A Study Being Conducted at Multiple Locations to Compare Safety and Efficacy of Three Different Regimens; (1) High-Dose Lenalidomide; (2) Lenalidomide + Azacitidine; or (3) Azacitidine in Subjects ≥ 65 Years With Newly-Diagnosed Acute Myeloid Leukemia

Study Overview
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Brief Summary
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The study aim is to compare safety and efficacy of high-dose lenalidomide regimen, sequential azacitidine and lenalidomide and an azacitidine in persons ≥65 years with newly-diagnosed acute myeloid leukemia (AML).

Detailed Description
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On September 11, 2013, randomization into the continuous 50 mg lenalidomide only arm was temporarily suspended based on review of the data from the first 13 participants and a high rate of discontinuation (11/13 participants). The Data Monitoring Committee assessed the study data on September 20, 2013 and reported no safety concerns. The high rate of early discontinuation is inconsistent with the treatment duration required for testing the study primary endpoint of survival at one year. Consequently, Celgene has decided not to reopen the lenalidomide only arm.

Official Title
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A Phase 2, Multicenter, Randomized, Open-label, Parallel-group Study of a Lenalidomide (Revlimid®) Regimen or a Sequential Azacitidine (Vidaza®) Plus Lenalidomide (Revlimid®) Regimen Versus an Azacitidine (Vidaza®) Regimen for Therapy of Older Subjects With Newly Diagnosed Acute Myeloid Leukemia

Conditions
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Acute Myeloid Leukemia, Acute Myelogenous Leukemia

Intervention / Treatment
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* Drug: Azacitidine
* Drug: Lenalidomide
* Other: Best Supportive Care (BSC)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Newly diagnosed acute myeloid leukemia (AML), AML with antecedent hematologic disorder or therapy-related AML Male or female subjects aged ≥ 65 Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2 White blood cell (WBC) count ≤ 10 x 10⁹/L at screening Exclusion Criteria: Previous treatment with azacitidine, decitabine, cytarabine or lenalidomide Previous cytotoxic or biologic treatment of any kind for AML or prior use of targeted therapy agents. Suspected or proven acute promyelocytic leukemia Prior bone marrow or stem cell transplantation Candidate for allogeneic bone marrow or stem cell transplantation AML antecedent hematologic disorder such as chronic myelogenous leukemia or myeloproliferative neoplasms Presence of malignant disease within the previous 12 months with exceptions

