Lack of efficacy - Inability to meet the primary response endpoint

The purpose of the trial is to study how the elderly patients who have previously undergone treatment for acute myeloid leukemia and high-rRisk myelodysplastic syndromes, respond to a combined treatment with azacitidine and lenalidomide.

This is an open label, single-center, and phase 2 study of the combination of azacitidine with lenalidomide in previously treated elderly patients with acute myeloid leukemia (AML) and/or high-risk myelodysplastic syndrome (MDS) who have failed prior therapy with either a demethylating agent and/or IMIDs. MDS includes Chronic Myeloid Leukemia (CML).

Participants patients will receive azacitidine on the first 7 days followed by lenalidomide. Disease assessments with bone marrow examinations will be performed and if a complete response (CR); Complete remission with incomplete count recovery (CRi); partial response (PR); or stable disease (SD) is documented after 6 total cycles, participants will continue treatment until evidence of disease progression, provided they are tolerating treatment. Participants who have progressive disease or relapsed disease after the 6th cycle will be taken off the study, and participants with excessive toxicity at any time will be taken off the study.

• CR = Less than 5% blasts with no Auer rods, absence of extramedullary disease, absolute neutrophil count (ANC) > 1000/µL, platelets > 100,000/µL, and independence of red cell transfusion)
• CR with incomplete recovery (CRi) = all criteria of a CR with the exception of a platelet count less than 100,000/µL or residual neutropenia (< 1000/µL).
• PR = Meeting all hematologic criteria for CR with an allowance for 5% to 25% bone marrow blasts or decrease of pretreatment bone marrow blast percentage by ≥ 50%.
• SD = Change in bone marrow aspirate blast count within 10% of baseline.
• PD = Progressive / relapsed disease defined as reappearance of blasts in the blood or bone marrow blasts ≥ 5%, and development of extramedullary disease.

Inclusion Criteria:

• acute myeloid leukemia (AML) (according to the WHO 2008 classification):

  • De novo
  • Secondary AML previously treated with demethylating agents for AML
  • Secondary AML previously treated with demethylating agents for MDS
  • Secondary AML previously treated with high dose lenalidomide for AML (≥ 25mg)

• High Risk MDS:

  • Del (5q)
  • Non-del (5q), previously-treated with lenalidomide.
  • Novo or secondary HR-MDS previously treated with demethylating agents

• White blood cell (WBC) ≤ 10,000

• Age ≥ 60

• Not an immediate candidate for allogeneic stem cell transplantation

• Unwilling or unable to receive conventional chemotherapy

• Prior therapy:

  • with single agent demethylator (5-Azacitidine or Decitabine)
  • with Lenalidomide

• Eastern Cooperative Oncology Group performance status ≤ 2

• Life expectancy > 2 months

• All study participants must be registered into the mandatory RevAssist program

• Willing and able to comply with the requirements of RevAssist

• Females of childbearing potential (FCBP)† must have a negative serum or urine pregnancy test 10-14 days prior to study enrollment and again within 24 hours of prescribing lenalidomide

  • Must commit to either continued abstinence from intercourse or begin two acceptable methods of birth control, at least 28 days before she starts taking lenalidomide.
  • Must also agree to ongoing pregnancy testing.

• Men must agree to use a latex condom during sexual contact with a FCBP even if they have had a successful vasectomy.

• Willing and able to understand and voluntarily sign a written informed consent

• Able to adhere to the study visit schedule and other protocol requirements

Exclusion Criteria:

• Patients with LR-MDS progressing to HR-MDS after low dose lenalidomide or 5-day azacitidine will not be eligible.

• History of intolerance to thalidomide

  -development of erythema nodosum while taking thalidomide or similar drugs

• Known or suspected hypersensitivity to azacitidine or mannitol

• Patients with advanced malignant hepatic tumors.

• Concomitant treatment with other anti-neoplastic agents, with the exception of hydroxyurea

• Previous participation on the VIREL study with the concomitant use of azacitidine plus lenalidomide.

• Anti-neoplastic treatment less than four weeks prior to enrollment, with the exception of 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

• Pregnant

• Breast feeding

• Lactating females must agree not to breast feed while taking lenalidomide

• Other medical or psychiatric illness or organ dysfunction or laboratory abnormality

• Laboratory abnormalities:

  • Either creatinine ≥ 1.5 mg / dL or creatinine clearance ≤ 50 mL / min
  • Total bilirubin >1.5 x institutional ULN
  • AST and ALT > 2.5 x institutional ULN

16 months