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

• Sponsor: Celgene (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02538965
• Collaborator: (none)
• Enrollment: 17
• Locations: 62
• Arm: 1
• Actual Duration (Months): 37.7
• Patients Per Site: 0.3
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief 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.

Condition or Disease	Intervention/Treatment	Phase
Leukemia, Myeloid	Drug: Lenalidomide	Phase 2

Detailed Description

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 17 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 2, Multicenter, Single-arm, Open-label Study to Evaluate the Activity, Safety and Pharmacokinetics of Lenalidomide (Revlimid®) in Pediatric Subjects From 1 to = 18 Years of Age With Relapsed or Refractory Acute Myeloid Leukemia.
• Actual Study Start Date: Nov 19, 2015
• Actual Primary Completion Date: Jul 22, 2017
• Actual Study Completion Date: Jan 11, 2019

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Lenalidomide Lenalidomide API will administered at a starting dose of 2 mg/kg/day. Lenalidomide will be provided as either a capsule (2.5 mg, 5 mg, 10 mg, 15 mg, 20 mg or 25 mg) or as an oral suspension (10mg/mL).

Drug: Lenalidomide; 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.

Outcome Measures

Primary Outcome Measures

1. Number of Participants Who Achieved a Morphologic Complete Response Within the First Four Cycles of Lenalidomide Treatment According to the Modified International Working Group (IWG) Criteria [From day of the first dose of IP to end of cycle 4; Response was assessed at the completion of the 21-day treatment period of cycles 1, 2, 3, and 4 and at treatment discontinuation.]

   The morphological complete response rate was defined as the total number of participants with morphological CR observed within the first 4 cycles of lenalidomide (regardless of whether the CR/CRi was observed at the end of Cycle 1, 2, 3 or 4) over the total number of participants evaluable for this endpoint. According to Modified IWG criteria, morphologic CR was defined as: Absolute neutrophil count (ANC) ≥ 1000/μL and platelets ≥ 100,000 without transfusions and/or exogenous growth factor support (i.e., no transfusion or exogenous growth factor within 7 days of assessment; Bone marrow < 5% blasts evidence of trilineage hematopoiesis; No evidence of extramedullary disease. Morphologic CRi was defined as: ANC < 1000/μL and platelets < 100,000/μL or > 100,000/μL without platelet recovery (requiring transfusion within 7 days of assessment); BM with < 5% blasts and evidence of trilineage hematopoiesis; No evidence of extramedullary disease.

Secondary Outcome Measures

1. Number of Participants Who Achieved a Bone Marrow Confirmed CR/CRi Lasting 3 Months (Durable Response Rate) [From date of confirmed complete response observed until treatment failure or worse; up to data cut-off date of 31 December 2017]

   Durable response rate was defined as the percentage of participants who achieved a BM confirmed CR/CRi according to the Modified IWG Response Assessment Lasting 3 Months (from the time to complete response observed until treatment failure or worse) or until transplantation if earlier among all participants eligible for durable response rate analysis, provided the CR/CRi was confirmed in a bone marrow sample). Due to scarcity of relevant data, it was not practical or meaningful to analyze the durable response rate. Only 1 participant had a response and the participant was censored soon after, as the consent was withdrawn; unable to calculate duration of response.

2. Duration of Response [From date of first time of complete response observed until treatment failure or worse; up to data cut-off date of 31 December 2017]

   Duration of response was defined as the time from date of the first observed response (CR, CRi or PR) until morphologic relapse, molecular/cytogenetic relapse, or death only for participants who achieved a response. Due to scarcity of relevant data, it was not practical or meaningful to analyze the duration of response. Only 1 participant had a response and the participant was censored soon after, as the consent was withdrawn; unable to calculate duration of response.

3. Number of Participants Who Achieved a Best Response of Morphologic Complete Remission, Morphologic Complete Remission Incomplete or Partial Remission [Response was assessed at the completion of the 21-day treatment period of cycles 1, 2, 3.]

   Overall response rate was defined as the number of participants with best response of CR, CRi or PR. A CR was defined as: ANC ≥ 1000/μL and platelets ≥ 100,000 without transfusions and/or exogenous growth factor support (no transfusion or exogenous growth factor within 7 days of assessment); BM < 5% blasts evidence of trilineage hematopoiesis; No evidence of extramedullary disease. A CRi was defined as: ANC < 1000/μL and platelets < 100,000/μL or > 100,000/μL without platelet recovery (requiring transfusion within 7 days of assessment); BM with < 5% blasts and evidence of trilineage hematopoiesis; No evidence of extramedullary disease. A PR was defined as: ANC of ≥ 1000/μL and platelets ≥ 100,000 without transfusions and/or exogenous growth factor support (no transfusion or exogenous growth factor within 7 days of assessment); BM with 5% to 25% blasts and at least a 50% decrease in BM blast percent from baseline; No evidence of extramedullary disease.

4. Number of Participants With a Morphologic CR, CRi, PR or Treatment Failure at Cycles 1, 2 and 3 [Response was assessed at the completion of the 21-day treatment period of cycles 1, 2, 3.]

   Disease assessment outcome at the end of Cycles 1-3 based on Cheson criteria: Morphologic CR = ANC ≥ 1000/μL and platelet ≥ 100,000 without transfusions and/or exogenous growth factor support (no transfusion or exogenous growth factor within 7 days of assessment) BM < 5% blasts evidence of trilineage hematopoiesis No evidence of extramedullary disease Morphologic CRi = 1. ANC< 1000/μL and Platelets < 100,000/μL or > 100,000/μL without platelet recovery (requiring transfusion within 7 days of assessment) 2. BM with < 5% blasts and evidence of trilineage hematopoiesis 3. No evidence of extramedullary disease PR = ANC ≥ 1000/μL and platelets ≥ 100,000 without transfusions and/or exogenous growth factor support BM with < 5%-25% blasts and at least a 50% decrease in BM blast percent from baseline No evidence of extramedullary disease Treatment Failure = resistant disease; survival ≥ 7 days post-therapy; failed to achieve CR, CRi, or PR but stable with persistent AML

5. Number of Participants Who Received a Haematopoietic Stem Cell Transplant (HSCT) [From first dose of study drug up to 5 years post HSCT]

   The number of participants who had undergone a haematopoietic stem cell transplant was calculated over the total number of participants in the ITT population. Percentages were also calculated based on whether the transplantation was the first, second, or subsequent transplant post IP administration.

6. Number of Participants Who Experienced Treatment Emergent Adverse Events (TEAE) [From the first dose of study drug until 28 days after the last dose of study drug; up to data cut off date of 31 December 2017; maximum duration of treatment was 12 weeks]

   A TEAE was defined as any adverse event (AE) occurring or worsening on or after the first treatment of lenalidomide and within 28 days after the last dose. A serious AE = any AE which results in death; is life-threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect; constitutes an important medical event. The severity of AEs was graded based on National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), Version 4.3 and based on the following scale: Grade 1 = Mild Grade 2 = Moderate Grade 3 = Severe Grade 4 = Life threatening Grade 5 = Death.

