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

Sponsor

Princess Maxima Center for Pediatric Oncology (Other)

Overall Status

Not yet recruiting

CT.gov ID

NCT05327894

Collaborator

Amgen Europe B.V (Other), University of Milano Bicocca (Other)

160

Enrollment

Arms

Anticipated Duration (Months)

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Acute Lymphoblastic Leukemia Mixed Phenotype Acute Leukemia	Drug: Blinatumomab Drug: Blinatumomab	Phase 3

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 Design

Study Type:

Interventional

Anticipated Enrollment :

160 participants

Allocation:

Non-Randomized

Intervention Model:

Sequential Assignment

Intervention Model Description:

Definition: Provide details about the Interventional Study Model. Limit: 1000 characters.Definition: Provide details about the Interventional Study Model. Limit: 1000 characters.

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Anticipated Study Start Date :

Sep 1, 2022

Anticipated Primary Completion Date :

Sep 1, 2027

Anticipated Study Completion Date :

Sep 1, 2030

Arms and Interventions

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

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

Other Names:

Cycle 1

Outcome Measures

Primary Outcome Measures

Event free survival (EFS). [5 years]
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.

Secondary Outcome Measures

Overall survival [8 years]
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.
Endpoints by risk group [8 years]
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.
Outcome for the entire study cohort and according to risk group [8 years]
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.
Minimal Residual Disease [8 years]
MRD response as defined in the protocol and frequencies of MRD levels
CD19 (cluster of differentiation antigen 19) negative relapse [8 years]
Proportion of CD19 negative relapses in the entire study cohort and according to risk group
Myeloid lineage switches [8 years]
Proportion of myeloid lineage switches in the entire study cohort and according to risk group
Grade ≥3 adverse event [8 years]
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.
Grade ≥2 cardiac disorders [5 years]
Proportion of grade ≥2 cardiac disorders at 2 and 5 years after diagnosis
Overall survival after 1st relapse [8 years]
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

Eligibility Criteria

Criteria

Ages Eligible for Study:

1 Day to 365 Days

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

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.
≤365 days of age at time of diagnosis of ALL
Written informed consent of the parents or other legally authorized guardian of the patient according to local law and regulations.

Exclusion Criteria:

KMT2A-germline patients
T-ALL
Age > 365 days at the time of diagnosis
Relapsed ALL
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:

CD19 negative B-precursor ALL at diagnosis
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).
Proven hypersensitivity to the active substance or any of the excipients in blinatumomab.
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.