Azacitidine and Lenalidomide for Relapsed and Refractory Patients With Acute Myeloid Leukemia

Phase 2

Completed

Conditions: Acute Myeloid Leukemia

Interventions: Drug: Azacitidine
Drug: Lenalidomide
Other: Off Therapy

Registration Number: NCT01743859

Lead Sponsor: University of Colorado, Denver

Brief Summary: The primary objective of this study is to determine the complete remission/complete remission with incomplete recovery of blood counts (CR/CRi) rate for relapsed and refractory acute myeloid leukemia (AML) and high-risk myelodysplastic syndrome (MDS) patients.

Detailed Description: AML patients with relapsed and refractory disease have very poor outcomes. Sequential azacitidine and lenalidomide was recently shown by the PI of this study to be well-tolerated and effective in elderly, treatment naïve AML patients. Observations from this study and others that have piloted this combination have suggested that patients who received and failed prior treatments may also respond to this regimen. Therefore, the sequential combination of azacitidine with lenalidomide could potentially improve outcomes for relapsed and refractory AML patients by providing them with a treatment option that is tolerable and potentially clinically synergistic. To determine the efficacy of this combination in this population, we will pilot this phase 2 study.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 37

Inclusion Criteria

• World Health Organization (WHO)-confirmed AML, other than Acute Promyelocytic Leukemia (APL)
- Age >18 years
- White blood cell count (WBC) at initiation of treatment ≤ 10,000/L
  
  o If WBC is > 10,000/L patients may be started on an appropriate dose of hydroxyurea (to be determined by the investigators), until WBC < 10,000/L, at which time the hydroxyurea will be discontinued for 12 hours prior to enrollment
- Relapsed or refractory (resistant) disease, as defined by standard criteria21:
  - Relapsed: Bone marrow blasts ≥5%; reappearance of blasts in the blood; development of extramedullary disease
  - Refractory (resistant): Failure to achieve Complete Remission (CR) or complete remission with incomplete recovery of blood counts (CRi) in patients who survive ≥7 days following completion of initial treatment, with evidence of persistent leukemia by blood and/or bone marrow examination
- Failure of at least one prior therapy
- Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 (See Appendix D: ECOG Performance Status Scale)
- Life expectancy > 2 months
- All study participants must be registered into the mandatory RevAssist® program, and be willing and able to comply with the requirements of RevAssist® (RevAssist is a restricted distribution program for receiving lenalidomide)
- Females of childbearing potential (FCBP)† must have a negative serum or urine pregnancy test with a sensitivity of at least 50 million International Units per milliliter (mIU/mL) 10 - 14 days prior to study enrollment and again within 24 hours of prescribing lenalidomide (prescriptions must be filled within 7 days) and must either commit to 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 she starts taking lenalidomide. FCBP 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. See Appendix F: Risks of Fetal Exposure, Pregnancy Testing Guidelines and Acceptable Birth Control Methods
- 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

• Known or suspected hypersensitivity to azacitidine or mannitol
- Patients with advanced malignant hepatic tumors.
- Treatment less than four weeks prior to enrollment with other experimental therapies or antineoplastic agents, with the exception of hydroxyurea
- Inability to swallow or absorb drug
- Prior treatment with lenalidomide for AML
- 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
- Significant uncontrolled cardiac arrhythmias
- Uncontrolled psychiatric illness that would limit compliance with requirements
- Known Human immunodeficiency virus (HIV) infection
- Graft vs. host disease ≥ grade 2
- Relapse after allogeneic stem cell transplantation prior to post-transplant day 30
- Pregnant or breast feeding females; lactating females must agree not to breast feed 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:
  - Either creatinine >2.0 mg/dL or creatinine clearance <30 mL/min
  - Total bilirubin > 2 x institutional upper limit of normal (ULN) (unless documented Gilbert's syndrome)
  - Aspartate Aminotransferase (AST) and Alanine Aminotransferase (ALT) > 3 x institutional ULN

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Azacitidine + Lenalidomide + Off Therapy	Off Therapy	Patients will receive 7 days of azacitidine followed by 3 weeks of lenalidomide. They will then have 2 weeks off therapy, for a maximum of 12 cycles.
Azacitidine + Lenalidomide + Off Therapy	Azacitidine	Patients will receive 7 days of azacitidine followed by 3 weeks of lenalidomide. They will then have 2 weeks off therapy, for a maximum of 12 cycles.
Azacitidine + Lenalidomide + Off Therapy	Lenalidomide	Patients will receive 7 days of azacitidine followed by 3 weeks of lenalidomide. They will then have 2 weeks off therapy, for a maximum of 12 cycles.

Primary Outcome Measures

Name	Time	Method
Percentage of Participants With Complete Remission or Complete Remission With Incomplete Recovery Blood Counts	Interim assessment after 18 patients (estimated 2 years) and full assessment after 37 patients (estimated 3-4 years)	Change in baseline to end of study. To be assessed by standard criteria based on bone marrow examination. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR
Overall Response Rate	Planned assessment after enrollment of all 37 patients (estimated 3-4 years)	Change in baseline to end of study. To be assessed by standard criteria based on bone marrow examination

Secondary Outcome Measures

Name	Time	Method
Response or Remission Duration	Depending on outcomes, will initiate this assessment after 2 years and will continue until completion of study, estimated at 4 years	Change in baseline to end of study. To be assessed by standard criteria based on bone marrow examination
Toxicity and SAEs Related to Treatment	Will begin assessment with first patient and will continue until completion of study, estimated to be 4 years	Change in baseline to end of study. To be measured based on Common Terminology Criteria for Adverse Events (CTCAE) criteria
Overall Survival	Depending on outcomes, will begin assessment at 2 years and will continue until completion of study, estimated to be at four years	Change in baseline to end of study
Progression-free Survival	Depending on outcomes, will initiate this assessment after 2 years and will continue until completion of study, estimated at 4 years	Change in baseline to end of study. To be assessed by standard criteria based on bone marrow examination
Determine Biomarkers That Predict Response/Toxicity	Three years after initiating study	Change in baseline to end of study. Planned assessments of methylation changes and other biomarkers. Computational biology modeling used to identify biomarkers and predict response.