Phase 1-2 of Azacitidine + Lenalidomide for Previously Untreated Elderly Patients With Acute Myeloid Leukemia (AML)

Study Overview
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Brief Summary
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This study has a phase 1 and a phase 2 component. In phase 1, the objective is to determine the maximum tolerated dose (MTD) of lenalidomide when after azacitidine. In phase 2, the objective is to determine the efficacy of the combination treatment.

Detailed Description
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The treatment regimen in this study is 7 day courses of azacitidine 75 mg/m2 followed by a 21-day courses of lenalidomide. For the primary objective, each 28-day cycle was repeated for a total of up to 6 cycles. Study completion was defined as 18 cycles of treatment, disease progression, or death. In phase 1, the objective was to determine the maximum tolerated dose (MTD) of lenalidomide 5 mg, 10 mg, 25 mg or 50 mg, when administered after azacitidine. In phase 2, the objective was to assess the efficacy of MTD lenalidomide administered after azacitidine, in up to six 28-day cycles.

Official Title
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A Phase 1-2 Study of Azacitidine in Combination With Lenalidomide for Previously Untreated Elderly Patients With Acute Myeloid Leukemia

Conditions
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Acute Myeloid Leukemia (AML), Adult Acute Myeloblastic Leukemia

Intervention / Treatment
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* Drug: Lenalidomide
* Drug: Azacitidine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria WHO-confirmed acute myeloid leukemia (AML), except acute promyelocytic leukemia (APL) White blood cell count (WBC) at initiation of treatment ≤ 10,000 ◦If WBC is > 10,000 patients may be started on an appropriate dose of hydroxyurea (to be determined by the investigators), until WBC < 10,000, at which time the hydroxyurea will be discontinued for 24 hours prior to enrollment Age ≥ 60 years and not a candidate for allogeneic stem cell transplantation Unwilling or unable to receive conventional chemotherapy No prior therapy, except supportive care measures such as growth factor support, blood product transfusions, apheresis, or hydroxyurea ECOG performance status ≤ 2 Life expectancy > 2 months All study participants must be registered into the mandatory RevAssist® program, and must be willing and able to comply with the requirements of RevAssist If a female of childbearing potential (FCBP): Must have a negative serum or urine pregnancy test with a sensitivity of at least 50 mIU/mL within 10 to 14 days prior to study enrollment and again within 24 hours of prescribing lenalidomide (prescriptions must be filled within 7 days) Must commit to either continued abstinence from heterosexual intercourse or begin two acceptable methods of birth control, one highly effective method and one additional effective method at the same time, at least 28 days before starting lenalidomide. Must also agree to ongoing pregnancy testing. Male partners must use a latex condom during sexual contact, including if the male partners has previously had a successful vasectomy. Able to adhere to the study visit schedule and other protocol requirements Willing and able to understand and voluntarily sign a written informed consent Exclusion Criteria Relapsed or refractory disease Prior therapy with lenalidomide History of intolerance to thalidomide or development of erythema nodosum while taking thalidomide or similar drugs Known or suspected hypersensitivity to azacitidine or mannitol Advanced malignant hepatic tumors Concomitant treatment with other anti-neoplastic agents, except hydroxyurea Anti-neoplastic treatment less than four weeks prior to enrollment, except hydroxyurea Use of any other experimental drug or therapy within 28 days of baseline Inability to swallow or absorb drug Active opportunistic infection or treatment for opportunistic infection within four weeks of first day of study drug dosing New York Heart Association Class III or IV heart failure Unstable angina pectoris Uncontrolled cardiac arrhythmia Uncontrolled psychiatric illness that would limit compliance with requirements Known HIV infection If female: Pregnant Breast-feeding females, if they do not agree to not breastfeed while taking lenalidomide Other medical or psychiatric illness or organ dysfunction or laboratory abnormality which in the opinion of the investigator would compromise the patient's safety or interfere with data interpretation Laboratory abnormalities: Creatinine ≥ 1.5 mg/dL Creatinine clearance ≤ 50 mL/min Total bilirubin > 1.5 x institutional upper limit of normal (ULN), except documented Gilbert's syndrome AST > 2.5 x institutional ULN ALT > 2.5 x institutional ULN

Ages Eligible for Study
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Minimum Age: 60 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: Azacitidine followed by lenalidomide<br>Dose escalation then dose expansion | Drug: Lenalidomide<br>* 5 mg, 10 mg, 25 mg, and/or 50 mg of lenalidomide administered PO from day 8 to Day 28 of each cycle<br>* Other names: Revlimid;Drug: Azacitidine<br>* 75 mg/m2 Azacitidine administered intravenously (IV) or subcutaneously (SC) for days 1 to 7 of each cycle<br>* Other names: Vidaza;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Compete Remission (CR) Rate | Compete Remission (CR) includes subjects with CR but incomplete recovery of blood counts (CRi). CR was assessed according to the European LeukemiaNet (ELN) guidelines, and is defined as the absence of clonal lymphocytes in the peripheral blood. | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 4-week Survival Rate | Early death was assessed as death within 28 days of the start of treatment | 28 days | 
| Maximum Tolerated Dose (MTD) of Lenalidomide | The maximum tolerated dose (MTD) of lenalidomide was determined in study phase 1, for use in study Phase 2 (not conducted). The outcome is reported as the dose of lenalidomide that represents the MTD. | 15 months | 
| Remission Duration | Responses and remission were assessed according to the ELN guidelines. | 26 months | 
| Overall Response Rate (ORR) | ORR includes subjects with CR, CRi, and partial response (PR). Responses were assessed according to the ELN guidelines. | 26 months | 
| Overall Survival (OS) | OS from the start of treatment was assessed at a median follow up of 88 weeks from the end of treatment (range, 1-120), and was censored at 1 April 2012. | 88 weeks (median) | 
| Time to CR | CR includes subjects with CR but incomplete recovery of blood counts (CRi). Responses were assessed according to the ELN guidelines. | 18 weeks | 
| Time to PR | Responses were assessed according to the ELN guidelines. | 36 weeks | 
| OS of Responders | OS from the start of treatment of responders (per ELN guidelines) was assessed at a median follow up of 88 weeks from the end of treatment (range, 1-120), and was censored at 1 April 2012. | 88 weeks (median) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Acute myeloid leukemia, Acute myeloblastic leukemia, AML