A Phase 2 Superiority Study with InO Monotherapy vs ALLR3 for Induction Treatment of Childhood HR or VHR First Relapse BCP ALL

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• 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; • Presence of Grade 3 or Grade 4 peripheral neuropathy as defined in the Delphi consensus of acute toxic effects for childhood ALL; • Hypersensitivity to the active ingredient of InO or any of its excipients; • Hypersensitivity/allergy to both PEG-ASP and Erwinia-ASP; • Intolerance to any of the ALLR3 agents (mitoxantrone, vincristine, dexamethasone, asparaginase); • Grade 3 or Grade 4 pancreatitis due to any cause, as defined by CTCAE v4.03; • Grade 3 or Grade 4 allergic reaction to a monoclonal antibody; • Participants not fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy, defined as resolution of all such non-hematologic toxicities to Grade ≤2 per the NCI CTCAE v 4.03 prior to randomization, with the exception of the laboratory abnormalities as defined by other inclusion/exclusion criteria; • Down syndrome; • Other medical or psychiatric condition including recent (within the past year) or active suicidal ideation/behavior or laboratory abnormality that may increase the risk of study participation or, in the investigator's judgment, make the participant inappropriate for the study; • Charcot-Marie-Tooth disease.
• Prior/Concomitant therapy with: • A calicheamicin-conjugated antibody (eg, InO or gemtuzumab ozogamicin) or prior therapy with a CD22-targeted therapy (immunotoxin or CAR T-cell therapy); • Cytotoxic therapy within 7 days prior to enrollment, with the exception of hydroxyurea and corticosteroids, which are permitted prior to initiating study intervention. Participants may have received intrathecal chemotherapy at any time prior to study entry. NOTE: No waiting period is required for participants who relapse while receiving first-line maintenance chemotherapy. • Any radiation therapy within 28 days prior to enrollment; • The last dose of granulocyte colony-stimulating factor (ie, Neupogen or equivalent) administered within 7 days prior to study enrollment and/or the last dose of pegfilgrastim (Neulasta®) given within 14 days prior to enrollment; • Less than 3 half-lives elapsed after the last dose of a mAb (eg, rituximab=66 days, epratuzumab=69 days). Participants must not have received blinatumomab within 4 weeks before study enrollment; • Current use of any prohibited concomitant medication(s) or participants unwilling/unable to use a permitted concomitant medication(s). Refer to Section 6.8,, Concomitant Therapy. • Any vaccination with live viral vaccines within 2 weeks of the start of study therapy.
• Administration of an IP (eg, drug or vaccine) concurrent with study intervention or within 30 days (or as determined by the local requirement) or 5 half-lives preceding the first dose of study intervention used in this study (whichever is longer). A participant may be eligible if they are in the follow-up phase of an investigational study if they meet the criterion for time elapsed from previous administration of IP. Cases must be discussed with sponsor's medical monitor to judge eligibility.
• Diagnostic Assessments: Serum or urine pregnancy test positive at screening.
• Baseline 12 lead ECG that demonstrates clinically relevant abnormalities that may affect participant safety or interpretation of study results (eg, QTcF interval >470 msec, complete LBBB, signs of an acute or indeterminate age myocardial infarction, STT interval changes suggestive of myocardial ischemia, second- or thirddegree AV block, or serious bradyarrhythmias or tachyarrhythmias). If QTcF >470 msec, the ECG should be repeated 2 more times the average of the 3 QTcF values should be used to determine the participant’s eligibility. Computer interpreted ECGs should be overread locally by a physician experienced in reading ECGs before excluding participants.
• Participants with active infection, including (but not limited to) HBV, HCV, and known HIV or AIDS-related illness. • HIV infection with CD4+ count <200/mm3 and viral load of >400 copies/mm3. Participants with stable well-controlled HIV infection may be eligible after consultation with the sponsor. HBV • Participants with a positive HBsAg (ie, either acute or chronic active hepatitis) are excluded. • Participants with HBV antibody positivity indicating immunity, either due to vaccination or prior natural infection, are eligible. •Participants with positive anti-HBcAb but negative HBsAg and anti- HBsAb profile, depending on clinical circumstances, may be eligible. Discussion with the sponsor is indicated. HCV • Participants with active HCV as determined by viral load.