| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Acute Lymphoblastic Leukemia (ALL) |
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| E.1.1.1 | Medical condition in easily understood language |
| A type of cancer that affects the white blood cells and bone marrow; and progresses quickly and aggressively, requiring immediate treatment. |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10000845 |
| E.1.2 | Term | Acute lymphoblastic leukemia |
| E.1.2 | System Organ Class | 100000004864 |
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| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To demonstrate the superiority of Inotuzumab Ozogamicin (InO) monotherapy vs ALLR3 induction in paediatric participants between 1 and less than 18 years with HR first bone marrow relapse CD22-positive B-cell precursor acute lymphoblastic leukaemia (BCP ALL.) |
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| E.2.2 | Secondary objectives of the trial |
To evaluate the long-term efficacy of InO monotherapy vs ALLR3 regimen with respect to event-free survival (EFS).
To evaluate the long-term efficacy of InO monotherapy vs ALLR3 regimen with respect to:
• Duration of response (DOR)
• Hematopoietic stem cell transplant (HSCT) rate
• Chimeric antigen receptor (CAR) T-cell therapy
• Overall survival (OS)
To evaluate the safety and tolerability of InO monotherapy vs ALLR3 induction
To evaluate the pharmacokinetics (PK) of InO
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Male or female participants between 1 and less than 18 years of age.
Type of Participant and Disease Characteristics:
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 (ie, KMT2A-rearrangements, TCF3-HLF, TCF3-PBX1, hypodiploidy [<45 chromosomes], TP53 alteration)
• CD22-positive ALL as defined by local institution;
• Bone marrow involvement of ≥ 5% leukemic blasts (≥ M2 status).
Other Inclusion Criteria:
3. Adequate serum chemistry parameters:
• An estimated glomerular filtration rate (eGFR) in participants 1 to less than 2 years of age, or estimated creatinine clearance (eCrCl) in those 2 to less than 18 years of age, ≥30 mL/min using the recommended formula
• Aspartate aminotransferase (AST) and alanine aminotransferase (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 participant receives anti-coagulant prophylaxis per institutional guidelines.
5. Cardiac shortening fraction ≥ 30% by echocardiogram or ejection fraction > 50% by MUGA.
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| E.4 | Principal exclusion criteria |
Medical Conditions:
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)];
• Prior allo-HSCT or CAR T-cell therapy;
• Isolated extramedullary leukemia;
• Confirmed testicular relapse unless orchiectomy was performed prior to randomization;
• 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 PEG-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.
2. 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 stimulating factor (ie, Neupogen or equivalent) administered within 7 days prior to study enrollment and 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);
• Any vaccination with live viral vaccines within 2 weeks of the start of study therapy.
Prior/Concurrent Clinical Study Experience:
3. 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:
4. Serum or urine pregnancy test positive at screening.
5. 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 third degree 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 over read locally by a physician experienced in reading ECGs before excluding participants.
6. 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.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| Minimal residual disease (MRD)-negative, CR/CRp/CRi (per investigator assessment) at the end of induction therapy (MRD negativity is assessed by central lab and defined as leukemic blasts <1x10-4 by real time quantitative polymerase chain reaction (RQ-PCR) [with reflex to FC result if MRD is non-evaluable by RQ-PCR]). |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| MRD-negative, CR/CRp/CRi (per investigator assessment) will be evaluated at the end of induction therapy |
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| E.5.2 | Secondary end point(s) |
EFS, defined as the time from randomization until objective progression, relapse from CR/CRp/CRi, based on investigator assessment per response criteria, failure to achieve CR/CRp/CRi by the end of induction, MRD persistence prior to HSCT, second malignancy, or death due to any cause.
DOR, defined as time from date of first documented response (CR/CRp/CRi) to the date of first documented objective progression, relapse from CR/CRp/CRi as determined by investigator assessment per modified NCCN response criteria, MRD persistence prior to HSCT, or death due to any cause, whichever occurs first.
HSCT (and CAR T-cell therapy) rate, defined as the number and percentage of participants being transplanted and those receiving CAR T-cell therapy after treatment with InO or ALLR3.
OS, defined as the time from the date of randomization to the date of death due to any cause.
Incidence and severity of AEs graded per NCI CTCAE v4.03.
Cmax and Ctrough
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
EFS will be evaluated from randomization until objective progression, relapse from CR/CRp/CRi, based on investigator assessment per response criteria, failure to achieve CR/CRp/CRi by the end of induction, MRD persistence prior to HSCT, second malignancy, or death due to any cause.
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 64 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Israel |
| Switzerland |
| Austria |
| Belgium |
| Czechia |
| Denmark |
| Finland |
| France |
| Germany |
| Greece |
| Hungary |
| Italy |
| Netherlands |
| Norway |
| Poland |
| Slovakia |
| Spain |
| Sweden |
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| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| The end of the study is defined as the date of the last visit of the last participant in the study or last scheduled procedure for the last participant in the trial. |
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 8 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 8 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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