7. Percentage of Participants With of Graft Versus Host Disease (GVHD) [From the first dose of study drug to 28 days after the last dose of study drug; up to data cut off date of 31 December 2017; maximum treatment was 12 weeks]

   Acute graft versus host disease generally occurs after allogeneic hematopoietic stem cell transplantation. It is a reaction of donor immune cells against host tissues. The 3 main tissues that acute GVHD affects are the skin, liver, and gastrointestinal tract. Chronic GVHD is scored per the National Institute of Health consensus conference grading system. Clinical manifestations of chronic GVHD include skin involvement resembling lichen planus or the cutaneous manifestations of scleroderma; dry oral mucosa with ulcerations and sclerosis of the gastrointestinal tract; and a rising serum bilirubin concentration.

8. Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration of Lenalidomide (AUC-t) [Pharmacokinetic (PK) sampling was conducted after lenalidomide administration at Cycle 1 and was weight dependent at these timepoints: 0.5, 1, 2, 4, 6, 8 and 24 hours. The 24 hour PK sample was taken prior to the lenalidomide dose on Day 2.]

   Area under the plasma concentration-time curve from time 0 to the time of the last quantifiable concentration, calculated by linear trapezoidal method when concentrations were increasing and the logarithmic trapezoidal method when concentrations were decreasing.

9. Area Under the Plasma Concentration Time Curve From 0 Extrapolated to Infinity (AUC-inf, AUC0∞) Of Lenalidomide [Pharmacokinetic sampling was conducted after lenalidomide administration at Cycle 1 and was weight dependent at these timepoints: 0.5, 1, 2, 4, 6, 8 and 24 hours. The 24 hour PK sample was taken prior to the lenalidomide dose on Day 2.]

   Area under the plasma concentration-time curve from time 0 extrapolated to infinity, calculated as [AUCt + Ct/ λz]. Ct is the last quantifiable concentration. No AUC extrapolation was performed with unreliable λz.

10. Maximum Observed Concentration (Cmax) of Lenalidomide [PK sampling was conducted after lenalidomide administration at Cycle 1 and was weight dependent at these timepoints: 0.5, 1, 2, 4, 6, 8 and 24 hours. The 24 hour PK sample was taken prior to the lenalidomide dose on Day 2.]

    Maximum observed plasma concentration, obtained directly from the observed concentration versus time data.

11. Time to Reach Maximum Concentration (Tmax) of Lenalidomide [Pk sampling was conducted after lenalidomide administration at Cycle 1 and was weight dependent at these timepoints: 0.5, 1, 2, 4, 6, 8 and 24 hours. The 24 hour PK sample was taken prior to the lenalidomide dose on Day 2.]

    Time to cmax was obtained directly from the observed concentration versus time data.

12. Terminal Half-Life (t1/2) of Lenalidomide [Pharmacokinetic sampling was conducted after lenalidomide administration at Cycle 1 and was weight dependent at these timepoints: 0.5, 1, 2, 4, 6, 8 and 24 hours. The 24 hour PK sample was taken prior to the lenalidomide dose on Day 2.]

    Terminal phase half-life in plasma, calculated as [(ln 2)/λz]. Terminal half-life was only calculated when a reliable estimate for λz could be obtained.

13. Apparent Total Clearance (CL/F) of Lenalidomide [Pharmacokinetic sampling was conducted after lenalidomide administration at Cycle 1 and was weight dependent at these timepoints: 0.5, 1, 2, 4, 6, 8 and 24 hours. The 24 hour PK sample was taken prior to the lenalidomide dose on Day 2.]

    Apparent volume of distribution, calculated as [(CL/F)/λz].

14. Apparent Volume of Distribution (Vz/F) of Lenalidomide [Pharmacokinetic sampling was conducted after lenalidomide administration at Cycle 1 and was weight dependent at these timepoints: 0.5, 1, 2, 4, 6, 8 and 24 hours. The 24 hour PK sample was taken prior to the lenalidomide dose on Day 2.]

    Apparent volume of distribution, calculated as [(CL/F)/λz].

15. Correlation of Peripheral White Blood Cell Count, Absolute Blast Count and Cytogenetics With Response to Lenalidomide [Not Performed]

    Correlation of peripheral white blood cell count, absolute blast count and cytogenetics with response to lenalidomide was not performed since only 1 participant met the primary efficacy endpoint of morphological CR/CRi, and due to scarcity of relevant data, it was not practical or meaningful to analyze to perform the analysis on blood counts and response to lenalidomide.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 1 Year to 18 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

1. Participants are willing and able to adhere to the study visit schedule and other protocol requirements.

2. Participants have a Karnofsky score of ≥ 50% (participants ≥ 16 years of age) or a Lansky score ≥ 50% (participants < 16 years of age).

3. Participants have a resting left ventricular ejection fraction (LVEF) of ≥ 40% obtained by echocardiography.

4. 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.

5. 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.

1. 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.

1. At least 4 weeks (from first dose) elapsed from donor lymphocyte infusion (DLI) without conditioning.

2. 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.

1. 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.

1. 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).

2. 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.

1. 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.

1. Participants have cardiac disorders (Common Terminology Criteria for Adverse Events [CTCAE] version 4.03 Grade 3 or 4).