Ages Eligible for Study
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Minimum Age: 65 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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Lenalidomide in combination with azacitidine<br>Repeated cycles of azacitidine 75 mg/m^2/day subcutaneous (SC) on Days 1-7 and lenalidomide 50 mg/day by mouth (PO) on Days 8-28 followed by a 14-day break plus best supportive care | Drug: Azacitidine<br>* Azacitidine at 75 mg/m^2/day subcutaneous on Days 1-7<br>* Other names: Vidaza;Drug: Lenalidomide<br>* Lenalidomide 50 mg PO daily x 28 days for the first 2 cycles then 25 mg PO daily x 28 days for the next 2 cycles followed by continuous 28-day cycles of lenalidomide 10 mg PO daily<br>* Other names: CC-5013;Other: Best Supportive Care (BSC)<br>* The use of BSC was considered as concomitant treatment and must be documented as concomitant medication. BSC includes, but is not limited to, treatment with Red Blood Celll (RBC) or whole blood transfusions, fresh frozen plasma transfusions, platelet transfusions, antibiotic or antifungal therapy, and nutritional support<br>|
| Experimental: Lenalidomide - single agent<br>Lenalidomide 50 mg PO daily for 28 days for the first 2 cycles and lenalidomide 25 mg daily for 28 days for the next 2 cycles followed by continuous 28-day cycles of lenalidomide 10 mg daily PO plus best supportive care | Drug: Lenalidomide<br>* Lenalidomide 50 mg PO daily x 28 days for the first 2 cycles then 25 mg PO daily x 28 days for the next 2 cycles followed by continuous 28-day cycles of lenalidomide 10 mg PO daily<br>* Other names: CC-5013;Other: Best Supportive Care (BSC)<br>* The use of BSC was considered as concomitant treatment and must be documented as concomitant medication. BSC includes, but is not limited to, treatment with Red Blood Celll (RBC) or whole blood transfusions, fresh frozen plasma transfusions, platelet transfusions, antibiotic or antifungal therapy, and nutritional support<br>|
| Experimental: Azacitidine-single agent<br>Repeated cycles of azacitidine 75mg/m^2/day subcutaneous on Days 1-7 followed by a 21-day break plus best supportive care | Drug: Azacitidine<br>* Azacitidine at 75 mg/m^2/day subcutaneous on Days 1-7<br>* Other names: Vidaza;Other: Best Supportive Care (BSC)<br>* The use of BSC was considered as concomitant treatment and must be documented as concomitant medication. BSC includes, but is not limited to, treatment with Red Blood Celll (RBC) or whole blood transfusions, fresh frozen plasma transfusions, platelet transfusions, antibiotic or antifungal therapy, and nutritional support<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Kaplan Meier Estimates for One Year Survival | One-year survival rate was defined as all deaths within one year from the date of randomization. All others censored at the at year 1 or date of discontinuation | Up to 24 months | 
| Overall Survival | Overall Survival reported at the end of the study are for those participants who were alive at the end of the study | From date of randomization until the date of the first documented date of progression or date of death of any cause; the overall median follow-up for survivng participants was 4.1 months (range 0.2 to 54.8 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With a Complete Response or Morphologic Incomplete Response. | Based on IWG response criteria for AML. Complete remission (CR), morphologic complete remission (CR) was defined as < 5% bone marrow blasts, an absolute neutrophil count ≥ 1 x 10^9/L, platelets ≥100 x 10^9/L, and transfusion independence (no transfusions for 1 week prior to each assessment). No duration of these findings is required for confirmation of this response. Morphologic CR with incomplete blood count recovery (CRi) was defined as a morphologic complete remission but the ANC count may be <1 x 10^9/L and/or the platelet count may be <100 x 10^9/L. Because of a high rate of discontinuation in one of the investigational cohorts, secondary endpoints were not analyzed. | Complete Response or Morphologic Incomplete Response data not analyzed. | 
| Duration of Remission (DoR) | Duration of remission was defined as the time from the date of CR or CRi until relapse. Because of a high rate of discontinuation in one of the investigational cohorts, secondary endpoints were not analyzed. | Duration of Remission (DoR) time frame not analyzed. | 
| Cytogenetic Complete Remission Rate (CRc) | The CRc response category is comprised of the subset of participants who had abnormal cytogenetics at baseline and subsequently achieved CR during treatment in conjunction with a reversion to a normal karyotype. For the primary definition of CRc, a normal karyotype is defined as no clonal abnormalities after review of at least 10 metaphases using conventional cytogenetic techniques. Cytogenetic complete remission rate (CRc) 1) CR criteria met AND 2) Abnormal karyotype present at baseline AND 3) Reversion to normal karyotype at time of CR (based on ≥ 10 metaphases), where date of cytogenetic sample = date of BM sample used for the CR assessment. Because of a high rate of discontinuation in one of the investigational cohorts, secondary endpoints were not analyzed. | Cytogenetic Complete Remission timeframe was not analyzed. | 
| Percentage of Participants With an Overall Response Rate (CR +CRi+ PR) | Morphologic complete remission (CR) is defined as a leukemia-free state defined as less than 5% blasts in a one marrow aspirate with spicules and with at least 200 nucleated cells (there should be no blasts with auer rods) and ANC of ≥ 1 x 10^9/L, a platelet count ≥ 100 x 10^9/L, no transfusions for 1 week prior to each assessment. No duration of these findings is required for confirmation of this response. Morphologic complete remission with incomplete blood count recovery was defined as a morphologic complete remission but the ANC may be < 1 x 10^9/L and/or the platelet count may be < 100 x 10^9/L. Partial remission was defined as an ANC > 1 x 10^9/L and platelet count ≥ 100 x 10^9/L with a > 50% decrease in the percentage of bone marrow blasts to 5% to 25% (a blast count value of ≤ 5% may also be considered a partial remission if auer rods are present). Because of a high rate of discontinuation in one of the investigational cohorts, secondary endpoints were not analyzed. | Overall response rate time frame was not analyzed. | 
| Progression-Free Survival (PFS) | PFS is defined as the time from randomization to the first observation of documented disease progression or death from any cause whichever occurred first. Because of a high rate of discontinuation in one of the investigational cohorts, secondary endpoints were not analyzed. | Progression-Free survival data and time frame was not analyzed. | 
| Event-Free Survival (EFS) | EFS was defined as the interval from the date of randomization to the date of treatment failure, progressive disease, relapse after CR or CRi, or death from any cause, whichever occurred first. Because of a high rate of discontinuation in one of the investigational cohorts, secondary endpoints were not analyzed. | Event-Free survival time was not analyzed. | 
| Relapse-Free Survival (RFS) | RFS is defined only for subjects that achieve CR and CRi and is measured as the interval from that date to the date of disease relapse, death from any cause, whichever occurs first, censoring at the last visit date for subjects alive in continuous CR/CRi. Because of a high rate of discontinuation in one of the investigational cohorts, secondary endpoints were not analyzed. | Relapse-Free survival time frame was not analyzed. | 
| Percentage of Participants With 30-Day Treatment-Related Mortality | 30-day mortality rate was defined as death from any cause within 30 days after first dose. | 30 days | 
| Number of Participants With Treatment Emergent Adverse Events (TEAE) | TEAEs were defined as those events that started on or after the first day of study drug up until 28 days after the last dose of study drug; Serious AE (SAE) = any AE which results in death; is life-threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability; is a congenital anomaly/birth defect; constitutes an important medical event. Severity of AEs were graded based upon the participants symptoms according to the Common Terminology Criteria for Adverse Events (CTCAE, Version 4.0); and according to the scale: Grade (Gr) 1 = Mild - transient or mild discomfort; no medical intervention required; Grade 2 = Moderate - mild to moderate limitation in activity; Grade 3 = Severe; Grade 4 = Life threatening; Grade 5 = Death | From the first dose of study drug up to 28 days after the last dose of study drug; up to 15 May 2018 | 
| Number of Participants With a Second Primary Malignancy | Second primary malignancies were monitored as events of interest and reported as serious adverse events regardless of the treatment arm the participant was enrolled in. | From randomization of the last participant up to a minimum of 4 years following discontinuation | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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AML, elderly, acute myelogenous leukemia, vidaza, azacitidine, elderly AML, revlimid, lenalidomide