CHIP-AML22/Master: An Open Label Complex Clinical Trial in Newly Diagnosed Pediatric de Novo AML Patients

Study Overview
=================
Brief Summary
-----------------
The CHIP-AML22 Master protocol has the overall aim of increasing the cure rate in newly diagnosed pediatric de novo AML patients, while avoiding unnecessary toxicity.

Detailed Description
-----------------
This is a master protocol comprising a complex clinical trial with a stratification approach to allocate patients to randomized studies described in the master protocol or linked trials. The overarching objective of the CHIP-AML22 study is to improve event-free survival (EFS) in children and adolescents with AML, as compared to NOPHO-DBH 2012. The consortium strives to achieve the overarching aim by: Avoiding unnecessary toxicity. This will be investigated in a randomized setting (non-inferiority) by omitting a third standard-of-care consolidation course for standard-risk patients (4 versus 5 courses of chemotherapy). Introducing quizartinib as FLT3-inhibitor in addition to the first three sequential chemotherapy courses for all patients with FLT3-ITD/NPM1wt, and as post-SCT continuation treatment for the subset of patients that have MRD ≥0.1% after course 1 or at any time-point later on (historical comparison, higher efficacy). Refining risk-group adapted treatment, by classifying patients with KMT2A-rearrangement (except KMT2A/MLLT3) and MRD≥0.1% in BM after course 1 as high-risk (historical comparison, higher efficacy), as well as patients with the RAM-phenotype and/or CBFA2T3::GLIS2 fusion (historical comparison, higher efficacy). High-risk (non-FLT3-ITD/NPM1wt patients) will also be concluded for patients having ≥15% leukemic cells in BM after course 1, or ≥0.1-5% after course 2. Refractory disease will be defined as ≥5% leukemic cells in bone marrow after 2 courses of induction treatment, or disease elsewhere, or both. Recommending the use of the cardioprotective drug dexrazoxane in all courses incorporating an anthracycline or mitoxantrone (exploratory objective, no statistical design), with the aim to prevent cardiotoxicity. Furthermore, a randomized study with gemtuzumab ozogamicin in induction course 1 is planned and will be added later by amendment. Children with FLT3-ITD/NPM1wt are not eligible for this randomization. To explore health-related Quality of Life during and after completion of treatment by using short questionnaires (exploratory objective, no statistical design).

Official Title
-----------------
An Open Label Complex Clinical Trial in Newly Diagnosed Pediatric de Novo AML Patients - a Study by the NOPHO-DB-SHIP Consortium, Master Protocol

Conditions
-----------------
Acute Myeloid Leukemia in Children

Intervention / Treatment
-----------------
* Drug: Standard Intervention
* Drug: Investigational Intervention


