| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Acute Lymphoblastic Leukemia |
|
| E.1.1.1 | Medical condition in easily understood language |
| Cancer of white blood cells |
|
| 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 | 18.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10000845 |
| E.1.2 | Term | Acute lymphoblastic leukemia |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
To determine if the administration of post-Induction age adjusted ITT on an MBFM-IMHDM backbone will improve 5-year DFS of children with HR B-ALL compared to age adjusted IT MTX.
To determine, in a randomized fashion, if the cyclophosphamide + etoposide containing regimen (Experimental Arm 1) will improve the 4-year DFS of children, adolescents, and young adults with VHR B-ALL compared to a modified MBFM-IMHDM regimen that contains a second IM (Control Arm). |
|
| E.2.2 | Secondary objectives of the trial |
• To determine the toxicity and tolerability of post-Induction age adjusted ITT compared to age adjusted IT MTX in children with HR B-ALL.
• To determine the toxicity and tolerability of Experimental Arm 1 compared to the Control Arm in children, adolescents, and young adults with VHR B-ALL
• To determine whether a single-arm, modified Induction with limited anthracycline exposure and post-Induction therapy regimen with MBFM-IMIDM and reduced vincristine/steroid pulse frequency and enhanced supportive care in children with DS and HR B-ALL will result in a ≥ 65% 5-year DFS and < 10% Induction mortality.
• To determine the toxicity and tolerability of MBFM-IMIDM in children with DS and HR B-ALL. Please see protocol section 1.2 for further secondary trial objectives |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
•This Study will also incorporate Studies of High Risk B-ALL genomics and molecular risk classifiers, for the early identification of patient subset at risk of relapse.
•It will also determine the incidence of long and short term therapy associated side effects with studies of the natural progression of osteonecrosis via MRI (patients >= 10 yrs at time of B-ALL diagnosis) and declines in neurocognitive function (patients 6 to 11 years old at the time of ALL diagnosis) in non-DS children receiving post-Induction therapy on AALL1131 for High Risk or Very High Risk B-ALL |
|
| E.3 | Principal inclusion criteria |
•Patients must be enrolled on AALL08B1 prior to enrollment on AALL1131.
•Age
Patients must be > 365 days and < 31 years of age
3.2.3 White Blood Cell Count (WBC) Criteria
Age 1-9.99 years: WBC ≥ 50 000/μL
Age 10-30.99 years: Any WBC
Age 1-30.99 years: Any WBC with:
a) Testicular leukemia
b) CNS leukemia (CNS3)
c) Steroid pretreatment (see Section 3.3 )
•Diagnosis
Patients must have newly diagnosed B lymphoblastic leukemia (2008 WHO classification) (also termed B-precursor acute lymphoblastic leukemia). Patients with Down syndrome are also eligible. |
|
| E.4 | Principal exclusion criteria |
• With the exception of steroid pretreatment or the administration of intrathecal cytarabine, patients must not have received any prior cytotoxic chemotherapy for either the current diagnosis of B-ALL or any cancer diagnosed prior to the initiation of protocol therapy on AALL1131. Patients cannot have secondary B-ALL that developed after treatment of a prior malignancy with cytotoxi chemotherapy.Patients receiving prior steroid therapy may be eligible for AALL1131
• Patients with BCR-ABL1 fusion (not eligible for post-Induction therapy on this study; non-DS patients may be eligible to enroll in AALL1122 or successor COG Ph+ ALL trial by Day 15 Induction)
• DS HR B-ALL patients with Induction failure or BCR-ABL1
• Female patients who are pregnant are ineligible since fetal toxicities and teratogenic effects have been noted for several of the study drugs.
• Lactating females are not eligible unless they have agreed not to breastfeed their infant.
• Female patients of childbearing potential are not eligible unless a negative pregnancy test result has been obtained.
• Sexually active patients of reproductive potential are not eligible unless they have agreed to use an effective contraceptive method for the duration of their study participation.
• Eligibility criteria for the Incidence and Natural History of Osteonecrosis study
A) Patients must be 10 years of age or greater at the time of B-ALL diagnosis, enrolled on AALL1131.
