| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| E.1.1.1 | Medical condition in easily understood language |
Acute Myeloid Leukemia is a type of cancer that starts in cells that form
new blood cells. AML starts in the bone marrow but in most cases it
quickly moves into the blood. |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10000886 |
| E.1.2 | Term | Acute myeloid leukemia |
| E.1.2 | System Organ Class | 100000012984 |
|
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To determine the activity of lenalidomide in the treatment of pediatric subjects with relapsed/refractory 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. |
|
| E.2.2 | Secondary objectives of the trial |
- To evaluate subject demographics and leukemic blast characteristics and their
correlation with response to lenalidomide.
- To further evaluate lenalidomide activity with regards to response assessment
outcome rates, transplantation rate, duration of response (DoR) and durable response rate.
- To evaluate the safety of lenalidomide including rates of graft-versus-host disease (GVHD) flare and reactivation.
- To determine the pharmacokinetics (PK) of lenalidomide in plasma. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
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.Subject (when applicable, parental/legal representative) must understand and voluntarily provide permission to the ICF/IAF prior to conducting any study-related assessments/procedures.
3.Subject has Relapsed or Refractory Acute Myeloid Leukemia (rrAML) after at least 2 prior induction attempts
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 echocardiography.
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 pelvis.
◦6 weeks if other bone marrow radiation has been administered.
9.Graft-versus-host disease criteria:
- Subject must be at least 2 months (from first dose of lenalidomide) from stem cell infusion.
- Subject must have no evidence of active acute or chronic GVHD (Grade 0) for 4 weeks prior to the first dose of lenalidomide.
◦Physiologic dosing of hydrocortisone is permitted.
10.At least 4 weeks (from first dose) elapsed from donor lymphocyte infusion (DLI) without conditioning.
11.Subject has adequate renal function
12.Subject has adequate liver function
13.Female Children of Childbearing Potential (FCCBP), Female of Childbearing Potential (FCBP) 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:
- 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.
•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 Prevention Program.
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 complete abstinence |
|
| E.4 | Principal exclusion criteria |
1. Subject has Down syndrome.
2.Subject has French-American-British classification (FAB) type M3 leukemia (acute promyelocytic leukemia) or identification of t(15;17).
3.Subject has isolated Central Nervous System (CNS) involvement or extramedullary relapse. (Subjects with combined CNS/marrow relapse may be Subject has 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. Subject has 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. Subject has had prior treatment with lenalidomide. 7. Subject is pregnant or lactating. 8. Subject has 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. Subject has known Human Immunodeficiency Virus (HIV) positivity (subjects who are receiving antiretroviral therapy for HIV disease).
10. Subject has 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 subject from enrollment:
•Subject has any significant medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from participating in the study.
•Subject has any condition including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study.
•Subject has any condition that confounds the ability to interpret data from the study.
12. Subject has cardiac disorders (Common Terminology Criteria for Adverse Events [CTCAE] version 4.03 Grade 3 or 4).
13. Subject has a history of well-documented prior veno-occlusive disease (VOD).
14. Subject has any other organ dysfunction (CTCAE version 4.03 Grade 4) that will interfere with the administration of the therapy according to this protocol. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Morphologic complete response rate (CR or CRi) within the first 4 cycles of
treatment with lenalidomide. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Up to approximately 4 months |
|
| E.5.2 | Secondary end point(s) |
- Durable response rate.
- Duration of response (DoR).
- Disease assessment outcomes and overall response rate (ORR).
- Rate of hematopoietic stem cell transplant (HSCT).
- Incidence and severity of treatment-emergent adverse events (TEAEs).
- Rates of acute and chronic graft-versus-host disease (GVHD).
- Plasma pharmacokinetic (PK) parameters including lenalidomide apparent clearance and volume of distribution.
- Correlation of peripheral white blood cell count, absolute blast count and cytogenetics with response to lenalidomide. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Up to approximately 60 months |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | No |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.3 |
Will this trial be conducted at a single site globally?
| No |
| E.8.4 | Will this trial be conducted at multiple sites globally? | Yes |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Yes |
| E.8.6.3 | Specify the countries outside of the EEA in which trial sites are planned |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| The End of Trial is defined as either the date of the last visit of the last subject to complete the post-treatment follow-up, or the date of receipt of the last data point from the last subject that is required for primary, secondary and/or exploratory analysis, as prespecified in the protocol, whichever is the later date. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.2 | In all countries concerned by the trial years | 8 |
| E.8.9.2 | In all countries concerned by the trial months | 3 |
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