A Study of Lenalidomide in Pediatric Subjects With Relapsed or Refractory Acute Myeloid Leukemia
Condition: Leukemia, Myeloid
MeSH terms: Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute
Intervention: Lenalidomide
Intervention description: Lenalidomide will be administered orally once daily for the first 21 days of every 28-day cycle. The starting dose will be 2 mg/kg/day with a maximum dose of 70 mg/day. Number of cycles: 12, or until evidence of progressive disease. Participants will also be discontinued if unresolved toxicities as described in the protocol occur, or if dose reductions are required and subject does not tolerate minimum dose level of 1mg/kg/day.
Intervention MeSH terms: Lenalidomide
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 17.0
Sex: All
Minimum age: 1 Year
Maximum age: 18 Years
Healthy volunteers: No
Keywords: Lenalidomide; Revlimid; Pediatric; Relapsed or Refractory; Acute Myeloid Leukemia; Leukemia

Summary:

      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.
    

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.