B) Patients with Down syndrome are not eligible
• Eligibility criteria for the Longitudinal, Computerized Assessment of Neurocognitive Functioning study
A)Patients must be aged 6 to 11 years at time of B-ALL diagnosis, enrolled on AALL1131
B) Patients must be English-, French- or Spanish-speaking (languages in which the assessment is available)
C) Patients must have no known history of neurodevelopmental disorder prior to diagnosis of B-ALL (e.g., Down syndrome, Fragile X, William‘s Syndrome, mental retardation)
D) Patients must have no significant visual impairment that would prevent computer use and recognition of the visual test stimuli
• Eligibility criteria for the NCI standard risk patients from AALL0932 enrolling on this study at the end of Induction. - Patients enrolled on AALL0932, without Down syndrome, meeting the following criteria will NOT be eligible to continue on AALL0932 but WILL BE eligible to enroll on the HR B-ALL stratum of this study at the end of Induction: a) Without favorable cytogenetics (no ETV6-RUNX1 or double trisomies 4+10), with Day 8 PB MRD ≥ 1% and Day 29 BM MRD < 0.01%. b) With favorable cytogenetics (ETV6-RUNX1 or double trisomies 4+10), with any Day 8 PB MRD and Day 29 BM MRD > 0.01%. Both NCI SR and HR patients without Down syndrome and with testicular disease at diagnosis, who do not meet other VHR criteria, will be eligible for the HR stratum.
• Patients enrolled on AALL0932, without Down syndrome, meeting the following criteria will NOT be eligible to continue on AALL0932 but WILL BE eligible to enroll on the VHR B-ALL stratum of this study at the end of Induction: a) iAMP21 b) MLL rearrangement c) Hypodiploidy (n< 44 chromosomes and/or a DNA index < 0.81) d) Induction Failure (M3 BM at Day 29) e) Without favorable cytogenetics (no ETV6-RUNX1 or double trisomies 4+10), with Day 29 BM MRD > 0.01%
• Patients enrolled on AALL0932, with Down syndrome, meeting the following criteria will NOT be eligible to continue on AALL0932 but WILL BE eligible to enroll on the DS HR B-ALL stratum of this study at the end of Induction: a) Day 29 MRD ≥ 0.01% b) MLL rearrangement c) Hypodiploidy (n< 45 chromosomes and/or DNA index < 0.81)
• DS HR B-ALL patients initially enrolled on AALL0932 or this study who have Induction Failure (M3 BM Day 29) or Philadelphia chromosome (BCR-ABL1) will not be eligible for post-Induction therapy on either trial (AALL0932 or AALL1131). |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
To determine if the administration of post-Induction age adjusted ITT on an MBFM-IMHDM backbone will improve 5-year disease free survival (DFS) of children with HR B-ALL compared to age adjusted IT MTX.
• To determine, in a randomized fashion, if the cyclophosphamide + etoposide containing regimen
(Experimental Arm 1) will improve the 4-year DFS of children, adolescents, and young adults with VHR B-ALL compared to a modified MBFM-IMHDM + CMTX regimen that contains a second IM (Control Arm). |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
See section 10.3 of protocol
|
|
| E.5.2 | Secondary end point(s) |
To determine the toxicity and tolerability of post-Induction age adjusted ITT compared to age adjusted IT MTX in children with HR B-ALL.
• To determine the toxicity and tolerability of Experimental Arm 1 compared to the Control Arm in
children, adolescents, and young adults with VHR B-ALL.
• To determine whether a single-arm, modified Induction and post-Induction therapy regimen with MBFM-IMIDM and enhanced supportive care in children with DS and HR B-ALL will result in a ≥ 65% 5-year DFS and < 10% Induction mortality.
• To determine the toxicity and tolerability of MBFM-IMIDM in children with Down’s syndrome.
• To estimate overall survival (OS) rates both overall and by regimen for a) HR B-ALL and b) VHR B-ALL. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| See section 10.3 of protocol |
|
| 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 | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | No |
| E.6.6 | Pharmacokinetic | No |
| 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 | No |
| 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) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| 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) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 6 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Australia |
| Canada |
| New Zealand |
| Switzerland |
| United States |
|
| 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
|
| 10 years from the date the last patient is enrolled (Last follow up data on last patient) |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 7 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 7 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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