Interfant-21 Treatment Protocol for Infants Under 1 Year With KMT2A-rearranged ALL or Mixed Phenotype Acute Leukemia

Interfant-21 International Collaborative Treatment Protocol for Infants Under One Year With KMT2A-rearranged Acute Lymphoblastic Leukemia or Mixed Phenotype Acute Leukemia.

This study is a treatment protocol with blinatumomab for infants under 1 year old who are diagnosed with acute lymphoblastic leukemia with a specific unfavorable genetic alteration. The purpose of the study is to improve the outcome of this disease in infants.

Study Overview

• Status: Not yet recruiting
• Conditions: Acute Lymphoblastic Leukemia; Mixed Phenotype Acute Leukemia
• Intervention / Treatment: Drug: Blinatumomab; Drug: Blinatumomab

Detailed Description

All infants that are eligible for this study and for whom the parents/legal representatives give informed consent will be enrolled in this study. All patients will receive one cycle of blinatumomab on top of the standard treatment backbone after induction therapy. Medium risk patients, that respond well to the 1st cycle will be treated with a 2nd cycle of blinatumomab replacing one chemo course after consolidation therapy. If they do not respond well enough they will be treated according to the current treatment standard. Minimal residual disease will be used to determine the response to blinatumomab. High risk patients will be eligible for allogeneic stem cell transplantation after the first blinatumomab cycle if they are Minimal Residual Disease (MRD) negative (defined as < 0.01%). Also medium risk patients with insufficient MRD response after induction or after the 1st cycle of blinatumomab will be allocated to high risk treatment and will be eligible for allogeneic stem cell transplantation.

• Study Type: Interventional
• Enrollment (Anticipated): 160
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Judith Hoevenaars; Phone Number: 0031 6 5017 30 12; Email: trialmanagement@prinsesmaximacentrum.nl
• Study Contact Backup: Name: Peggy Scholte-Van Houtem; Phone Number: 0031 6 50 17 30 43; Email: trialmanagement@prinsesmaximacentrum.nl

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 day to 1 year (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Patients with newly diagnosed B- precursor acute lymphoblastic leukemia (ALL) or B- cell mixed phenotype acute leukemia (MPAL) according to the World Health Organization (WHO) classification of tumours of haematopoietic and lymphoid tissues (revised 4th edition 2017, with KMT2A-rearrangement.
2. ≤365 days of age at time of diagnosis of ALL
3. Written informed consent of the parents or other legally authorized guardian of the patient according to local law and regulations.

Exclusion Criteria:

1. KMT2A-germline patients
2. T-ALL
3. Age > 365 days at the time of diagnosis
4. Relapsed ALL
5. Treatment with systemic corticosteroids (equivalent prednisone >10 mg/m2/day) for more than one week and/or any chemotherapeutic agent in the 4-week interval prior to diagnosis. Patients who received corticosteroids by aerosol are eligible for the study.

Additional exclusion criteria for blinatumomab:

1. CD19 negative B-precursor ALL at diagnosis
2. CNS involvement (CNS2/CNS3 status) at the EOI. Patients with CNS disease at the time of diagnosis are eligible if CNS1 status is achieved prior to the start of the first blinatumomab cycle (lumbar puncture at ~day 33 of induction).
3. Proven hypersensitivity to the active substance or any of the excipients in blinatumomab.
4. Patients who have received a live vaccine 28 days prior to blinatumomab administration or plan to receive a live vaccine prior to B-cell recovery after the last dose of blinatumomab.

If exclusion criteria for blinatumomab are met, the patient should be treated according to the protocol but without blinatumomab.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: Medium Risk (MR); Subject is defined as MR if > 6months of age at diagnosis, OR < 6 months of age with White Blood cell Count (WBC) < 300 at diagnosis and good prednisone response. Subject gets 1st cycle of blinatumomab. If MRD is >0.01%, after 1st cycle of blinatumomab, subject will be allocated to HR treatment from that phase, and will be eligible for HSCT. If MRD is undetectable or < 0.01% after the 1st cycle of blinatumomab (TP2) patient will be eligible for replacement of MARMA by 2nd cycle of blinatumomab after receipt of lymphoid style consolidation (Protocol IB) or of myeloid style consolidation (ADE/MAE).	Drug: Blinatumomab; 1st cycle: 15 μg/m2/day as a 4 week continuous IV infusion for patients with a M1 marrow. For patients with a M2/M3 marrow a step-dosing strategy is required with a dose of 5 μg/m2/day in week 1 followed by 15 μg/m2/day in weeks 2, 3, and 4.; Other Names: Cycle 1; Drug: Blinatumomab; 2nd cycle: 15 μg/m2/day as a 4 week continuous iv infusion; Other Names: Cycle 2
Other: High risk (HR); Subject is defined as HR if < 6 months of age with WBC > 300 at diagnosis OR poor prednisone response. Also MR patients with end of induction MRD ≥ 1%, or MRD > 0.01% after the 1st cycle of blinatumomab, will be allocated to HR treatment. Subject gets 1 cycle of blinatumomab. Thereafter patient is eligible for hematopoietic stem cell transplantation (HSCT) with or without experimental therapy in an investigational window.	Drug: Blinatumomab; 1st cycle: 15 μg/m2/day as a 4 week continuous IV infusion for patients with a M1 marrow. For patients with a M2/M3 marrow a step-dosing strategy is required with a dose of 5 μg/m2/day in week 1 followed by 15 μg/m2/day in weeks 2, 3, and 4.; Other Names: Cycle 1; Drug: Blinatumomab; 2nd cycle: 15 μg/m2/day as a 4 week continuous iv infusion; Other Names: Cycle 2

