Lenalidomide and Azacitidine in Treating Patients With Advanced Myelodysplastic Syndromes

Study Overview
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Brief Summary
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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
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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.

Official Title
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A Phase I/II Study of Revlimid (Lenalidomide) in Combination With Vidaza (Azacitidine) in Patients With Advanced Myelodysplastic Syndrome (MDS)

Conditions
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Leukemia, Myelodysplastic Syndromes

Intervention / Treatment
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* Drug: azacitidine
* Drug: lenalidomide


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 120 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Lenalidomide and Azacitidine<br> | Drug: azacitidine<br>* 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.<br>* Other names: Vidaza®;Drug: lenalidomide<br>* Oral lenalidomide once daily on days 1-14 or days 1-21.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.<br>* Other names: Revlimid®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PHASE I: Maximum Tolerated Dose of Azacitidine | Participants will be enrolled on the Phase I study portion in blocks of 3 to varying doses of Revlimid® (lenalidomide) and Vidaza® (azacitidine) (Table 1). To determine the MTD, a standard 3+3 design will be used. DLT will be assessed during the first cycle of therapy within each treatment group. No Maximum dose was reach but the go-forward dose agreed upon by the investigators is reported here. | After 1 courses (1 months) | 
| PHASE II: Determine the Number of Patients With Responses for Efficacy(Measured as Response Rate) | For the Phase II study portion, to determine the efficacy (measured as response rate) of the combination therapy as defined by the International Working Group (IWG) criteria (CR, complete remission; PR, partial remission; or HI, hematological improvement. Complete response (CR) is defined as: Disappearance of the chromosomal abnormality without appearance of new ones. Partial response (PR) is defined as: At least 50% reduction of the chromosomal abnormality. Hematologic Improvement (HI) is defined as: red blood cell increase of >=1.5g/dL, a platelet response of >=30X10^9/L or by at least 100% for values starting <20X10^9/L, or a neutrophil response of at least 100% and absolute increase of >0.5X10^9/L | After 4 courses (4 months) | 
| PHASE II: Determine the Number of Patients With Responses for Efficacy(Measured as Response Rate) | For the Phase II study portion, to determine the efficacy (measured as response rate) of the combination therapy as defined by the International Working Group (IWG) criteria (CR, complete remission; PR, partial remission; or HI, hematological improvement) Complete response (CR) is defined as: Disappearance of the chromosomal abnormality without appearance of new ones. Partial response (PR) is defined as: At least 50% reduction of the chromosomal abnormality. Hematologic Improvement (HI) is defined as: red blood cell increase of >=1.5g/dL, a platelet response of >=30X10^9/L or by at least 100% for values starting <20X10^9/L, or a neutrophil response of at least 100% and absolute increase of >0.5X10^9/L | After 7 courses (months) | 
| PHASE I: Maximum Tolerated Dose of Lenalidomide | Participants will be enrolled on the Phase I study portion in blocks of 3 to varying doses of Revlimid® (lenalidomide) and Vidaza® (azacitidine) (Table 1). To determine the MTD, a standard 3+3 design will be used. DLT will be assessed during the first cycle of therapy within each treatment group. No Maximum dose was reach but the go-forward dose agreed upon by the investigators is reported here. | After 1 courses (1 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Transformation to Acute Myeloid Leukemia or Death | Time (in months) patients took to evolve to myeloid leukemia or death after achieving a complete response using the RECIST criteria | After 7 months of treatment, until the date of first documented myeloid leukemia or death, whichever came first, assessed up to 55 months | 
| Time to Relapse After Achieving Complete Response |  | After 7 months of treatment, until the date of first documented myeloid leukemia or death, whichever came first, assessed up to 55 months | 
| Number of Patients That Experience Grade 3 or 4 Treatment Related Non-hematologic Adverse Events |  | After 7 months | 
| Overall Survival Among Patients With Complete Response | Time (in months) patients who achieved a complete response using the RECIST criteria were alive on study | After 7 months of treatment, until the date of first documented myeloid leukemia or death, whichever came first, assessed up to 55 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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refractory anemia with excess blasts, previously treated myelodysplastic syndromes, chronic myelomonocytic leukemia, de novo myelodysplastic syndromes, secondary myelodysplastic syndromes