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

Condition(s) targeted: Leukemia; Myelodysplastic Syndromes

Intervention: azacitidine (Drug); vorinostat (Drug)

Phase: Phase 1/Phase 2

Status: Recruiting

Sponsored by: New York Cancer Consortium

Official(s) and/or principal investigator(s):
Lewis R. Silverman, MD, Study Chair, Affiliation: Mount Sinai School of Medicine

RATIONALE: 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 or by stopping them from dividing. Giving vorinostat together with azacitidine may kill more cancer or abnormal cells.

PURPOSE: This phase I/II trial is studying the side effects and best dose of vorinostat and azacitidine in treating patients with myelodysplastic syndromes or acute myeloid leukemia.

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

Study design: Treatment, Open Label

Primary outcome:

Safety and tolerability of vorinostat (SAHA) in combination with azacitidine

Clinical efficacy

Effect of combination therapy on clinical and biologic response

Secondary outcome:

Time to response

Time to leukemic transformation

Frequency of leukemic transformation

Detailed description: OBJECTIVES:

Primary

- Determine safe doses of vorinostat (SAHA) and azacitidine in patients with

myelodysplastic syndromes (MDS) or acute myeloid leukemia. (Phase I)

- Determine the safety and toxicity of this regimen in these patients. (Phase I)

- Determine the response rate in patients with MDS treated with this regimen. (Phase II)

Secondary

- Determine time to response in patients with MDS treated with this regimen. (Phase II)

- Determine time to leukemic transformation in patients with MDS treated with this

regimen. (Phase II)

- Determine frequency of transformation to leukemia in patients with MDS treated with this

regimen. (Phase II)

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 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.

PROJECTED ACCRUAL: A total of 48 patients will be accrued for the phase I portion of this study. A total of 37 patients will be accrued for the phase II portion of this study.

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

Criteria:

DISEASE CHARACTERISTICS:

- 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 NOTE: *Patients with AML are eligible only for the phase I portion of the study

- MDS cannot be due to leukemic relapse

- No advanced hepatic tumors

- No CNS involvement

- No history of leukemia (phase II)

PATIENT CHARACTERISTICS:

- 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

PRIOR CONCURRENT THERAPY:

- See Disease Characteristics

- 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

- No other concurrent anticancer agents or therapies

Albert Einstein Cancer Center at Albert Einstein College of Medicine, Bronx, New York 10461, United States; Recruiting
Samir S. Parekh, MD, Phone: 718-920-4826, Email: sparekh@montefiore.org

Don Monti Comprehensive Cancer Center at North Shore University Hospital, Manhasset, New York 11030, United States; Recruiting
Clinical Trials Office - Don Monti Comprehensive Cancer Center, Phone: 516-734-8900

Mount Sinai Medical Center, New York, New York 10029, United States; Recruiting
Lewis R. Silverman, MD, Phone: 212-241-5520, Email: lewis.silverman@mssm.edu

New York Weill Cornell Cancer Center at Cornell University, New York, New York 10021, United States; Recruiting
Clinical Trials Office - New York Weill Cornell Cancer Center, Phone: 212-746-1848

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

Starting date: November 2006
Last updated: October 22, 2008