Clinical trial NCT00352001: Lenalidomide and Azacitidine in Treating Patients With Advanced Myelodysplastic Syndromes
Official title: A Phase I/II Study of Revlimid (Lenalidomide) in Combination With Vidaza (Azacitidine) in Patients With Advanced Myelodysplastic Syndrome (MDS)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Leukemia
Myelodysplastic Syndromes
Keywords: refractory anemia with excess blasts
previously treated myelodysplastic syndromes
chronic myelomonocytic leukemia
de novo myelodysplastic syndromes
secondary myelodysplastic syndromes
Lead sponsor: Case Comprehensive Cancer Center
Sponsor class: OTHER
Collaborators: name: National Cancer Institute (NCI)
First posted: 2006-07-14
Enrollment: 37
Sex: ALL
Minimum age (years): 18
Maximum age (years): 120
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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.

Detailed 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.

Eligibility 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

Primary outcomes:
measure: PHASE I: Maximum Tolerated Dose of Azacitidine
timeFrame: After 1 courses (1 months)
measure: PHASE II: Determine the Number of Patients With Responses for Efficacy(Measured as Response Rate)
timeFrame: After 4 courses (4 months)
measure: PHASE II: Determine the Number of Patients With Responses for Efficacy(Measured as Response Rate)
timeFrame: After 7 courses (months)
measure: PHASE I: Maximum Tolerated Dose of Lenalidomide
timeFrame: After 1 courses (1 months)
Secondary outcomes:
measure: Time to Transformation to Acute Myeloid Leukemia or Death
timeFrame: After 7 months of treatment, until the date of first documented myeloid leukemia or death, whichever came first, assessed up to 55 months
measure: Time to Relapse After Achieving Complete Response
timeFrame: After 7 months of treatment, until the date of first documented myeloid leukemia or death, whichever came first, assessed up to 55 months
measure: Number of Patients That Experience Grade 3 or 4 Treatment Related Non-hematologic Adverse Events
timeFrame: After 7 months
measure: Overall Survival Among Patients With Complete Response
timeFrame: After 7 months of treatment, until the date of first documented myeloid leukemia or death, whichever came first, assessed up to 55 months
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: University of California at Los Angeles
state: California
city: Tampa
country: United States
facility: H. Lee Moffitt Cancer Center and Research Institute at University of South Florida
state: Florida
city: Cleveland
country: United States
facility: Cleveland Clinic Taussig Cancer Instititute, Case Comprehensive Cancer Center
state: Ohio
Study officials:
affiliation: The Cleveland Clinic
name: Mikkael A. Sekeres, MD, MS
role: STUDY_CHAIR
References:
citation: Sekeres MA, Tiu RV, Komrokji R, Lancet J, Advani AS, Afable M, Englehaupt R, Juersivich J, Cuthbertson D, Paleveda J, Tabarroki A, Visconte V, Makishima H, Jerez A, Paquette R, List AF, Maciejewski JP. Phase 2 study of the lenalidomide and azacitidine combination in patients with higher-risk myelodysplastic syndromes. Blood. 2012 Dec 13;120(25):4945-51. doi: 10.1182/blood-2012-06-434639. Epub 2012 Aug 22.