Vorinostat and Idarubicin in Treating Patients With Relapsed or Refractory Leukemia or Myelodysplastic Syndromes

Condition(s) targeted: Leukemia; Myelodysplastic Syndromes

Intervention: idarubicin (Drug); vorinostat (Drug); biopsy (Procedure); gene expression profiling (Procedure); laboratory biomarker analysis (Procedure); pharmacological study (Procedure)

Phase: Phase 1

Status: Recruiting

Sponsored by: M.D. Anderson Cancer Center

Official(s) and/or principal investigator(s):
Guillermo Garcia-Manero, MD, Study Chair, Affiliation: M.D. Anderson Cancer Center

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.

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

Study design: Treatment, Randomized

Primary outcome:

Maximum tolerated dose of vorinostat (SAHA) as measured by NCI CTCAE v.30

Dose-limiting toxicities of vorinostat (SAHA) as measured by NCI CTCAE v.30

Clinical activity

In vivo molecular effects on DNA topoisomerase IIα messenger ribonucleic acid (mRNA) expression as measured by real-time polymerase chain reaction assays

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

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

Changes in the gene expression profile as measured by microarrays or other standard methods

Pharmacokinetics

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.

Minimum age: 18 Years. Maximum age: N/A. Gender(s): Both.

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

M. D. Anderson Cancer Center at University of Texas, Houston, Texas 77030-4009, United States; Recruiting
Clinical Trials Office - M. D. Anderson Cancer Center at the U, Phone: 713-792-3245

Clinical trial summary from the National Cancer Institute's PDQ® database

Starting date: March 2006
Last updated: July 23, 2008