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

Official title

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 OR VERY HIGH-RISK FIRST RELAPSE B-CELL PRECURSOR ACUTE LYMPHOBLASTIC LEUKAEMIA

Overview

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 High Risk (HR) or very high risk (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 will continue for up to 5 years from randomization.

Detailed description

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.

Interventions

• 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.
• 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)

Primary outcome measures

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

Secondary outcome measures (9)

• Event Free Survival (EFS) [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]
• Duration of Response (DoR) for Participants Who Achieved CR/CRp/CRi [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]
• Rate of hematopoietic stem cell transplantation (HSCT) [Time frame: Up to 5 years from randomization]
• Overall Survival (OS) [Time frame: From start of treatment to date of death due to any cause: up to 5 years from randomization]
• Number of participants reporting an Adverse Event (AE) [Time frame: From time of informed consent up to a minimum of 60 calendar days after the last dose of study drug.]
• Pharmacokinetics (PK) parameter: InO Cmax [Time frame: 1 treatment cycle: 28 days]
• Number of Adverse Events (AE) reported by severity [Time frame: From time of informed consent up to a minimum of 60 calendar days after the last dose of study drug.]
• Pharmacokinetics (PK) parameter: InO trough levels [Time frame: 1 treatment cycle: 28 days]
• Rate of Chimeric antigen receptor (CAR) T-cell therapy [Time frame: Up to 5 years from randomisation]

Eligibility criteria

Inclusion criteria

• Male or female participants between 1 and <18 years of age.
• 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).
• 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;
• Prior history of thrombosis during corticosteroid use and/or asparaginase are eligible provided the patient receives anti-coagulant prophylaxis per institutional guidelines.
• 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

• 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

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

Germany · 14 centers

• Universitaetsklinikum Freiburg — Freiburg im Breisgau
• Universitaetsklinikum Ulm — Ulm
• Universitaetsklinikum Wuerzburg — Würzburg
• Universitätsklinikum Frankfurt Goethe-Universität — Frankfurt am Main
• Medizinische Hochschule Hannover — Hanover
• Universitaetsklinikum Essen — Essen
• Universitätsklinikum Münster - Albert Schweitzer Campus — Münster
• Universitaetsklinikum Schleswig-Holstein Campus Kiel — Kiel
• … and 6 more centers

France · 12 centers

• Centre Hospitalier Universitaire de Nice - Hôpital l'Archet — Nice
• CHU Strasbourg-Hautepierre, Service d'hematologie oncologie pediatrique, pediatrie 3 — Strasbourg
• Bordeaux University Hospital - Pellegrin — Bordeaux
• CHU de Toulouse - Hôpital des Enfants - Hemato-Immuno-Oncologie — Toulouse
• Hôpital Arnaud de Villeneuve - CHU Montpellier — Montpellier
• Centre Hospitalier Régional Universitaire de Nancy - Hôpitaux de Brabois — Vandœuvre-lès-Nancy
• Hôpital Jeanne de Flandre - CHRU — Lille
• Assistance Publique - Hopitaux de Paris (AP-HP) - Hopital Robert Debre - Centre Hospitalo — Paris
• … and 4 more centers

Italy · 9 centers

• Azienda Ospedaliera di Rilievo Nazional Santobono Pausilipon — Naples
• IRCCS Istituto Giannina Gaslini — Genoa
• Fondazione IRCCS San Gerardo dei Tintori — Monza
• Ospedale Pediatrico Bambino Gesù IRCCS — Rome
• Policlinico "G. Rodolico" — Catania
• Azienda Ospedale - Università Padova — Padova
• Fondazione IRCCS Policlinico San Matteo — Pavia
• Ospedale Regina Margherita — Torino
• … and 1 more center

Spain · 9 centers

• CHUS - Hospital Clinico Universitario — Santiago de Compostela
• Hospital Universitari Vall d'Hebron — Barcelona
• Hospital Sant Joan de Déu — Esplugues de Llobregat
• Hospital Infantil Universitario Niño Jesús — Madrid
• Hospital Clinico Universitario Virgen de la Arrixaca — El Palmar
• Hospital Universitario La Paz — Madrid
• CHUS - Hospital Clinico Universitario — Santiago de Compostela
• Hospital Universitario Virgen Del Rocio — Seville
• … and 1 more center

Israel · 4 centers

• Schneider Children's Medical Center — Petah Tikva
• The Edmond and Lily Safra Children's Hospital; The Chaim Sheba Medical Center — Ramat Gan
• Rambam Health Care Campus — Haifa
• Tel-Aviv Sourasky Medical Center Dana-Dwek Children's Hospital — Tel Aviv

Belgium · 3 centers

• Cliniques universitaires Saint-Luc — Brussels
• UZ Gent — Ghent
• UZ Leuven — Leuven

Sweden · 3 centers

• Skånes Universitetssjukhus Lund — Lund
• Sahlgrenska Universitetssjukhuset Östra — Gothenburg
• Astrid Lindgrens Barnsjukhus — Stockholm

Switzerland · 3 centers

• Inselspital Bern — Bern
• CHUV (centre hospitalier universitaire vaudois) — Lausanne
• Kinderspital Zürich — Zurich

Czechia · 2 centers

• Detska nemocnice FN Brno — Brno
• Fakultni Nemocnice Motol a Homolka — Prague

Norway · 2 centers

• Oslo Universitetssykehus Rikshospitalet — Oslo
• Radium Hospital — Oslo

Poland · 2 centers

• Szpital Uniwersytecki nr 1 im. dr. A. Jurasza w Bydgoszczy — Bydgoszcz
• Uniwersytecki Szpital Kliniczny im. Jana Mikulicza-Radeckiego we Wrocławiu — Wroclaw

Austria · 1 center

• St. Anna Kinderspital — Vienna

Denmark · 1 center

• Rigshospitalet — Copenhagen

Finland · 1 center

• Helsinki university hospital — Helsinki

Netherlands · 1 center

• Prinses Maxima Centrum voor Kinderoncologie — Utrecht

Slovakia · 1 center

• Narodny ustav detskych chorob — Bratislava

Publications

• 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

Identifiers

NCT: NCT05748171 · B1931036 · 2023-509810-13-00

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