AAML1522 (CC-5013-AML-002), A Phase 2, Multicenter, Single-arm, Open-label Study to Evaluate the Activity, Safety and Pharmacokinetics of Lenalidomide (Revlimid(RegisteredTM)) in Pediatric Subjects 1 to <= 18 Years of Age with Relapsed or Refractory Acute Myeloid Leukemia
- Children’s Medical Center (Dallas, Plano, Southlake)
Tamra Slone, M.D.
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 PK of lenalidomide in pediatric subjects from 1 to [LessThanorequalTo] 18 years of age with second or greater rraML. a total of 43 evaluable subjects (18 subjects in Stage 1 and an additional 25 subjects in Stage 2) are required for assessment of the primary endpoint. To allow for subjects 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 subjects may be enrolled for a maximum of 47 evaluable subjects across approximately 75 sites.
approximately 50% of enrolled subjects 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 subjects 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 aML to warrant subsequent study.
Morphological response will be assessed using the modified aML international Working Group (iWG) criteria (Cheson, 2003) (appendix C of the protocol).
The optional extension Phase will allow subjects 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.
an external data monitoring committee (DMC) will evaluate safety and treatment activity data in an ongoing, periodic manner to assess benefit-to-risk considerations throughout the study. The function of the DMC is to monitor the safety and activity of the study treatment. after 4 subjects have completed at least 1 cycle of study treatment, the DMC will evaluate the safety data and provide a recommendation. The DMC will also provide recommendations about the continuation of the study from Stage 1 to Stage 2 (continue as planned, continue with modifications or stop treatment and/or enrollment) and advise on ways to improve quality. The study will consist of 3 phases: Screening Phase, Treatment Phase and Follow-up Phase.
Subjects 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 ICF/IAF.
2. Subject (when applicable, parental/legal representative) must understand and voluntarily
provide permission to the ICF/IAF prior to conducting any study-related
3. Subject has rrAML 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 (ie, ADE, MA) is a separate reinduction attempt.
* Donor lymphocyte infusion (DLI) is considered a reinduction attempt.
4. Subject is willing and able to adhere to the study visit schedule and other protocol requirements.
5. Subject has a Karnofsky score of >= 50% (subjects >= 16 years of age) or a Lansky score >=
50% (subjects < 16 years of age).
6. Subject has a resting left ventricular ejection fraction (LVEF) of >= 40% obtained by
7. Subject has 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
* 6 weeks if other bone marrow radiation has been administered.
9. Graft-versus-host disease criteria:
* Subject is at least 2 months (from first dose of lenalidomide) from stem cell infusion.
* Subject has no evidence of active acute or chronic GVHD (Grade 0) for 4 weeks prior
to the first dose of lenalidomide.
* Subject with a history of maximum Grade 1 or 2 GVHD must have no evidence of
active acute or chronic GVHD (Grade 0) for 4 weeks prior to the first dose of
* Subject has a history of maximum Grade 1 or 2 GVHD that was treated with systemic
steroid (>= 0.5mg/kg/day prednisone equivalents) or other non-steroid systemic IST,
must be off all IST for at least 2 weeks, and has ceased treatment doses of steroids for
GVHD (>= 0.5mg/kg/day prednisone equivalents) for at least 4 weeks. Topical and/or
prophylactic treatment is permitted. Subject must have no evidence of active acute or
chronic GVHD (Grade 0) for 4 weeks prior to the first dose of lenalidomide.
* Subject has a history of Grade 3 or greater GVHD and has been off systemic IST for
4 weeks with no evidence of GVHD for 4 weeks prior to the first dose of
lenalidomide. Prophylactic and/or topical IST is permitted.
* Physiologic dose of hydrocortisone is permitted.
10. At least 4 weeks (from first dose) elapsed from donor lymphocyte infusion (DLI) without
11. Subject has adequate renal function, which is defined as:
* Creatinine clearance calculated (Table 4) using the Schwartz formula, or radioisotope glomerular filtration rate (GFR) > 70 mL/min/1.73 m2.
12. Subject has adequate liver function, which is defined as:
* Total bilirubin is <= 2 mg/dL unless the increase in bilirubin is attributable to Gilbert[Single Quote]s
* AST/ALT is <= 3.0 x upper normal limit (ULN) for age
13. Female Children of Childbearing Potential, Female of Childbearing Potential and male
subjects 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 subjects and/or parents/guardians must have an understanding that lenalidomide could
have a potential teratogenic risk. Female Children of Childbearing Potential, 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 x 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. The subject may not receive 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 subjects 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 subjects must follow all requirements defined in the Pregnancy
15. Male subjects, 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