A Study of Lenalidomide in Pediatric Subjects With Relapsed or Refractory Acute Myeloid Leukemia

To determine the activity of lenalidomide in the treatment of pediatric subjects with relapsed/refractory acute myeloid leukemia (AML) (with second or greater relapse or refractory to at least 2 prior induction attempts) measured by morphological complete response defined as either a CR or CRi within the first 4 cycles of treatment.

This is a multicenter, open-label, single-arm, Phase 2, Simon's Optimal two-stage design study, with an Optional Extension Phase (OEP), that will assess the activity, safety and pharmacokinetics (PK) of lenalidomide in pediatric subjects from 1 to ≤ 18 years of age with second or greater Relapsed or Refractory Acute Myeloid Leukemia (rrAML). A total of 43 evaluable participants (18 participants in Stage 1 and an additional 25 participants in Stage 2) are required for assessment of the primary endpoint. To allow for participants found to be unevaluable for the primary endpoint due to an incorrect diagnosis, not having a disease assessment post screening, or who discontinued prior to receiving lenalidomide, up to 4 additional participants may be enrolled for a maximum of 47 evaluable subjects across approximately 70 sites. Approximately 50% of enrolled participants will be younger than 12 years of age to provide adequate PK data for this age subset.

If during Stage 1, at least 3 of 18 participants achieve a morphologic complete response (either CR or CRi) within the first 4 cycles of study treatment, then the study will proceed to Stage 2; otherwise, the study will be terminated. Similarly, if at the final analysis, at least 8 of 43 evaluable subjects across Stages 1 and 2 achieve a response (CR/CRi) within the first 4 cycles of study treatment, it will be concluded that lenalidomide has sufficient activity in pediatric Acute Myeloid Leukemia (AML) to warrant subsequent study. The optional extension phase (OEP) will allow participants who demonstrate clinical benefit, as assessed by the Investigator at the completion of 12 cycles of lenalidomide therapy, to continue receiving oral lenalidomide until they meet the criteria for study discontinuation. In the OEP, only safety, dosing, concomitant medications/procedures, and second primary malignancies (SPMs) will be monitored.

Eligibility Criteria:
Inclusion Criteria:

- Participants must satisfy the following criteria to be enrolled in the study:

1. Male or female is 1 to ≤ 18 years of age at the time of signing the Informed Consent Form / Informed Assent Form (ICF/IAF).
2. Participants (when applicable, parental/legal representative) must understand and voluntarily provide permission to the ICF/IAF prior to conducting any study-related assessments/procedures.
3. Participants have relapsed or refractory acute myeloid leukemia after at least 2 prior induction attempts:

   * Bone marrow aspirate or biopsy must have ≥ 5% blasts by morphology and/or flow cytometry.
   * Each block of chemotherapy is a separate reinduction attempt.
   * Donor lymphocyte infusion (DLI) is considered a reinduction attempt.
4. Participants are willing and able to adhere to the study visit schedule and other protocol requirements.
5. Participants have a Karnofsky score of ≥ 50% (participants ≥ 16 years of age) or a Lansky score ≥ 50% (participants \< 16 years of age).
6. Participants have a resting left ventricular ejection fraction (LVEF) of ≥ 40% obtained by echocardiography.
7. Participants have recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to first dose. All prior treatment-related toxicities must have resolved to ≤ Grade 2 prior to enrollment.
8. Regarding radiation therapy, time elapsed prior to first dose of lenalidomide:

   * 2 weeks for local palliative radiation therapy (XRT).
   * 8 weeks if prior craniospinal chemoradiation therapy (CRT) or if ≥ 50% radiation of pelvis.
   * 6 weeks if other bone marrow radiation has been administered.
9. Graft-versus-host disease criteria:

   * Participants must be at least 2 months (from first dose of lenalidomide) from stem cell infusion.
   * Participants must have no evidence of active acute or chronic GVHD (Grade 0) for 4 weeks prior to the first dose of lenalidomide.
   * If the participants have a history of maximum Grade 1 or 2 GVHD that was treated with systemic steroid (≥ 0.5 mg/kg/day prednisone equivalents) or other non-steroid systemic IST, the participant must be off all IST for at least 2 weeks, and must have ceased treatment doses of steroids for GVHD (≥ 0.5 mg/kg/day prednisone equivalents) for at least 4 weeks.

     * If the participants have a history of Grade 3 or greater GVHD, the participants must be off all systemic IST for 4 weeks
     * Topical therapy is permitted and does not imply the participants have active acute or chronic GVHD.
   * Physiologic dosing of hydrocortisone is permitted.
10. At least 4 weeks (from first dose) elapsed from donor lymphocyte infusion (DLI) without conditioning.
11. Participants have adequate renal function, which is defined as:

    - Creatinine clearance calculated using the Schwartz formula, or radioisotope glomerular filtration rate (GFR) \> 70 mL/min/1.73 m2.
12. Participants have adequate liver function, which is defined as:

    * Total bilirubin is ≤ 2 mg/dL unless the increase in bilirubin is attributable to Gilbert's Syndrome
    * Aspartate aminotransferase (AST) is ≤ 3.0 x upper normal limit (ULN) for age. For the purpose of this study, the ULN for AST is 50 U/L.
    * Alanine transaminase (ALT) is ≤ 3.0 x upper normal limit (ULN) for age. For the purpose of this study, the ULN for ALT is 45 U/L.
13. Female Children of Childbearing Potential (FCCBP), Female of Childbearing Potential (FCBP) and male participants that have reached puberty must agree to undergo physician-approved reproductive education and discuss the side effects of the study therapy on reproduction with parent(s) and/or guardian(s).
14. All participants and/or parents/guardians must have an understanding that lenalidomide could have a potential teratogenic risk. Female children of childbearing potential, is defined as females who have achieved menarche and/or breast development in Tanner Stage 2 or greater and have not undergone a hysterectomy or bilateral oophorectomy and FCBP defined as a sexually mature woman who has not undergone a hysterectomy or bilateral oophorectomy and has not been naturally postmenopausal for at least 24 consecutive months (ie, has had menses at any time in the preceding 24 consecutive months) must meet the following conditions below (Note: Amenorrhea following cancer therapy does not rule out childbearing potential):

    * Medically supervised serum pregnancy tests with a sensitivity of at least 25 mIU/mL must be conducted in FCCBP/FCBP, including those who commit to complete abstinence\*. FCCBP/FCBP must have two pregnancy tests (with a minimum sensitivity of 25 mIU/mL) prior to starting treatment with lenalidomide. The first pregnancy test must be performed within 10 - 14 days prior to the start of lenalidomide treatment and the second pregnancy test must be performed within 24 hours prior to starting treatment with lenalidomide.

NOTE: The pregnancy test 10 to 14 days prior to initiation of lenalidomide may be omitted, at the discretion of the investigator, for any FCCBP/FCBP who has high acuity disease requiring immediate treatment with lenalidomide. The pregnancy test within 24 hours prior to the first dose of lenalidomide is required to be performed.

The participants may not received Investigational Product (IP) until the investigator has verified that the results of these pregnancy tests performed on Cycle 1 Day 1 are negative. FCCBP/FCBP with regular or no menstrual cycles must agree to have pregnancy tests weekly for the first 28 days of study participation and then every 28 days while on study, at study Treatment Discontinuation Visit, and at Day 28 following IP discontinuation. If menstrual cycles are irregular, the pregnancy testing must occur weekly for the first 28 days and then every 14 days while on study, at study Treatment Discontinuation Visit, and at Days 14 and 28 following IP discontinuation.

* Female participants must, as appropriate to age and at the discretion of the study Investigator, either commit to true abstinence\* from heterosexual contact (which must be reviewed on a monthly basis) and/or agree to the use of two reliable forms of approved and effective contraceptive methods simultaneously. The two methods of reliable contraception must include one highly effective method and one additional effective (barrier) method (oral, injectable, or implantable hormonal contraceptive; tubal ligation; intra-uterine device; barrier contraceptive with spermicide; or vasectomized partner) without interruption, 28 days prior to starting lenalidomide treatment, throughout the entire duration of study treatment including dose interruptions and 28 days after the end of study treatment.
* All male and female participants must follow all requirements defined in the Pregnancy Prevention Program.

  16. Male participants, as appropriate to age and the discretion of the study physician:
* Must practice true abstinence\* or agree to use a condom during sexual contact with a pregnant female or a female of childbearing potential while participating in the study, during dose interruptions and for at least 28 days following lenalidomide discontinuation, even if he has undergone a successful vasectomy or practices complete abstinence.

Exclusion Criteria:

1. Participants have Down syndrome.
2. Participants have French-American-British classification (FAB) type M3 leukemia (acute promyelocytic leukemia) or identification of t(15;17).
3. Participants have isolated central nervous system (CNS) involvement or extramedullary relapse. (Participants with combined CNS/marrow relapse may be enrolled).
4. Participants had prior treatment with cytotoxic chemotherapy within 2 weeks of the first dose of lenalidomide with the exception of hydroxyurea (allowed prior to the first dose of lenalidomide and through Day 14 of Cycle 1) and intrathecal (IT) cytarabine will be administered within 2 weeks prior to administration of lenalidomide.
5. Participants have had prior treatment with biologic antineoplastic agents less than 7 days before the first dose of lenalidomide. For agents that have known adverse events (AEs) occurring beyond 7 days after administration (ie, monoclonal antibodies), this period must be extended beyond the time during which acute AEs are known to occur.
6. Participants have had prior treatment with lenalidomide.
7. Participant is pregnant or lactating.
8. Participants have an uncontrolled systemic fungal, bacterial, or viral infection (defined as ongoing signs/symptoms related to the infection without improvement despite appropriate antibiotics, antiviral therapy, and/or other treatment).
9. Participants has known Human Immunodeficiency Virus (HIV) positivity (participants who are receiving antiretroviral therapy for HIV disease).
10. Participants have a prior history of malignancies other than AML unless the subject has been free of the disease for ≥ 5 years from first dose of lenalidomide.
11. The presence of any of the following will exclude a participant from enrollment:

    * Participants have any significant medical condition, laboratory abnormality, or psychiatric illness that would prevent the participant from participating in the study.
    * Participants have any condition including the presence of laboratory abnormalities, which places the participant at unacceptable risk if he/she were to participate in the study.
    * Participants have any condition that confounds the ability to interpret data from the study.
12. Participants have cardiac disorders (Common Terminology Criteria for Adverse Events \[CTCAE\] version 4.03 Grade 3 or 4).
13. Participants have a history of well-documented prior veno-occlusive disease (VOD).
14. Participants have any other organ dysfunction (CTCAE version 4.03 Grade 4) that will interfere with the administration of the therapy according to this protocol.