2. Participants have a history of well-documented prior veno-occlusive disease (VOD).

3. 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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Children's Hospital	Birmingham	Alabama	United States	35294
2	Phoenix Childrens Hospital	Phoenix	Arizona	United States	85016
3	Arkansas Children's Hospital	Little Rock	Arkansas	United States	72202
4	Miller Children's Hospital	Long Beach	California	United States	90806
5	Children's Hospital of Los Angeles	Los Angeles	California	United States	90027
6	Southern California Permanente Medical Group	Los Angeles	California	United States	90027
7	Valley Children's Hospital	Madera	California	United States	93636
8	Children's Hospital of Orange County	Orange	California	United States	92868
9	Lucile Salter Packard Children's Hospital at Stanford	Palo Alto	California	United States	94304
10	Loma Linda University	San Bernardino	California	United States	92408
11	UCSF Children's Hospital	San Francisco	California	United States	94143
12	Colorado Children's Hospital	Aurora	Colorado	United States	80045
13	Connecticut Children's Medical Center	Hartford	Connecticut	United States	06106
14	Alfred I Dupont Hospital For Children	Wilmington	Delaware	United States	19803
15	Children's Hospital National Medical Center	Washington	District of Columbia	United States	20010-2970
16	Golisano Children's Hospital of Southwest Florida	Fort Myers	Florida	United States	33908
17	Nemours Children's Clinic	Jacksonville	Florida	United States	32207
18	All Children's Hospital	Saint Petersburg	Florida	United States	33701
19	Children's Healthcare of Atlanta	Atlanta	Georgia	United States	30322
20	Ann and Robert H Lurie Childrens Hospital of Chicago	Chicago	Illinois	United States	60611
21	Advocate Chilldren's Hospital	Oak Lawn	Illinois	United States	60453
22	Riley Hospital For Children at IU Health	Indianapolis	Indiana	United States	46202
23	Kosair Children's Hospital	Louisville	Kentucky	United States	40202
24	Children's Hospital New Orleans	New Orleans	Louisiana	United States	70118
25	Johns Hopkins University	Baltimore	Maryland	United States	21287
26	University of Michigan	Ann Arbor	Michigan	United States	48109
27	Children's Hospitals and Clinics of Minnesota	Minneapolis	Minnesota	United States	55404
28	University of Minnesota	Minneapolis	Minnesota	United States	55455
29	University of Mississippi Medical Center	Jackson	Mississippi	United States	39216
30	Children's Mercy Hospital	Kansas City	Missouri	United States	64108
31	Washington University School of Medicine	Saint Louis	Missouri	United States	63110
32	Children's Specialty Center of Nevada	Las Vegas	Nevada	United States	89109
33	Hackensack University Medical Center	Hackensack	New Jersey	United States	07601
34	Morristown Memorial Hosp	Morristown	New Jersey	United States	07962
35	Cancer Institute of New Jersey	New Brunswick	New Jersey	United States	08903
36	Roswell Park Cancer Inst	Buffalo	New York	United States	14263
37	Columbia University Medical Center	New York	New York	United States	10032
38	University of Rochester Medical Center	Rochester	New York	United States	14642
39	New York Medical College	Valhalla	New York	United States	10595
40	University of North Carolina	Chapel Hill	North Carolina	United States	27599
41	Cincinnati Children's Hospital Medical Center	Cincinnati	Ohio	United States	45229
42	Nationwide Children's Hospital	Columbus	Ohio	United States	43205
43	Legacy Emanuel Hospital and Health Center	Portland	Oregon	United States	97227
44	Penn State Milton S Hershey Medical Center	Hershey	Pennsylvania	United States	17033
45	UPMC Childrens Hospital of Pittsburgh	Pittsburgh	Pennsylvania	United States	15224
46	Carolinas Healthcare System	Charleston	South Carolina	United States	28203
47	Greenville Health System	Greenville	South Carolina	United States	29605
48	Vanderbilt University Medical Center	Nashville	Tennessee	United States	37212
49	Dell Children's Medical Center of Central Texas	Austin	Texas	United States	78723
50	University of Texas Southwestern Medical Center	Dallas	Texas	United States	75235
51	Texas Children's Cancer Center	Houston	Texas	United States	77030
52	Methodist Hospital	San Antonio	Texas	United States	78229
53	Primary Children's Medical Center	Salt Lake City	Utah	United States	84113
54	Children's Hospital of The King's Daughters	Norfolk	Virginia	United States	23507
55	Seattle Children's Hospital	Seattle	Washington	United States	98105
56	Midwest Children's Cancer Center	Milwaukee	Wisconsin	United States	53226
57	Alberta Childrens Hospital	Calgary	Alberta	Canada	T3B 6A8
58	British Columbia Children's Hospital	Vancouver	British Columbia	Canada	V6H3V4
59	IWK Health Center	Halifax	Nova Scotia	Canada	B3K 6R8
60	Childrens Hospital of Eastern Ontario	Ottawa	Ontario	Canada	K1H 8L1
61	McGill University Health Center	Montreal	Quebec	Canada	H4A 3J1
62	Hospital For Sick Children	Torento		Canada	M5G 1X8

Sponsors and Collaborators

• Celgene

Investigators

• Study Director: Bouchra Benettaib, MD, Celgene Corporation

Study Documents (Full-Text)

• Study Protocol - Dec 13, 2016
• Statistical Analysis Plan - Jan 2, 2018

More Information

Publications

None provided.

• Responsible Party: Celgene
• ClinicalTrials.gov Identifier: NCT02538965
• Other Study ID Numbers: CC-5013-AML-002
• First Posted: Sep 2, 2015
• Last Update Posted: Jan 7, 2020
• Last Verified: Dec 1, 2019

• Keywords provided by Celgene: Lenalidomide; Revlimid; Pediatric; Relapsed or Refractory; Acute Myeloid Leukemia; Leukemia
• Additional relevant MeSH terms: Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Lenalidomide

Study Results

Participant Flow

Recruitment Details	Participants were enrolled at 15 centers within the United States and Canada.
Pre-assignment Detail	The study population consisted of pediatric participants with relapsed or refractory Acute Myeloid Leukemia (rrAML) from 1 to ≤ 18 years of age and were required to have a fresh bone marrow aspirate and biopsy submitted for confirmation of disease.

Arm/Group Title	Lenalidomide
Arm/Group Description	Participants received oral lenalidomide (capsules or suspension) at 2 mg/kg/day with a maximum dose of 70 mg/day for the first 21 days of each 28-day treatment cycle up to a maximum of 12 cycles of study treatment unless there was the development of a toxicity or adverse event (AE), death, withdrawal by parent/guardian of participant, lost to follow-up, pregnancy, non-compliance with investigational product (IP), physician decision, protocol violation or other reason. Upon completion or discontinuation of study treatment, participants entered the follow-up period for up to 5 years.
Period Title: Treatment Period
STARTED	17
COMPLETED	0
NOT COMPLETED	17
Period Title: Treatment Period
STARTED	17
COMPLETED	0
NOT COMPLETED	17

Baseline Characteristics

Arm/Group Title	Lenalidomide
Arm/Group Description	Participants received oral lenalidomide (capsules or suspension) at 2 mg/kg/day with a maximum dose of 70 mg/day for the first 21 days of each 28-day treatment cycle up to a maximum of 12 cycles of study treatment unless there was the development of a toxicity or adverse event (AE), death, withdrawal by parent/guardian of participant, lost to follow-up, pregnancy, non-compliance with investigational product (IP), physician decision, protocol violation or other reason. Upon completion or discontinuation of study treatment, participants entered the follow-up period for up to 5 years.
Overall Participants	17
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	11.5 (4.56)
Sex: Female, Male (Count of Participants)
Female	7 41.2%
Male	10 58.8%
Race/Ethnicity, Customized (Count of Participants)
Asian	1 5.9%
Black or African American	0 0%
White	12 70.6%
Not Collected or Reported	3 17.6%
Other	1 5.9%
Age Categories (Count of Participants)
≤ 2 years	0 0%
3-6 years	4 23.5%
7-12 years	6 35.3%
13-16 years	4 23.5%
≥ 17 years	3 17.6%
Peripheral Blood Smear Blasts (Percent of Blasts) [Median (Full Range) ]
Median (Full Range) [Percent of Blasts]	8.7
White Blood Cell Count (10^9/L) [Median (Full Range) ]
Median (Full Range) [10^9/L]	3.700
Bone Marrow (BM) Myeloblasts Count (Percent of Myeloblasts) [Median (Full Range) ]
Median (Full Range) [Percent of Myeloblasts]	57.5
Number of Participants With at Least One Cytogenetic Abnormality (Count of Participants)
t(8;21)	1 5.9%
+8	1 5.9%
complex (>/= 3 abnormalities)	5 29.4%
-7	1 5.9%
7q-	2 11.8%
11q 23 abnormalities	3 17.6%
inv (3)	1 5.9%
Other	9 52.9%
Number of Prior Systemic Anti-Cancer Regimens (regimens) [Median (Full Range) ]
Median (Full Range) [regimens]	5