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Event free survival (EFS).	The primary endpoint is EFS, defined as the time from diagnosis to resistance to induction, relapse, death from any cause or second malignancy (whichever occurs first), or time to last follow-up (censored) for patients without events.	5 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall survival	The endpoints for analysis by risk group will be EFS, cumulative incidence (or percentage) of resistance to induction, cumulative incidence of relapse (CIR), death in complete remission (CR) and second malignancy.	8 years
Endpoints by risk group	The endpoints for analysis by risk group will be EFS, cumulative incidence (or percentage) of resistance to induction, cumulative incidence of relapse (CIR), death in complete remission (CR) and second malignancy.	8 years
Outcome for the entire study cohort and according to risk group	Outcome for the entire study cohort and according to risk group will be evaluated in terms of the protocol specific definition of EFS follows: the time from diagnosis to, resistance to proto-col, relapse, death from any cause or second malignancy (whichever occurs first), or time to last follow-up for patients without events. Cumulative incidence (or percentage) of resistance, CIR, death in CR and second malignancy will also be estimated.	8 years
Minimal Residual Disease	MRD response as defined in the protocol and frequencies of MRD levels	8 years
CD19 (cluster of differentiation antigen 19) negative relapse	Proportion of CD19 negative relapses in the entire study cohort and according to risk group	8 years
Myeloid lineage switches	Proportion of myeloid lineage switches in the entire study cohort and according to risk group	8 years
Grade ≥3 adverse event	Proportion of grade ≥3 adverse event (AEs) during the blinatumomab course(s). Proportion of adverse events of special interest (AESIs) and serious adverse events (SAEs) in all protocol phases.	8 years
Grade ≥2 cardiac disorders	Proportion of grade ≥2 cardiac disorders at 2 and 5 years after diagnosis	5 years
Overall survival after 1st relapse	Overall survival (OS) after first relapse, defined as the time from first relapse to death from any cause, in the entire study cohort and according to risk group	8 years

Collaborators and Investigators

• Sponsor: Princess Maxima Center for Pediatric Oncology
• Collaborators: University of Milano Bicocca; Amgen Europe B.V
• Investigators: Principal Investigator: Janine Stutterheim, Dr, Princess Maxima Center for Pediatric Oncology in The Netherlands

Study record dates

Study Major Dates

• Study Start (Anticipated): September 1, 2022
• Primary Completion (Anticipated): September 1, 2027
• Study Completion (Anticipated): September 1, 2030

Study Registration Dates

• First Submitted: April 7, 2022
• First Submitted That Met QC Criteria: April 7, 2022
• First Posted (Actual): April 14, 2022

Study Record Updates

• Last Update Posted (Actual): April 14, 2022
• Last Update Submitted That Met QC Criteria: April 7, 2022
• Last Verified: April 1, 2022

More Information

Terms related to this study

• Keywords: infant under one year; KMT2A-rearranged
• Additional Relevant MeSH Terms: Pathologic Processes; Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Disease Attributes; Leukemia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Lymphoid; Acute Disease; Physiological Effects of Drugs; Antineoplastic Agents; Immunologic Factors; Blinatumomab; Antibodies, Bispecific
• Other Study ID Numbers: 2021-000213-16

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: all individual participant data that underlie results in a publication
• IPD Sharing Time Frame: The Clinical Study Report (CSR) will be made available within 6 months upon study end.
• IPD Sharing Access Criteria: A summary of the study results will be made public via www.clinical trials.gov as well as to Ethical committees/ Health Authorities and all participating patients by providing them through their treating physicians a patient letter with a summary of the results.
• IPD Sharing Supporting Information Type: Clinical Study Report (CSR)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No