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

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.

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