Inotuzumab Ozogamicin for Children With MRD Positive CD22+ Lymphoblastic Leukemia

Study Overview
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Brief Summary
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This trial is a limited multi-center, Phase II study to evaluate inotuzumab ozogamicin (Besponsa) in pediatric patients with MRD positive CD22-positive B-lymphoblastic leukemia (B-ALL). Some patients with newly diagnosed ALL maintain low levels of MRD, despite achieving complete remission with less than 5% blasts in the bone marrow. Others experience re-emergence of low level MRD or increasing levels of MRD on therapy or post-transplant. New approaches are needed to achieve undetectable MRD in these high-risk patients. Inotuzumab ozogamicin is an antibody-drug conjugate composed of a humanized IgG subtype 4 monoclonal CD22-targeted antibody linked to calicheamicin, a potent anti-tumor antibiotic. CD22 is expressed in more than 90% of patients with B-cell ALL, making it an attractive target in this patient population. Inotuzumab ozogamicin has demonstrated exceptional activity in adults with relapsed or refractory B-ALL. Primary Objective Assess the efficacy of inotuzumab ozogamicin in patients with MRD positive CD22+ B-ALL with 0.1 - 4.99% blasts in bone marrow. Secondary Objectives Study the safety of inotuzumab ozogamicin when used in patients with MRD - positive CD22+ B-ALL with < 5 % blasts in bone marrow. Estimate the incidence, severity, and outcome of hepatotoxicity and sinusoidal obstruction syndrome/veno-occlusive disease (SOS/VOD) in patients during inotuzumab ozogamicin and following subsequent treatment, including hematopoietic stem cell transplant (HSCT).

Detailed Description
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The drug will be administered intravenously on days 1, 8, and 15 of each 28-day cycle. Patients who do not meet the definition of treatment failure after the first cycle may receive up to five additional cycles of therapy. . After completion of study treatment, patients are followed for 1 year.

Official Title
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Inotuzumab Ozogamicin for Children With MRD Positive CD22+ Lymphoblastic Leukemia

Conditions
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Acute Lymphoblastic Leukemia

Intervention / Treatment
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* Drug: Inotuzumab ozogamicin
* Drug: Methotrexate
* Drug: Hydrocortisone
* Drug: Cytarabine
* Drug: Diphenhydramine
* Drug: Acetaminophen
* Drug: Methylprednisolone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age Participants must be < 22 years of age. Diagnosis Participants must have B-ALL with persistent or rising MRD between 0.1 and 4.99% without extramedullary disease following at least two prior induction attempts, relapse or after hematopoietic stem cell transplant Leukemia blasts demonstrating surface expression of CD22 Performance Level Karnofsky or Lansky performance score ≥ 50% (corresponding to ECOG Score of ≥ 2). The Lansky performance score should be used for participants < 16 years and the Karnofsky performance score for participants ≥ 16 years. Prior Therapy Patients must have fully recovered from the acute toxic effects of all prior anticancer therapy, defined as resolution of all such toxicities to ≤ Grade 2 or lower per the inclusion/exclusion criteria prior to entering this study. At least 14 days must have elapsed since the completion of cytotoxic therapy, with the exception of standard maintenance therapy and steroids. At least 7 days must have elapsed since completion of therapy with a biologic agent. For agents that have known adverse events occurring beyond 7 days after administration, this period prior to enrollment must be extended beyond the time during which adverse events are known to occur. At least 3 half-lives must have elapsed since prior therapy that included a monoclonal antibody with the exception of blinatumomab. Patients must have been off blinatumomab infusion for at least 7 days and all drug related toxicity must have resolved to Grade 2 or lower as outlined in the inclusion/exclusion criteria. At least 42 days must have elapsed since CAR-T cell therapy. Participant has received ≤ 1 prior bone marrow transplant. At least 90 days have elapsed since bone marrow transplant and participant is off immune suppression for ≥ 2 weeks, if applicable with no evidence of active GVHD. At least 2 weeks must have elapsed since local XRT (small port); ≥ 3 months must have elapsed if prior cranial or craniospinal XRT was received, if ≥ 50% of the pelvis was irradiated, or if TBI was received; ≥ 6 weeks must have elapsed if other substantial bone marrow irradiation was given. Organ Function Requirements Adequate renal function defined as glomerular filtration rate ≥ 60 cc/min/1.73m2 or serum creatinine based on age as follows: Age: <6 months; maximum serum creatinine (mg/dL): 0.4 (male, female); Age: 6 months to <1 year; maximum serum creatinine (mg/dL): 0.5 (male, female); Age: 1 to < 2 years; maximum serum creatinine (mg/dL): 0.6 (male, female); Age: 2 to < 6 years; maximum serum creatinine (mg/dL): 0.8 (male, female); Age: 6 to <10 years; maximum serum creatinine (mg/ dL): 1 (male, female); Age: 10 to <13 years; maximum serum creatinine (mg/dL): 1.2 (male, female); Age: 13 to <16 years; maximum serum creatinine (mg/dL): 1.5 (male), 1.4 (female); Age: ≥ 16 years; maximum serum creatinine (mg/dL): 1.7 (male), 1.4 (female) Adequate hepatic function defined as: Direct bilirubin ≤ 1.4 mg/dL (if total bilirubin > 1.4 mg/dL) and AST or ALT ≤ 3 x ULN for age. Adequate cardiac function defined as shortening fraction of ≥ 27% or ejection fraction ≥ 45%. Exclusion Criteria: History of sinusoidal obstruction syndrome/veno-occlusive disease (SOS/VOD) of any severity. Concurrent chemotherapy or targeted anti-cancer agents, other than intrathecal therapy. Patient with concurrent severe and/or uncontrolled medical conditions that, in the opinion of the investigator, may impair participation in the study or the evaluation of safety and/or efficacy. Known HIV infection or active hepatitis B (defined as hepatitis B surface antigen-positive) or C (defined as hepatitis C antibody-positive). Pregnant or lactating (female participant of childbearing potential must have negative serum or urine pregnancy test required within 7 days prior to start of treatment). Male or female participant of reproductive potential must agree to use appropriate methods of contraception for the duration of study treatment and for at least 30 days after last dose of protocol treatment. Inability or unwillingness of research participant or legal guardian/representative to give written informed consent.

