A Study to Learn More About the Study Medicine Called Inotuzumab Ozogamicin (InO) in Children (1 to <18 Years) With First Relapse ALL

Study Overview
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Brief Summary
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This prospective, randomized, multicenter, open-label Phase 2 study is designed to evaluate the superiority of InO monotherapy vs ALLR3 after 1 cycle of induction treatment in paediatric participants (between 1 and <18 years) with High Risk (HR) first bone marrow relapse CD22-positive BCP ALL, and to evaluate the safety and tolerability, PK and long-term efficacy. Treatment with study intervention will end after induction therapy; follow-up will continue for up to 5 years from randomization.

Detailed Description
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This prospective, randomized, multicenter, open-label, Phase 2 study is designed to evaluate the superiority of InO monotherapy vs ALLR3, after 1 cycle of induction treatment in paediatric participants (between 1 and <18 years) with HR first bone marrow relapse CD22-positive BCP ALL, and to evaluate the safety and tolerability, PK and long-term efficacy. Treatment with study intervention will end after induction therapy; follow-up for efficacy and safety will continue for up to 5 years from randomization. End of Treatment is defined as occurring upon recovery from 1 cycle of study therapy (Day 28 ± 2 days), or one day before initiation of new anticancer therapy, whichever occurs first. Approximately 100 participants will be randomized (2:1) to receive 1 cycle of either InO monotherapy or ALLR3 (block 1) therapy during induction. After completion of induction therapy (ie, study therapy), it is anticipated that the majority of responding participants will proceed immediately to consolidation therapy. Non-responders are expected to proceed with salvage therapy at the investigator's discretion. Participants responding to induction therapy are expected to proceed to SOC consolidation therapy upon recovery of blood counts, but no sooner than 7 days after last dose of study intervention. All participants (responders and non-responders) will proceed to long-term follow-up for this study. All subsequent anticancer therapy will be determined by the treating physician.

Official Title
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A PROSPECTIVE, RANDOMIZED, OPEN-LABEL PHASE 2 STUDY TO EVALUATE THE SUPERIORITY OF INOTUZUMAB OZOGAMICIN MONOTHERAPY VERSUS ALLR3 FOR INDUCTION TREATMENT OF CHILDHOOD HIGH RISK FIRST RELAPSE B-CELL PRECURSOR ACUTE LYMPHOBLASTIC LEUKAEMIA

Conditions
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ACUTE LYMPHOBLASTIC LEUKEMIA

Intervention / Treatment
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* Drug: Inotuzumab ozogamicin
* Drug: ALLR3


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female participants between 1 and <18 years of age. Morphologically confirmed diagnosis of first relapse HR BCP ALL; HR first relapse is defined as relapse occurring within 18 to 30 months of original diagnosis of ALL or within 6 months of completion of primary therapy, and lacking any identified very high-risk genetic abnormalities (ie, KMT2A-rearrangements, TCF3-HLF, TCF3-PBX1, hypodiploidy, TP53 alteration) CD22-positive ALL as defined by local institution; Bone marrow involvement of ≥ 5% leukemic blasts (≥ M2 status). Adequate serum chemistry parameters: An eGFR in participants 1 to <2 years of age, or eCrCl in those 2 to <18 years of age, ≥30 mL/min using the recommended formula in Section 10.10.2. AST and ALT ≤5 × institutional ULN at the time of randomization or pre-cytoreduction/general anesthesia; Total bilirubin ≤1.5 × institutional ULN unless the participant has documented Gilbert's syndrome; Prior history of thrombosis during corticosteroid use and/or asparaginase are eligible provided the patient receives anti-coagulant prophylaxis per institutional guidelines. Cardiac shortening fraction ≥ 30% by echocardiogram or ejection fraction >50% by MUGA. 5.2. Exclusion Criteria Any history of prior or ongoing hepatic SOS or prior liver failure [defined as severe acute liver injury with encephalopathy and impaired synthetic function (INR of ≥1.5)]. Prior allo-HSCT or CAR T-cell therapy. Isolated extramedullary leukemia. Philadelphia-chromosome positive ALL, ie. BCR-ABL/t(9;22) present. Prior therapy with a calicheamicin-conjugated antibody (eg, InO or gemtuzumab ozogamicin). Participants with active, uncontrolled bacterial, fungal, or viral infection.