Outcome Measures

1. Primary Outcome

Title	Number of Participants Who Achieved a Morphologic Complete Response Within the First Four Cycles of Lenalidomide Treatment According to the Modified International Working Group (IWG) Criteria
Description	The morphological complete response rate was defined as the total number of participants with morphological CR observed within the first 4 cycles of lenalidomide (regardless of whether the CR/CRi was observed at the end of Cycle 1, 2, 3 or 4) over the total number of participants evaluable for this endpoint. According to Modified IWG criteria, morphologic CR was defined as: Absolute neutrophil count (ANC) ≥ 1000/μL and platelets ≥ 100,000 without transfusions and/or exogenous growth factor support (i.e., no transfusion or exogenous growth factor within 7 days of assessment; Bone marrow < 5% blasts evidence of trilineage hematopoiesis; No evidence of extramedullary disease. Morphologic CRi was defined as: ANC < 1000/μL and platelets < 100,000/μL or > 100,000/μL without platelet recovery (requiring transfusion within 7 days of assessment); BM with < 5% blasts and evidence of trilineage hematopoiesis; No evidence of extramedullary disease.
Time Frame	From day of the first dose of IP to end of cycle 4; Response was assessed at the completion of the 21-day treatment period of cycles 1, 2, 3, and 4 and at treatment discontinuation.

Outcome Measure Data

Analysis Population Description

The Intent to Treat (ITT) population consisted of all enrolled participants regardless of whether they received lenalidomide. Analysis was not completed due to scarcity of relevant data. See description.

Arm/Group Title	Lenalidomide
Arm/Group Description	Participants received oral lenalidomide (capsules or suspension) at 2 mg/kg/day with a maximum dose of 70 mg/day for the first 21 days of each 28-day treatment cycle up to a maximum of 12 cycles of study treatment unless there was the development of a toxicity or adverse event (AE), death, withdrawal by parent/guardian of participant, lost to follow-up, pregnancy, non-compliance with investigational product (IP), physician decision, protocol violation or other reason. Upon completion or discontinuation of study treatment, participants entered the follow-up period for up to 5 years.
Measure Participants	17
Count of Participants [Participants]	1 5.9%

2. Secondary Outcome

Title	Number of Participants Who Achieved a Bone Marrow Confirmed CR/CRi Lasting 3 Months (Durable Response Rate)
Description	Durable response rate was defined as the percentage of participants who achieved a BM confirmed CR/CRi according to the Modified IWG Response Assessment Lasting 3 Months (from the time to complete response observed until treatment failure or worse) or until transplantation if earlier among all participants eligible for durable response rate analysis, provided the CR/CRi was confirmed in a bone marrow sample). Due to scarcity of relevant data, it was not practical or meaningful to analyze the durable response rate. Only 1 participant had a response and the participant was censored soon after, as the consent was withdrawn; unable to calculate duration of response.
Time Frame	From date of confirmed complete response observed until treatment failure or worse; up to data cut-off date of 31 December 2017

Outcome Measure Data

Analysis Population Description

Due to scarcity of relevant data, it was not practical or meaningful to analyze the durable response rate. See description.

Arm/Group Title	Lenalidomide
Arm/Group Description	Participants received oral lenalidomide (capsules or suspension) at 2 mg/kg/day with a maximum dose of 70 mg/day for the first 21 days of each 28-day treatment cycle up to a maximum of 12 cycles of study treatment unless there was the development of a toxicity or adverse event (AE), death, withdrawal by parent/guardian of participant, lost to follow-up, pregnancy, non-compliance with investigational product (IP), physician decision, protocol violation or other reason. Upon completion or discontinuation of study treatment, participants entered the follow-up period for up to 5 years.
Measure Participants	0

3. Secondary Outcome

Title	Duration of Response
Description	Duration of response was defined as the time from date of the first observed response (CR, CRi or PR) until morphologic relapse, molecular/cytogenetic relapse, or death only for participants who achieved a response. Due to scarcity of relevant data, it was not practical or meaningful to analyze the duration of response. Only 1 participant had a response and the participant was censored soon after, as the consent was withdrawn; unable to calculate duration of response.
Time Frame	From date of first time of complete response observed until treatment failure or worse; up to data cut-off date of 31 December 2017

Outcome Measure Data

Analysis Population Description

ITT population participants that achieved at least a CR or CRi.

Arm/Group Title	Lenalidomide
Arm/Group Description	Participants received oral lenalidomide (capsules or suspension) at 2 mg/kg/day with a maximum dose of 70 mg/day for the first 21 days of each 28-day treatment cycle up to a maximum of 12 cycles of study treatment unless there was the development of a toxicity or adverse event (AE), death, withdrawal by parent/guardian of participant, lost to follow-up, pregnancy, non-compliance with investigational product (IP), physician decision, protocol violation or other reason. Upon completion or discontinuation of study treatment, participants entered the follow-up period for up to 5 years.
Measure Participants	0

4. Secondary Outcome

Title	Number of Participants Who Achieved a Best Response of Morphologic Complete Remission, Morphologic Complete Remission Incomplete or Partial Remission
Description	Overall response rate was defined as the number of participants with best response of CR, CRi or PR. A CR was defined as: ANC ≥ 1000/μL and platelets ≥ 100,000 without transfusions and/or exogenous growth factor support (no transfusion or exogenous growth factor within 7 days of assessment); BM < 5% blasts evidence of trilineage hematopoiesis; No evidence of extramedullary disease. A CRi was defined as: ANC < 1000/μL and platelets < 100,000/μL or > 100,000/μL without platelet recovery (requiring transfusion within 7 days of assessment); BM with < 5% blasts and evidence of trilineage hematopoiesis; No evidence of extramedullary disease. A PR was defined as: ANC of ≥ 1000/μL and platelets ≥ 100,000 without transfusions and/or exogenous growth factor support (no transfusion or exogenous growth factor within 7 days of assessment); BM with 5% to 25% blasts and at least a 50% decrease in BM blast percent from baseline; No evidence of extramedullary disease.
Time Frame	Response was assessed at the completion of the 21-day treatment period of cycles 1, 2, 3.

Outcome Measure Data

Analysis Population Description

Intent to Treat Population consisted of all enrolled participants regardless of whether they received lenalidomide.

