A Study to Learn More About the Study Medicine Called Inotuzumab Ozogamicin (InO) in Children (1 to <18 Years) With First Relapse ALL
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
1. Male or female participants between 1 and \<18 years of age.
2. 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 (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;
* 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
- 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.
- Hypersensitivity/allergy to both PEG-ASP and Erwinia-ASP
Participant Group/Arm
EXPERIMENTAL: Inotuzumab ozogamicin
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
Intervention/Treatment
DRUG: Inotuzumab ozogamicin
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.Participant Group/Arm
ACTIVE_COMPARATOR: ALLR3
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. In case of hypersensitivity/allergic reaction to PEG-asparaginase, each dose of PEG-asparaginase will be replaced by Erwinia-asparaginase at a dose of 20,000 units/m² IV or IM every other day for a total of 6 doses
Intervention/Treatment
DRUG: ALLR3
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)Outcome Measure
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)
Measure Description
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
Time Frame
After 1 treatment cycle: Day 28 +/- 2 days
Outcome Measure
Event Free Survival (EFS)
Measure Description
EFS will be summarized using Kaplan-Meier methods and displayed graphically by treatment arm.
Time Frame
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
Outcome Measure
Duration of Response (DoR) for Participants Who Achieved CR/CRp/CRi
Measure Description
DoR will be summarized using Kaplan-Meier methods.
Time Frame
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
Outcome Measure
Rate of hematopoietic stem cell transplantation (HSCT)
Measure Description
HSCT rate will be summarized by descriptive analyses (ie, percentage of participants who underwent HSCT after treatment).
Time Frame
Up to 5 years from randomization
Outcome Measure
Overall Survival (OS)
Measure Description
OS will be summarized by treatment arm using Kaplan-Meier methods.
Time Frame
From start of treatment to date of death due to any cause: up to 5 years from randomization
Outcome Measure
Number of participants reporting an Adverse Event (AE)
Measure Description
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.
Time Frame
From time of informed consent up to a minimum of 60 calendar days after the last dose of study drug.
Outcome Measure
Pharmacokinetics (PK) parameter: InO Cmax
Measure Description
Descriptive summary statistics will be provided for InO serum concentrations at scheduled visits.
Time Frame
1 treatment cycle: 28 days
Outcome Measure
Number of Adverse Events (AE) reported by severity
Measure Description
AEs will be graded by the investigator according to the CTCAE (Common Terminology Criteria for Adverse Events) version 4.03.
Time Frame
From time of informed consent up to a minimum of 60 calendar days after the last dose of study drug.
Outcome Measure
Pharmacokinetics (PK) parameter: InO trough levels
Measure Description
Descriptive summary statistics will be provided for InO serum concentrations at scheduled visits.
Time Frame
1 treatment cycle: 28 days
Outcome Measure
Rate of Chimeric antigen receptor (CAR) T-cell therapy
Measure Description
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).
Time Frame
Up to 5 years from randomisation
Pfizer