Ages Eligible for Study
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Minimum Age: 1 Year
Maximum Age: 17 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Participants will be randomized at 2:1 ratio, so that approximately 67 participants will receive InO and 33 participants will receive the comparator treatment regimen, ALLR3
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Inotuzumab ozogamicin<br>Each participant in the InO arm will receive 1 course (3 doses) of InO, as follows: Day 1: 0.8 mg/m2 Days 8 (±1 day) and Day 15 (±1 day): 0.5 mg/m2/dose | Drug: Inotuzumab ozogamicin<br>* Inotuzumab ozogamicin (BESPONSA™) is a CD22 targeted antibody drug conjugate (ADC) approved in several countries for the treatment of adults with relapsed or refractory B cell precursor acute lymphoblastic leukemia (ALL). The approved starting dose is 1.8mg/m2/cycle.<br>* Other names: Besponsa;|
| Active Comparator: ALLR3<br>Mitoxantrone 10 mg/m2 on Days 1 and 2 Vincristine 1.5 mg/m2 (max single dose 2 mg) administered on Days 3, 10, 17 and 24 Dexamethasone 20 mg/m2/day administered orally (or IV) divided into two daily doses (maximum 40 mg/day) as two 5-day blocks on Days 1-5 and Days 15-19. PEG-asparaginase 1000 units/m2 IV administered on Days 3 and 17 | Drug: ALLR3<br>* The ALLR3 chemotherapy regimen (vincristine, mitoxantrone, dexamethasone, and asparaginase) has been adopted by pediatric oncology groups as treatment for pediatric relapsed/refractory (R/R) acute lymphoblastic leukemia (ALL)<br>* Other names: R3;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Minimum Residual Disease (MRD) Negativity in participants achieving complete response (CR), complete response with incomplete platelet count recovery (CRp), or complete response with incomplete count recovery (CRi) | MRD negativity status is determined based on the minimum MRD percentage between the date of CR/CRp/CRi and end of treatment test as assessed by RQ-PCR, with reflex to FC result if MRD is non-evaluable by RQ-PCR | After 1 treatment cycle: Day 28 +/- 2 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Event Free Survival (EFS) | EFS will be summarized using Kaplan-Meier methods and displayed graphically by treatment arm. | From study start to first event (progression, relapse, failure to achieve CR/CRp/CRi by the end of induction, MRD persistence prior to HSCT [hematopoietic stem cell transplant], second malignancy, or death): up to 5 years from randomization | 
| Duration of Response (DoR) for Participants Who Achieved CR/CRp/CRi | DoR will be summarized using Kaplan-Meier methods. | From date of first response to date of first event (objective progression, relapse as determined by investigator assessment, MRD persistence prior to HSCT, or death due to any cause, whichever occurs first): up to 5 years from End of Treatment | 
| Rate of hematopoietic stem cell transplantation (HSCT) | HSCT rate will be summarized by descriptive analyses (ie, percentage of participants who underwent HSCT after treatment). | Up to 5 years from randomization | 
| Overall Survival (OS) | OS will be summarized by treatment arm using Kaplan-Meier methods. | From start of treatment to date of death due to any cause: up to 5 years from randomization | 
| Number of participants reporting an Adverse Event (AE) | The number and percentage of participants who experienced any AE, SAE (Serious Adverse Event), treatment related AE, and treatment related SAE will be summarized according to worst toxicity grades. | From time of informed consent up to a minimum of 60 calendar days after the last dose of study drug. | 
| Pharmacokinetics (PK) parameter: InO Cmax | Descriptive summary statistics will be provided for InO serum concentrations at scheduled visits. | 1 treatment cycle: 28 days | 
| Number of Adverse Events (AE) reported by severity | AEs will be graded by the investigator according to the CTCAE (Common Terminology Criteria for Adverse Events) version 4.03. | From time of informed consent up to a minimum of 60 calendar days after the last dose of study drug. | 
| Pharmacokinetics (PK) parameter: InO trough levels | Descriptive summary statistics will be provided for InO serum concentrations at scheduled visits. | 1 treatment cycle: 28 days | 
| Rate of Chimeric antigen receptor (CAR) T-cell therapy | CAR T-cell therapy rate will be summarized by descriptive analyses (ie, the number, percent of participants who underwent CAR T-cell therapy after treatment). | Up to 5 years from randomisation | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ALL, BCP ALL, High risk BCP ALL, Relapse ALL, Leukemia