Ages Eligible for Study
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Maximum Age: 21 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Inotuzumab ozogamicin<br>Experimental:Inotuzumab Ozogamicin (InO) Patients with B cell acute lymphoblastic leukemia (B-ALL) that is showing early signs of relapsing (coming back) or is not responding to treatment (refractory). Interventions:methotrexate, hydrocortisone and cytarabine into the central nervous system (called triple intrathecal chemotherapy or IT chemotherapy) during this study. Premedication: diphenhydramine, acetaminophen and methylprednisolone | Drug: Inotuzumab ozogamicin<br>* dose: 0.5 mg/m2 IV over 60 minutes, days: 1, 8 and 15 every 4 weeks (28 days per cycle) for up to 6 cycles.<br>* Other names: CMC-544;Drug: Methotrexate<br>* Intrathecal (IT) therapy<br>* Other names: Trexall®;Drug: Hydrocortisone<br>* Intrathecal (IT) therapy<br>* Other names: Cortisol;Drug: Cytarabine<br>* Intrathecal (IT) therapy<br>* Other names: Ara-C;Drug: Diphenhydramine<br>* 1 mg/kg (max 50 mg) IV<br>* Other names: Benadryl;Drug: Acetaminophen<br>* 10 mg/kg (max 650 mg) PO x 1<br>* Other names: Tylenol;Drug: Methylprednisolone<br>* 1 mg/kg IV x 1<br>* Other names: Solu-Medrol;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Treatment response Cycle1 - count | Number of patients that reach MRD negative at the end of cycle 1 | At the end of cycle 1 (each cycle is 28 days) | 
| Treatment Response Cycle 1 - percentage | Percentage of patients that reach MRD negative at the end of cycle 1 | At the end of cycle 1 (each cycle is 28 days) | 
| Treatment Response Cycle 2 - count | Number of patients that reach MRD negative at the end of cycle 2 | At the end of cycle 2 (each cycle is 28 days) | 
| Treatment Response Cycle 2 - percentage | Percentage of patients that reach MRD negative at the end of cycle 2 | At the end of cycle 2 (each cycle is 28 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Occurrence of death - count | Number of patient deaths that occur at any time during observation on study | up to 30 days from last dose of inotuzumab ozogamicin or up to 30 days post-transplant among the patients who proceed to transplant | 
| Occurrence of death - percentage | Percentage of patient deaths that occur at any time during observation on study | up to 30 days from last dose of inotuzumab ozogamicin or up to 30 days post-transplant among the patients who proceed to transplant | 
| Occurrence of Veno-occlusive disease (VOD) - count | Number of patients that develop VOD at any time during observation on study | up to 30 days from last dose of inotuzumab ozogamicin or up to 30 days post-transplant among the patients who proceed to transplant | 
| Occurrence of Veno-occlusive disease (VOD) - percentage | Percentage of patients that develop VOD at any time during observation on study | up to 30 days from last dose of inotuzumab ozogamicin or up to 30 days post-transplant among the patients who proceed to transplant | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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B-cell Acute Lymphoblastic Leukemia