Arm/Group Title	Lenalidomide
Arm/Group Description	Participants received oral lenalidomide (capsules or suspension) at 2 mg/kg/day with a maximum dose of 70 mg/day for the first 21 days of each 28-day treatment cycle up to a maximum of 12 cycles of study treatment unless there was the development of a toxicity or adverse event (AE), death, withdrawal by parent/guardian of participant, lost to follow-up, pregnancy, non-compliance with investigational product (IP), physician decision, protocol violation or other reason. Upon completion or discontinuation of study treatment, participants entered the follow-up period for up to 5 years.
Measure Participants	17
Count of Participants [Participants]	1 5.9%

5. Secondary Outcome

Title	Number of Participants With a Morphologic CR, CRi, PR or Treatment Failure at Cycles 1, 2 and 3
Description	Disease assessment outcome at the end of Cycles 1-3 based on Cheson criteria: Morphologic CR = ANC ≥ 1000/μL and platelet ≥ 100,000 without transfusions and/or exogenous growth factor support (no transfusion or exogenous growth factor within 7 days of assessment) BM < 5% blasts evidence of trilineage hematopoiesis No evidence of extramedullary disease Morphologic CRi = 1. ANC< 1000/μL and Platelets < 100,000/μL or > 100,000/μL without platelet recovery (requiring transfusion within 7 days of assessment) 2. BM with < 5% blasts and evidence of trilineage hematopoiesis 3. No evidence of extramedullary disease PR = ANC ≥ 1000/μL and platelets ≥ 100,000 without transfusions and/or exogenous growth factor support BM with < 5%-25% blasts and at least a 50% decrease in BM blast percent from baseline No evidence of extramedullary disease Treatment Failure = resistant disease; survival ≥ 7 days post-therapy; failed to achieve CR, CRi, or PR but stable with persistent AML
Time Frame	Response was assessed at the completion of the 21-day treatment period of cycles 1, 2, 3.

Outcome Measure Data

Analysis Population Description

The intent to treat population consisted of all enrolled participants regardless of whether they received lenalidomide. Data are reported for participants who began each treatment cycle.

Arm/Group Title	Lenalidomide
Arm/Group Description	Participants received oral lenalidomide (capsules or suspension) at 2 mg/kg/day with a maximum dose of 70 mg/day for the first 21 days of each 28-day treatment cycle up to a maximum of 12 cycles of study treatment unless there was the development of a toxicity or adverse event (AE), death, withdrawal by parent/guardian of participant, lost to follow-up, pregnancy, non-compliance with investigational product (IP), physician decision, protocol violation or other reason. Upon completion or discontinuation of study treatment, participants entered the follow-up period for up to 5 years.
Measure Participants	17
Cycle 1 Morphologic CR	0 0%
Cycle 1 Morphologic CRi	0 0%
Cycle 1 PR	1 5.9%
Cycle 1 Treatment Failure	13 76.5%
Cycle 2 Morphologic CR	0 0%
Cycle 2 Morphologic CRi	1 5.9%
Cycle 2 PR	0 0%
Cycle 2 Treatment Failure	5 29.4%
Cycle 3 Morphologic CR	0 0%
Cycle 3 Morphologic CRi	1 5.9%
Cycle 3 PR	0 0%
Cycle 3 Treatment Failure	0 0%

6. Secondary Outcome

Title	Number of Participants Who Received a Haematopoietic Stem Cell Transplant (HSCT)
Description	The number of participants who had undergone a haematopoietic stem cell transplant was calculated over the total number of participants in the ITT population. Percentages were also calculated based on whether the transplantation was the first, second, or subsequent transplant post IP administration.
Time Frame	From first dose of study drug up to 5 years post HSCT

Outcome Measure Data

Analysis Population Description

The intent to treat population consisted of all enrolled participants regardless of whether they received lenalidomide.

Arm/Group Title	Lenalidomide
Arm/Group Description	Participants received oral lenalidomide (capsules or suspension) at 2 mg/kg/day with a maximum dose of 70 mg/day for the first 21 days of each 28-day treatment cycle up to a maximum of 12 cycles of study treatment unless there was the development of a toxicity or adverse event (AE), death, withdrawal by parent/guardian of participant, lost to follow-up, pregnancy, non-compliance with investigational product (IP), physician decision, protocol violation or other reason. Upon completion or discontinuation of study treatment, participants entered the follow-up period for up to 5 years.
Measure Participants	17
Any Transplant After Treatment Start	2 11.8%
First Transplant After Treatment Start	2 11.8%
Second Transplant After Treatment Start	0 0%
Any Subsequent Transplant After Treatment Start	0 0%

7. Secondary Outcome

Title	Number of Participants Who Experienced Treatment Emergent Adverse Events (TEAE)
Description	A TEAE was defined as any adverse event (AE) occurring or worsening on or after the first treatment of lenalidomide and within 28 days after the last dose. A serious AE = any AE which results in death; is life-threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect; constitutes an important medical event. The severity of AEs was graded based on National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), Version 4.3 and based on the following scale: Grade 1 = Mild Grade 2 = Moderate Grade 3 = Severe Grade 4 = Life threatening Grade 5 = Death.
Time Frame	From the first dose of study drug until 28 days after the last dose of study drug; up to data cut off date of 31 December 2017; maximum duration of treatment was 12 weeks

Outcome Measure Data

Analysis Population Description

The safety population consisted of all participants who received at least one dose of lenalidomide.

Arm/Group Title	Lenalidomide
Arm/Group Description	Participants received oral lenalidomide (capsules or suspension) at 2 mg/kg/day with a maximum dose of 70 mg/day for the first 21 days of each 28-day treatment cycle up to a maximum of 12 cycles of study treatment unless there was the development of a toxicity or adverse event (AE), death, withdrawal by parent/guardian of participant, lost to follow-up, pregnancy, non-compliance with investigational product (IP), physician decision, protocol violation or other reason. Upon completion or discontinuation of study treatment, participants entered the follow-up period for up to 5 years.
Measure Participants	17
Any TEAE	17 100%
Any TEAE Related to Lenalidomide	15 88.2%
Any Grade 3/4 TEAE	17 100%
Any Grade 3/4 TEAE Related to Lenalidomide	11 64.7%
Any Grade 5 TEAE	1 5.9%
Any Serious TEAE	13 76.5%
Any Serious TEAE Related to Lenalidomide	5 29.4%
Any Serious TEAE Leading to Dose Discontinuation	3 17.6%
Any TEAE Leading to Dose Discontinuation	3 17.6%
Any TEAE Leading to Dose Reduction	4 23.5%
Any TEAE Leading to Dose Interruption	7 41.2%
Any TEAE Leading to Death	1 5.9%

8. Secondary Outcome

Title	Percentage of Participants With of Graft Versus Host Disease (GVHD)
Description	Acute graft versus host disease generally occurs after allogeneic hematopoietic stem cell transplantation. It is a reaction of donor immune cells against host tissues. The 3 main tissues that acute GVHD affects are the skin, liver, and gastrointestinal tract. Chronic GVHD is scored per the National Institute of Health consensus conference grading system. Clinical manifestations of chronic GVHD include skin involvement resembling lichen planus or the cutaneous manifestations of scleroderma; dry oral mucosa with ulcerations and sclerosis of the gastrointestinal tract; and a rising serum bilirubin concentration.
Time Frame	From the first dose of study drug to 28 days after the last dose of study drug; up to data cut off date of 31 December 2017; maximum treatment was 12 weeks

Outcome Measure Data

Analysis Population Description

The Safety population consisted of all participants who received at least 1 dose of lenalidomide.

