Lenalidomide and Azacitidine in Treating Patients With Advanced Myelodysplastic Syndromes

Mikkael Sekeres MD

Status and phase

Completed

Phase 2

Phase 1

Conditions

Leukemia

Myelodysplastic Syndromes

Treatments

Drug: lenalidomide

Drug: azacitidine

Study type

Interventional

Funder types

Other

NIH

Identifiers

NCT00352001

UCLA-0511032-01

CASE17Z05 (Other Identifier)

UCLA-RDN-5405

P30CA016042 (U.S. NIH Grant/Contract)

UCLA-05011032-01

Details and patient eligibility

About

RATIONALE: Lenalidomide may stop the growth of cancer cells by blocking blood flow to the cancer. Lenalidomide may also stimulate the immune system in different ways and stop cancer cells from growing. Drugs used in chemotherapy, such as azacitidine, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Azacitidine may also cause cancer cells to look more like normal cells, and to grow and spread more slowly. Giving lenalidomide together with azacitidine may kill more cancer cells.

PURPOSE: This phase I trial is studying the side effects and best dose of lenalidomide and azacitidine in treating patients with advanced myelodysplastic syndromes.

Full description

OBJECTIVES:

Primary

Determine the maximum tolerated dose and dose-limiting toxicity of lenalidomide and azacitidine in patients with advanced myelodysplastic syndromes (MDS).

Secondary

Review clinical outcomes, as defined by the International Working Group criteria, in patients treated with this regimen.
Determine time to transformation to acute myeloid leukemia or death in patients treated with this regimen.
Determine time to relapse after achieving complete or partial remission in patients treated with this regimen.
Determine time to disease progression in patients treated with this regimen.
Determine the effect of this regimen on hematologic status (including peripheral blood counts and the need for platelet and/or red blood cell transfusions) in these patients.

OUTLINE: This is an open-label, multicenter, dose-escalation study.

Patients receive oral lenalidomide once daily on days 1-14 or days 1-21 and azacitidine subcutaneously once daily on days 1-5 or days 1-5 and 8-12. Treatment repeats every 28 days for up to 7 courses in the absence of relapse (after achieving complete or partial remission), disease progression, or unacceptable toxicity.

Cohorts of 3-6 patients receive escalating doses and/or increasing dosing frequencies of lenalidomide and azacitidine until the maximum tolerated dose (MTD) is determined or the sixth dose level is reached, whichever occurs first. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity during the first course of therapy.

After completion of study treatment, patients are followed annually.

Enrollment

37 patients

Sex

All

Ages

18 to 120 years old

Volunteers

No Healthy Volunteers

Inclusion and exclusion criteria

DISEASE CHARACTERISTICS:

Diagnosis of myelodysplastic syndromes (MDS) meeting one of the following criteria:
- French-American-British histological classification criteria
  - Refractory anemia with excess blasts (RAEB), defined as 5-19% myeloblasts in the bone marrow
    - Patients with 20% blasts are considered to have acute myeloid leukemia (per WHO classification system) and are therefore excluded in this study
  - Chronic myelomonocytic leukemia (CMML), defined as 10-19% myeloblasts in the bone marrow and/or 5-19% blasts in the blood
- WHO histological classification criteria
  - RAEB-1, defined as 5-9% myeloblasts in the bone marrow
  - RAEB-2, defined as 10-19% myeloblasts in the bone marrow and/or 5-19% blasts in the blood
  - CMML-2, defined as 10-19% myeloblasts in the bone marrow and/or 5-19% blasts in the blood
- International Prognostic Scoring System (IPSS) score of intermediate 2 (1.5-2.0 points based on karyotype, cytopenias, and bone marrow blast percentage) or high (≥ 2.5 points), in the setting of ≥ 5% myeloblasts
Considered ineligible for bone marrow transplantation as first-line therapy

PATIENT CHARACTERISTICS:

Life expectancy ≥ 3 months
ECOG performance status 0-2
Not pregnant or nursing
Negative pregnancy test
Fertile patients must use effective double-method contraception for 4 weeks before, during, and for 4 weeks after completion of study treatment
No serious medical condition, laboratory abnormality, or psychiatric illness that, in the opinion of the treating physician, would preclude study participation or preclude giving informed consent
No preexisting neurotoxicity or neuropathy ≥ grade 2
No rash or prior hypersensitivity or allergic reaction ≥ grade 3 to thalidomide
Creatinine ≤ 2.0 mg/dL
AST and ALT ≤ 2.0 times upper limit of normal
Bilirubin ≤ 2 mg/dL
Platelet count ≥ 50,000/mm^3
Absolute neutrophil count ≥ 500/mm^3
No other malignancy within the past 3 years except curatively treated carcinoma in situ of the cervix or nonmelanoma skin cancer
No history of thromboembolic event or other condition requiring use of anticoagulation with warfarin or low molecular-weight heparin
No known or suspected hypersensitivity to azacitidine or mannitol

PRIOR CONCURRENT THERAPY:

More than 28 days since prior and no other concurrent investigational agents for MDS
More than 28 days since prior approved therapy for MDS
More than 14 days since prior growth factors
More than 28 days since prior and no concurrent supraphysiologic doses (equivalent to > 10 mg/day of prednisone) of corticosteroids
More than 12 months since prior radiotherapy, chemotherapy, or cytotoxic therapy for treatment of conditions other than MDS
No prior lenalidomide or azacitidine
No prior stem cell or bone marrow transplantation
No concurrent androgens, epoetin alfa, or chemotherapy for MDS