Participation Criteria
=================
Eligibility Criteria
-----------------
General inclusion criteria for CHIP-AML22/Master: Patients are eligible for the study if they fulfil all four criteria below: Newly diagnosed AML as defined by the diagnostic criteria in section 8.1. Note that different blast thresholds may apply for different genetic abnormalities in case of low blast percentages. The origin of AML must be de novo (not secondary to bone marrow failure or therapy-related). Age ≥ day and ≤18 years old at initial diagnosis. Written informed consent/assent from patients and/or from parents or legal guardians for minor patients, according to local law and regulations. Informed consent should ideally be obtained before day 7 of induction course 1, as patients that are eligible for the linked quizartinib trial should be enrolled before the end of induction course 1, and in view of the planned Mylotarg® randomisation. Thus, standard of care diagnostics and induction treatment may be started before informed consent has been obtained. Able to comply with scheduled follow-up and with management of toxicity. Additional inclusions criteria for Rc randomization Patients included in the CHIP-AML22 protocol and stratified to Standard Risk Group according to the stratification algorithm of the protocol Informed consent for participation in randomization Rc General exclusion criteria for CHIP-AML22/Master Patients are excluded if any of the criteria below are present: Previous chemotherapy or radiotherapy. This includes patients with therapy-related AML after previous cancer therapy. These patients may be treated according to the master protocol but will not be part of the formal study population, and data of these patients will not be collected. Patients with a (known) germline predisposition for bone marrow failure, like Fanconi anemia. Myeloid Leukemia of Down syndrome (ML-DS). Patients with ML-DS are recommended to be treated according to the international ML-DS protocol. Patients with AML and DS older than 5 years who often lack GATA1 mutation and do not have typical myeloid leukemia of DS may be treated according to the master protocol but will not be part of the formal study population, hence data of these patients will not be collected. Acute promyelocytic leukemia (APL). Myelodysplastic syndrome (MDS). Juvenile Myelomonocytic Leukemia (JMML). Known intolerance to any of the chemotherapeutic drugs in the protocol. Evidence of cardiac dysfunction (shortening fraction below 28%). Pregnant or lactating patients, or sexually active female patients of childbearing potential not willing to use an highly effective method of contraception for the duration of study therapy and up to 7 months after the completion of all study therapy. Sexually active, fertile male patients, not willing to use an effective method of contraception, for the duration of study therapy, and up to 6 months after the completion of all study therapy. Concomitant administration of any other experimental drug under investigation, or concurrent treatment with any other anti-cancer therapy other than specified in this protocol or in one of the trials linked to this Master protocol, is not allowed. Patients who in the opinion of the investigator, may not be able to comply with the study requirements of the study. Patients with known active hepatitis B, hepatitis C, or HIV infection. Patients for whom informed consent was not obtained.

Ages Eligible for Study
-----------------
Minimum Age: 1 Day
Maximum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Standard arm<br>3 consolidation courses (HAM + HA3E + FLA) | Drug: Standard Intervention<br>* 3 consolidation courses (HAM + HA3E + FLA)<br>|
| Experimental: Investigational arm<br>2 consolidation courses (HAM + FLA) | Drug: Investigational Intervention<br>* 2 consolidation courses (HAM + FLA)<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overarching primary objective | Event Free Survival (EFS) | 5 years | 
| Primary objective Randomisation Consolidation | Disease Free Survival (DFS) | 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overarching secondary objective - efficacy 1 | • Bone marrow blast counts by morphology and multicolor flow cytometry (MFCM) after course #1 and #2 and before allo-SCT | 8 months | 
| Overarching secondary objective - efficacy 2 | ORR (CR, CRp, and CRi) and morphologic leukemia-free state (MLFS) rates after course #1 and #2; | 3 months | 
| Overarching secondary objective - efficacy 3 | MRD negativity after course #1 and #2 and before allo-SCT | 8 months | 
| Overarching secondary objective - efficacy 4 | Absolute MRD levels after course #1 and #2 and before allo-SCT | 8 months | 
| Overarching secondary objective - efficacy 5 | • OS | 5 years | 
| Overarching secondary objective - efficacy 6 | • DFS | 5 years | 
| Overarching secondary objective - efficacy 7 | • CIR | 5 years | 
| Overarching secondary objective - toxicity 1 | • Cumulative toxicity, defined as the total of all grades AEs over time, which are graded by NCI CTCAE version 5.0. | 5 years | 
| Overarching secondary objective - toxicity 2 | • NRM. | 5 years | 
| Secondary objective Randomisation consolidation - safety 1 | • Cumulative toxicity, defined as the total of grade ≥3 AESIs over time, which are graded by NCI CTCAE version 5.0. | 8 months | 
| Secondary objective Randomisation consolidation - safety 2 | • NRM. | 5 years | 
| Secondary objective Randomisation consolidation - healthcare resources | Cumulative Hospitalized Days | 1 year | 
| Secondary objective Randomisation consolidation - efficacy 1 | • OS | 5 years | 
| Secondary objective Randomisation consolidation - efficacy 2 | • CIR | 5 years |