Arm/Group Title	Lenalidomide
Arm/Group Description	Participants received oral lenalidomide (capsules or suspension) at 2 mg/kg/day with a maximum dose of 70 mg/day for the first 21 days of each 28-day treatment cycle up to a maximum of 12 cycles of study treatment unless there was the development of a toxicity or adverse event (AE), death, withdrawal by parent/guardian of participant, lost to follow-up, pregnancy, non-compliance with investigational product (IP), physician decision, protocol violation or other reason. Upon completion or discontinuation of study treatment, participants entered the follow-up period for up to 5 years.
Measure Participants	17
Number [Percentage of Participants]	0 0%

9. Secondary Outcome

Title	Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration of Lenalidomide (AUC-t)
Description	Area under the plasma concentration-time curve from time 0 to the time of the last quantifiable concentration, calculated by linear trapezoidal method when concentrations were increasing and the logarithmic trapezoidal method when concentrations were decreasing.
Time Frame	Pharmacokinetic (PK) sampling was conducted after lenalidomide administration at Cycle 1 and was weight dependent at these timepoints: 0.5, 1, 2, 4, 6, 8 and 24 hours. The 24 hour PK sample was taken prior to the lenalidomide dose on Day 2.

Outcome Measure Data

Analysis Population Description

The pharmacokinetic population included participants who received at least one dose of lenalidomide and had at least one measurable lenalidomide concentration.

Arm/Group Title	Lenalidomide
Arm/Group Description	Participants received oral lenalidomide (capsules or suspension) at 2 mg/kg/day with a maximum dose of 70 mg/day for the first 21 days of each 28-day treatment cycle up to a maximum of 12 cycles of study treatment unless there was the development of a toxicity or adverse event (AE), death, withdrawal by parent/guardian of participant, lost to follow-up, pregnancy, non-compliance with investigational product (IP), physician decision, protocol violation or other reason. Upon completion or discontinuation of study treatment, participants entered the follow-up period for up to 5 years.
Measure Participants	17
Geometric Mean (Geometric Coefficient of Variation) [ng*h/mL]	5378.83 (57.3)

10. Secondary Outcome

Title	Area Under the Plasma Concentration Time Curve From 0 Extrapolated to Infinity (AUC-inf, AUC0∞) Of Lenalidomide
Description	Area under the plasma concentration-time curve from time 0 extrapolated to infinity, calculated as [AUCt + Ct/ λz]. Ct is the last quantifiable concentration. No AUC extrapolation was performed with unreliable λz.
Time Frame	Pharmacokinetic sampling was conducted after lenalidomide administration at Cycle 1 and was weight dependent at these timepoints: 0.5, 1, 2, 4, 6, 8 and 24 hours. The 24 hour PK sample was taken prior to the lenalidomide dose on Day 2.

Outcome Measure Data

Analysis Population Description

The pharmacokinetic population included participants who received at least one dose of lenalidomide and had at least one measurable lenalidomide concentration.

Arm/Group Title	Lenalidomide
Arm/Group Description	Participants received oral lenalidomide (capsules or suspension) at 2 mg/kg/day with a maximum dose of 70 mg/day for the first 21 days of each 28-day treatment cycle up to a maximum of 12 cycles of study treatment unless there was the development of a toxicity or adverse event (AE), death, withdrawal by parent/guardian of participant, lost to follow-up, pregnancy, non-compliance with investigational product (IP), physician decision, protocol violation or other reason. Upon completion or discontinuation of study treatment, participants entered the follow-up period for up to 5 years.
Measure Participants	17
Geometric Mean (Geometric Coefficient of Variation) [ng*h/mL]	5656.67 (52.8)

11. Secondary Outcome

Title	Maximum Observed Concentration (Cmax) of Lenalidomide
Description	Maximum observed plasma concentration, obtained directly from the observed concentration versus time data.
Time Frame	PK sampling was conducted after lenalidomide administration at Cycle 1 and was weight dependent at these timepoints: 0.5, 1, 2, 4, 6, 8 and 24 hours. The 24 hour PK sample was taken prior to the lenalidomide dose on Day 2.

Outcome Measure Data

Analysis Population Description

The pharmacokinetic population included participants who received at least one dose of lenalidomide and had at least one measurable lenalidomide concentration.

Arm/Group Title	Lenalidomide
Arm/Group Description	Participants received oral lenalidomide (capsules or suspension) at 2 mg/kg/day with a maximum dose of 70 mg/day for the first 21 days of each 28-day treatment cycle up to a maximum of 12 cycles of study treatment unless there was the development of a toxicity or adverse event (AE), death, withdrawal by parent/guardian of participant, lost to follow-up, pregnancy, non-compliance with investigational product (IP), physician decision, protocol violation or other reason. Upon completion or discontinuation of study treatment, participants entered the follow-up period for up to 5 years.
Measure Participants	17
Geometric Mean (Geometric Coefficient of Variation) [ng/mL]	1252.08 (43.8)

12. Secondary Outcome

Title	Time to Reach Maximum Concentration (Tmax) of Lenalidomide
Description	Time to cmax was obtained directly from the observed concentration versus time data.
Time Frame	Pk sampling was conducted after lenalidomide administration at Cycle 1 and was weight dependent at these timepoints: 0.5, 1, 2, 4, 6, 8 and 24 hours. The 24 hour PK sample was taken prior to the lenalidomide dose on Day 2.

Outcome Measure Data

Analysis Population Description

The pharmacokinetic population included participants who received at least one dose of lenalidomide and had at least one measurable lenalidomide concentration.

Arm/Group Title	Lenalidomide
Arm/Group Description	Participants received oral lenalidomide (capsules or suspension) at 2 mg/kg/day with a maximum dose of 70 mg/day for the first 21 days of each 28-day treatment cycle up to a maximum of 12 cycles of study treatment unless there was the development of a toxicity or adverse event (AE), death, withdrawal by parent/guardian of participant, lost to follow-up, pregnancy, non-compliance with investigational product (IP), physician decision, protocol violation or other reason. Upon completion or discontinuation of study treatment, participants entered the follow-up period for up to 5 years.
Measure Participants	17
Median (Full Range) [Hours]	2.000

13. Secondary Outcome

Title	Terminal Half-Life (t1/2) of Lenalidomide
Description	Terminal phase half-life in plasma, calculated as [(ln 2)/λz]. Terminal half-life was only calculated when a reliable estimate for λz could be obtained.
Time Frame	Pharmacokinetic sampling was conducted after lenalidomide administration at Cycle 1 and was weight dependent at these timepoints: 0.5, 1, 2, 4, 6, 8 and 24 hours. The 24 hour PK sample was taken prior to the lenalidomide dose on Day 2.

Outcome Measure Data

Analysis Population Description

The pharmacokinetic population included participants who received at least one dose of lenalidomide and had at least one measurable lenalidomide concentration.

