center National Cancer Institute (NCI)
Information provided by:	National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:	NCT00331513

Purpose

RATIONALE: Drugs used in chemotherapy, such as vorinostat and idarubicin, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Vorinostat may also stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving vorinostat together with idarubicin may kill more cancer cells.

PURPOSE: This randomized phase I trial is studying the side effects and best dose of vorinostat when given together with idarubicin in treating patients with relapsed or refractory leukemia or myelodysplastic syndromes.

Condition	Intervention	Phase
Leukemia Myelodysplastic Syndromes	Drug: idarubicin Drug: vorinostat Procedure: biopsy Procedure: gene expression profiling Procedure: laboratory biomarker analysis Procedure: pharmacological study	Phase I

MedlinePlus related topics: Cancer Leukemia, Adult Acute Leukemia, Adult Chronic

Drug Information available for: Idarubicin Idarubicin hydrochloride Suberoylanilide hydroxamic acid

U.S. FDA Resources

Study Type:	Interventional
Study Design:	Treatment, Randomized
Official Title:	A Phase I Study of Suberoylanilide Hydroxamic Acid (Vorinostat, SAHA) in Combination With Idarubicin in Relapsed or Refractory Leukemia

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

Primary Outcome Measures:

Maximum tolerated dose of vorinostat (SAHA) as measured by NCI CTCAE v.30 [ Designated as safety issue: Yes ]
Dose-limiting toxicities of vorinostat (SAHA) as measured by NCI CTCAE v.30 [ Designated as safety issue: Yes ]
Clinical activity [ Designated as safety issue: No ]
In vivo molecular effects on DNA topoisomerase IIα messenger ribonucleic acid (mRNA) expression as measured by real-time polymerase chain reaction assays [ Designated as safety issue: No ]
In vivo molecular effects on induction of γH2AX as measured by immunocytochemistry analysis of bone marrow aspirates at baseline and on days 14 and 21 in course 1 and by Western blot analysis at baseline and on days 0, 1, 3, 14, and 21 in course 1 [ Designated as safety issue: No ]
In vivo molecular effects on histone H3 and H4 acetylation as measured by Western blot analysis using peripheral blood mononuclear cells or by enzyme-linked immunosorbent assay (ELISA) at baseline and on days 0, 1, 3, 14, and 21 in course 1 [ Designated as safety issue: No ]
Changes in the gene expression profile as measured by microarrays or other standard methods [ Designated as safety issue: No ]
Pharmacokinetics [ Designated as safety issue: No ]

Estimated Enrollment:	40
Study Start Date:	March 2006
Estimated Primary Completion Date:	October 2007 (Final data collection date for primary outcome measure)

Detailed Description:

OBJECTIVES:

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.
Describe the clinical activity of this regimen in these patients.
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.
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.

PROJECTED ACCRUAL: A total of 40 patients will be accrued for this study.

Eligibility

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

Criteria

DISEASE CHARACTERISTICS:

Histologically or cytologically confirmed diagnosis of 1 of the following hematologic malignancies:
- Acute myeloid leukemia
  - Patients with acute promyelocytic leukemia should have received prior treatment with tretinoin and arsenic trioxide
- Acute lymphocytic leukemia
- 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
Relapsed or refractory disease
No known CNS disease
Considered ineligible for or refused potentially curative therapy, including allogeneic stem cell transplantation, with or without standard induction therapy

PATIENT CHARACTERISTICS:

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
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 unstable angina pectoris
No cardiac arrhythmia
No other uncontrolled illness
No psychiatric illness or social situation that would preclude study compliance

PRIOR CONCURRENT THERAPY:

See Disease Characteristics
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/m^2
No other concurrent investigational agents
No other concurrent anticancer agents or therapies
No concurrent combination antiretroviral therapy for HIV-positive patients
No concurrent epoetin alfa or hematopoietic colony-stimulating factors during the first course of study therapy
No concurrent prophylactic hematopoietic colony-stimulating factors

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00331513

Locations

United States, Texas
M. D. Anderson Cancer Center at University of Texas
Houston, Texas, United States, 77030-4009

Sponsors and Collaborators

M.D. Anderson Cancer Center

National Cancer Institute (NCI)

Investigators

Study Chair:

Guillermo Garcia-Manero, MD

M.D. Anderson Cancer Center

More Information

Clinical trial summary from the National Cancer Institute's PDQ® database This link exits the ClinicalTrials.gov site

Study ID Numbers:	CDR0000472062, MDA-2005-0031, NCI-6892
Study First Received:	May 30, 2006
Last Updated:	August 15, 2008
ClinicalTrials.gov Identifier:	NCT00331513
Health Authority:	United States: Food and Drug Administration

Keywords provided by National Cancer Institute (NCI):

recurrent adult acute myeloid leukemia
adult acute promyelocytic leukemia (M3)
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)

recurrent adult acute lymphoblastic leukemia
previously treated myelodysplastic syndromes
blastic phase chronic myelogenous leukemia
relapsing chronic myelogenous leukemia
secondary acute myeloid leukemia
secondary myelodysplastic syndromes
de novo myelodysplastic syndromes

Study placed in the following topic categories:

Blast Crisis
Leukemia, Lymphoid
Precancerous Conditions
Chronic myelogenous leukemia
Leukemia, Myeloid, Acute
Acute lymphoblastic leukemia, adult
Leukemia
Preleukemia
Leukemia, Promyelocytic, Acute
Neoplasm Metastasis
Acute myeloid leukemia, adult
Congenital Abnormalities
Acute myelocytic leukemia

Myelodysplastic syndromes
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Hematologic Diseases
Myelodysplastic Syndromes
Myelodysplasia
Vorinostat
Acute myelogenous leukemia
Acute promyelocytic leukemia
Leukemia, Myeloid
Recurrence
Idarubicin
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Bone Marrow Diseases

Additional relevant MeSH terms:

Anticarcinogenic Agents
Anti-Inflammatory Agents
Neoplasms by Histologic Type
Disease
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Physiological Effects of Drugs
Enzyme Inhibitors
Antibiotics, Antineoplastic
Protective Agents
Pharmacologic Actions

Neoplasms
Pathologic Processes
Analgesics, Non-Narcotic
Sensory System Agents
Syndrome
Therapeutic Uses
Anti-Inflammatory Agents, Non-Steroidal
Peripheral Nervous System Agents
Analgesics
Antirheumatic Agents
Central Nervous System Agents

ClinicalTrials.gov processed this record on January 15, 2009