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

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 or VHR 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. Two interim analyses (approximately 50% and 75% enrollment) fort the primary outcome measure followed by a final analysis are planned to assess efficacy and futility (non-binding).

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.

• Inotuzumab ozogamicin (Drug), also known as Besponsa: 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.
• ALLR3 (Drug), also known as R3: The ALLR3 chemotherapy regimen (vincristine, mitoxantrone, dexamethasone, and PEG-asparaginase \[or erwinia-asparaginase in the event of an allergic reaction to PEG-asparaginase\]) has been adopted by pediatric oncology groups as treatment for pediatric relapsed/refractory (R/R) acute lymphoblastic leukemia (ALL)

Primary outcomes

• 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) [After 1 treatment cycle: Day 28 +/- 2 days]: 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

Secondary outcomes

• Event Free Survival (EFS) [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]: EFS will be summarized using Kaplan-Meier methods and displayed graphically by treatment arm.
• Duration of Response (DoR) for Participants Who Achieved CR/CRp/CRi [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]: DoR will be summarized using Kaplan-Meier methods.
• Rate of hematopoietic stem cell transplantation (HSCT) [Up to 5 years from randomization]: HSCT rate will be summarized by descriptive analyses (ie, percentage of participants who underwent HSCT after treatment).
• Overall Survival (OS) [From start of treatment to date of death due to any cause: up to 5 years from randomization]: OS will be summarized by treatment arm using Kaplan-Meier methods.
• Number of participants reporting an Adverse Event (AE) [From time of informed consent up to a minimum of 60 calendar days after the last dose of study drug.]: 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.
• Pharmacokinetics (PK) parameter: InO Cmax [1 treatment cycle: 28 days]: Descriptive summary statistics will be provided for InO serum concentrations at scheduled visits.
• Number of Adverse Events (AE) reported by severity [From time of informed consent up to a minimum of 60 calendar days after the last dose of study drug.]: AEs will be graded by the investigator according to the CTCAE (Common Terminology Criteria for Adverse Events) version 4.03.
• Pharmacokinetics (PK) parameter: InO trough levels [1 treatment cycle: 28 days]: Descriptive summary statistics will be provided for InO serum concentrations at scheduled visits.
• Rate of Chimeric antigen receptor (CAR) T-cell therapy [Up to 5 years from randomisation]: 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).

Sex: All, ages: 1 Year to 17 Years

Inclusion Criteria:

1. Male or female participants between 1 and <18 years of age.
2. Morphologically confirmed diagnosis of first relapse HR or VHR 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 (Groeneveld-Krentz et al, 2019) (ie, KMT2A::AFF1 fusion \[t(4;11)(q21;q23)\], TCF3-HLF fusion \[t(17;19)(q22;p13)\], TCF3-PBX1 fusion \[t(1;19)(q23;p13.3)\], hypodiploidy \[<40 chromosomes\] or masked low hypodiploidy (Molina et al, 2021), TP53 alteration). VHR first relapse is defined as relapse within 18 months of original diagnosis of ALL and/or with any of the following genetic abnormalities at original diagnosis or at relapse (Groeneveld-Krentz et al, 2019) (ie, KMT2A::AFF1 fusion \[t(4;11)(q21;q23)\], TCF3-HLF fusion \[t(17;19)(q22;p13)\], TCF3-PBX1 fusion \[t(1;19)(q23;p13.3)\], hypodiploidy \[<40 chromosomes\] or masked low hypodiploidy (Molina et al, 2021), TP53 alteration).

   * CD22-positive ALL as defined by local institution;
   * Bone marrow involvement of ≥ 5% leukemic blasts (≥ M2 status).
3. 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; (Refer to Appendix 9 for France-specific requirement on the ALT/AST threshold);
   * Total bilirubin ≤1.5 × institutional ULN unless the participant has documented Gilbert's syndrome;
4. Prior history of thrombosis during corticosteroid use and/or asparaginase are eligible provided the patient receives anti-coagulant prophylaxis per institutional guidelines.
5. Cardiac shortening fraction ≥ 30% by echocardiogram or ejection fraction >50% by MUGA.

6 Participants with combined bone marrow and testicular relapse are eligible assuming orchiectomy is performed prior to randomization or is planned at the end of induction therapy.

5.2. Exclusion Criteria

1. Any history of prior or ongoing hepatic SOS or prior liver failure \[defined as severe acute liver injury with encephalopathy and impaired synthetic function (INR of ≥1.5)\].
2. Prior allo-HSCT or CAR T-cell therapy.
3. Isolated extramedullary leukemia.
4. Philadelphia-chromosome positive ALL, ie. BCR-ABL/t(9;22) present.
5. Prior therapy with a calicheamicin-conjugated antibody (eg, InO or gemtuzumab ozogamicin).
6. Participants with active, uncontrolled bacterial, fungal, or viral infection.
7. Hypersensitivity/allergy to both PEG-ASP and Erwinia-ASP

• Results publication: Davis KL, Yao CC, Zimmerman JAO, Rau RE. Immunotherapy in B-Cell Acute Lymphoblastic Leukemia. J Natl Compr Canc Netw. 2025 Dec;23(12):e257067. doi: 10.6004/jnccn.2025.7067. PMID 41671463

• Pfizer CT.gov Call Center, Study director, Pfizer

NIH grants: 2023