Arm/Group Title	Lenalidomide
Arm/Group Description	Participants received oral lenalidomide (capsules or suspension) at 2 mg/kg/day with a maximum dose of 70 mg/day for the first 21 days of each 28-day treatment cycle up to a maximum of 12 cycles of study treatment unless there was the development of a toxicity or adverse event (AE), death, withdrawal by parent/guardian of participant, lost to follow-up, pregnancy, non-compliance with investigational product (IP), physician decision, protocol violation or other reason. Upon completion or discontinuation of study treatment, participants entered the follow-up period for up to 5 years.
Measure Participants	17
Geometric Mean (Geometric Coefficient of Variation) [hours]	2.311 (43.3)

14. Secondary Outcome

Title	Apparent Total Clearance (CL/F) of Lenalidomide
Description	Apparent volume of distribution, calculated as [(CL/F)/λz].
Time Frame	Pharmacokinetic sampling was conducted after lenalidomide administration at Cycle 1 and was weight dependent at these timepoints: 0.5, 1, 2, 4, 6, 8 and 24 hours. The 24 hour PK sample was taken prior to the lenalidomide dose on Day 2.

Outcome Measure Data

Analysis Population Description

The pharmacokinetic population included participants who received at least one dose of lenalidomide and had at least one measurable lenalidomide concentration.

Arm/Group Title	Lenalidomide
Arm/Group Description	Participants received oral lenalidomide (capsules or suspension) at 2 mg/kg/day with a maximum dose of 70 mg/day for the first 21 days of each 28-day treatment cycle up to a maximum of 12 cycles of study treatment unless there was the development of a toxicity or adverse event (AE), death, withdrawal by parent/guardian of participant, lost to follow-up, pregnancy, non-compliance with investigational product (IP), physician decision, protocol violation or other reason. Upon completion or discontinuation of study treatment, participants entered the follow-up period for up to 5 years.
Measure Participants	17
Geometric Mean (Geometric Coefficient of Variation) [ml/min]	172.09 (52.5)

15. Secondary Outcome

Title	Apparent Volume of Distribution (Vz/F) of Lenalidomide
Description	Apparent volume of distribution, calculated as [(CL/F)/λz].
Time Frame	Pharmacokinetic sampling was conducted after lenalidomide administration at Cycle 1 and was weight dependent at these timepoints: 0.5, 1, 2, 4, 6, 8 and 24 hours. The 24 hour PK sample was taken prior to the lenalidomide dose on Day 2.

Outcome Measure Data

Analysis Population Description

The pharmacokinetic population included participants who received at least one dose of lenalidomide and had at least one measurable lenalidomide concentration.

Arm/Group Title	Lenalidomide
Arm/Group Description	Participants received oral lenalidomide (capsules or suspension) at 2 mg/kg/day with a maximum dose of 70 mg/day for the first 21 days of each 28-day treatment cycle up to a maximum of 12 cycles of study treatment unless there was the development of a toxicity or adverse event (AE), death, withdrawal by parent/guardian of participant, lost to follow-up, pregnancy, non-compliance with investigational product (IP), physician decision, protocol violation or other reason. Upon completion or discontinuation of study treatment, participants entered the follow-up period for up to 5 years.
Measure Participants	17
Geometric Mean (Geometric Coefficient of Variation) [Liters]	34.42 (57.0)

16. Secondary Outcome

Title	Correlation of Peripheral White Blood Cell Count, Absolute Blast Count and Cytogenetics With Response to Lenalidomide
Description	Correlation of peripheral white blood cell count, absolute blast count and cytogenetics with response to lenalidomide was not performed since only 1 participant met the primary efficacy endpoint of morphological CR/CRi, and due to scarcity of relevant data, it was not practical or meaningful to analyze to perform the analysis on blood counts and response to lenalidomide.
Time Frame	Not Performed

Outcome Measure Data

Analysis Population Description

Due to scarcity of relevant data, it was not practical or meaningful to analyze or perform the analysis on blood counts and response to lenalidomide.

Arm/Group Title	Lenalidomide
Arm/Group Description	Participants received oral lenalidomide (capsules or suspension) at 2 mg/kg/day with a maximum dose of 70 mg/day for the first 21 days of each 28-day treatment cycle up to a maximum of 12 cycles of study treatment unless there was the development of a toxicity or adverse event (AE), death, withdrawal by parent/guardian of participant, lost to follow-up, pregnancy, non-compliance with investigational product (IP), physician decision, protocol violation or other reason. Upon completion or discontinuation of study treatment, participants entered the follow-up period for up to 5 years.
Measure Participants	0

Adverse Events

Time Frame	From the date of the first dose of lenalidomide until 28 days after the last dose of lenalidomide; up to the date the last patient discontinued follow-up 11 January 2019; maximum treatment duration was 12 weeks.
Arm/Group Title	Lenalidomide
Arm/Group Description	Participants received oral lenalidomide (capsules or suspension) at 2 mg/kg/day with a maximum dose of 70 mg/day for the first 21 days of each 28-day treatment cycle up to a maximum of 12 cycles of study treatment unless there was the development of a toxicity or adverse event (AE), death, withdrawal by parent/guardian of participant, lost to follow-up, pregnancy, non-compliance with investigational product (IP), physician decision, protocol violation or other reason. Upon completion or discontinuation of study treatment, participants entered the follow-up period for up to 5 years.
All Cause Mortality
	Lenalidomide
	Affected / at Risk (%)	# Events
Total	13/17 (76.5%)
Serious Adverse Events
	Lenalidomide
	Affected / at Risk (%)	# Events
Total	13/17 (76.5%)
Blood and lymphatic system disorders
Febrile neutropenia	6/17 (35.3%)
Haemolytic anaemia	1/17 (5.9%)
Leukocytosis	1/17 (5.9%)
Eye disorders
Vitreous haemorrhage	1/17 (5.9%)
Gastrointestinal disorders
Diarrhoea	1/17 (5.9%)
Stomatitis	1/17 (5.9%)
Vomiting	1/17 (5.9%)
General disorders
General physical health deterioration	1/17 (5.9%)
Pyrexia	1/17 (5.9%)
Infections and infestations
Cellulitis	2/17 (11.8%)
Lung infection	1/17 (5.9%)
Pneumonia	2/17 (11.8%)
Sinusitis	1/17 (5.9%)
Injury, poisoning and procedural complications
Subdural haematoma	1/17 (5.9%)
Investigations
Activated partial thromboplastin time prolonged	1/17 (5.9%)
International normalised ratio increased	1/17 (5.9%)
Metabolism and nutrition disorders
Dehydration	1/17 (5.9%)
Hypokalaemia	1/17 (5.9%)
Musculoskeletal and connective tissue disorders
Arthralgia	1/17 (5.9%)
Pain in extremity	1/17 (5.9%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Paraneoplastic syndrome	1/17 (5.9%)
Tumour flare	1/17 (5.9%)
Nervous system disorders
Cerebrovascular accident	1/17 (5.9%)
Somnolence	1/17 (5.9%)
Renal and urinary disorders
Renal failure	1/17 (5.9%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea	1/17 (5.9%)
Hypoxia	2/17 (11.8%)
Pulmonary oedema	1/17 (5.9%)
Skin and subcutaneous tissue disorders
Rash pruritic	1/17 (5.9%)
Urticaria	1/17 (5.9%)
Other (Not Including Serious) Adverse Events
	Lenalidomide
	Affected / at Risk (%)	# Events
Total	17/17 (100%)
Blood and lymphatic system disorders
Anaemia	10/17 (58.8%)
Disseminated intravascular coagulation	1/17 (5.9%)
Febrile neutropenia	2/17 (11.8%)
Leukopenia	2/17 (11.8%)
Lymphopenia	1/17 (5.9%)
Neutropenia	3/17 (17.6%)
Splenic infarction	1/17 (5.9%)
Thrombocytopenia	10/17 (58.8%)
Cardiac disorders
Sinus bradycardia	1/17 (5.9%)
Supraventricular tachycardia	1/17 (5.9%)
Tachycardia	4/17 (23.5%)
Ear and labyrinth disorders
Hypoacusis	1/17 (5.9%)
Eye disorders
Diplopia	1/17 (5.9%)
Dry eye	1/17 (5.9%)
Photophobia	1/17 (5.9%)
Vision blurred	1/17 (5.9%)
Gastrointestinal disorders
Abdominal pain	6/17 (35.3%)
Abdominal pain upper	1/17 (5.9%)
Constipation	7/17 (41.2%)
Diarrhoea	3/17 (17.6%)
Nausea	9/17 (52.9%)
Neutropenic colitis	1/17 (5.9%)
Oral mucosal erythema	1/17 (5.9%)
Oral pain	3/17 (17.6%)
Peritoneal haemorrhage	1/17 (5.9%)
Proctalgia	1/17 (5.9%)
Stomatitis	4/17 (23.5%)
Vomiting	4/17 (23.5%)
General disorders
Catheter site haematoma	1/17 (5.9%)
Face oedema	1/17 (5.9%)
Fatigue	4/17 (23.5%)
Non-cardiac chest pain	2/17 (11.8%)
Oedema peripheral	4/17 (23.5%)
Pain	2/17 (11.8%)
Peripheral swelling	1/17 (5.9%)
Pyrexia	7/17 (41.2%)
Hepatobiliary disorders
Hepatosplenomegaly	1/17 (5.9%)
Hyperbilirubinaemia	3/17 (17.6%)
Infections and infestations
Sinusitis	2/17 (11.8%)
Staphylococcal bacteraemia	1/17 (5.9%)
Staphylococcal infection	2/17 (11.8%)
Upper respiratory tract infection	1/17 (5.9%)
Urinary tract infection	1/17 (5.9%)
Injury, poisoning and procedural complications
Contusion	1/17 (5.9%)
Laceration	1/17 (5.9%)
Skin wound	1/17 (5.9%)
Investigations
Activated partial thromboplastin time prolonged	2/17 (11.8%)
Alanine aminotransferase increased	4/17 (23.5%)
Anti-platelet antibody positive	1/17 (5.9%)
Aspartate aminotransferase increased	4/17 (23.5%)
Blood fibrinogen decreased	1/17 (5.9%)
Electrocardiogram QT prolonged	2/17 (11.8%)
Gamma-glutamyltransferase increased	1/17 (5.9%)
International normalised ratio increased	3/17 (17.6%)
Weight decreased	1/17 (5.9%)
Metabolism and nutrition disorders
Decreased appetite	4/17 (23.5%)
Dehydration	3/17 (17.6%)
Fluid overload	1/17 (5.9%)
Hypermagnesaemia	1/17 (5.9%)
Hyperuricaemia	1/17 (5.9%)
Hypoalbuminaemia	3/17 (17.6%)
Hypocalcaemia	4/17 (23.5%)
Hypokalaemia	9/17 (52.9%)
Hypomagnesaemia	4/17 (23.5%)
Hyponatraemia	3/17 (17.6%)
Hypophosphataemia	2/17 (11.8%)
Musculoskeletal and connective tissue disorders
Arthralgia	2/17 (11.8%)
Back pain	5/17 (29.4%)
Bone pain	3/17 (17.6%)
Muscle spasms	1/17 (5.9%)
Muscular weakness	2/17 (11.8%)
Musculoskeletal pain	2/17 (11.8%)
Myalgia	3/17 (17.6%)
Pain in extremity	3/17 (17.6%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Chloroma	1/17 (5.9%)
Nervous system disorders
Cerebrovascular accident	1/17 (5.9%)
Dizziness	1/17 (5.9%)
Headache	6/17 (35.3%)
Lethargy	1/17 (5.9%)
Somnolence	1/17 (5.9%)
Product Issues
Device issue	1/17 (5.9%)
Device occlusion	1/17 (5.9%)
Thrombosis in device	1/17 (5.9%)
Psychiatric disorders
Anxiety	1/17 (5.9%)
Insomnia	1/17 (5.9%)
Phonophobia	1/17 (5.9%)
Renal and urinary disorders
Chromaturia	1/17 (5.9%)
Haematuria	1/17 (5.9%)
Urinary hesitation	1/17 (5.9%)
Respiratory, thoracic and mediastinal disorders
Cough	4/17 (23.5%)
Dry throat	1/17 (5.9%)
Dyspnoea	2/17 (11.8%)
Epistaxis	3/17 (17.6%)
Haemoptysis	1/17 (5.9%)
Hypoxia	2/17 (11.8%)
Nasal congestion	1/17 (5.9%)
Oropharyngeal pain	5/17 (29.4%)
Painful respiration	1/17 (5.9%)
Pleural effusion	2/17 (11.8%)
Pulmonary oedema	2/17 (11.8%)
Wheezing	1/17 (5.9%)
Skin and subcutaneous tissue disorders
Drug eruption	1/17 (5.9%)
Hyperhidrosis	1/17 (5.9%)
Pruritus	1/17 (5.9%)
Purpura	1/17 (5.9%)
Rash macular	1/17 (5.9%)
Rash maculo-papular	5/17 (29.4%)
Rash papular	1/17 (5.9%)
Skin hyperpigmentation	1/17 (5.9%)
Vascular disorders
Flushing	1/17 (5.9%)
Hypertension	1/17 (5.9%)

Limitations/Caveats

The results of the efficacy analysis were reviewed by an independent Data Monitoring Committee, which concluded that the study would not proceed to Stage 2, given that the efficacy criteria for continuation of the study to Stage 2 had not been met.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Results from a center cannot be submitted for publication before results of multicenter study are published unless it is more than 1 year since study completion. Then, Investigator can publish if manuscript is submitted to Celgene 30 days prior to submission. If Celgene decides publication would hinder drug development, Investigator must delay submission for up to 60 additional days. Investigator must delete confidential data before submission or defer publication to permit patent applications.