This phase 1 study investigated the recommended phase 2 dose (RP2D) of inotuzumab ozogamicin (InO), a CD22-directed antibody-drug conjugate, in pediatric patients with multiple relapsed/refractory (R/R) CD22+ acute lymphoblastic leukemia (ALL). Patients (age ≥1 year or <18 years) received 3 doses of InO (days 1, 8, and 15) per course. Dose escalation was based on dose-limiting toxicities (DLTs) during course 1. Dose level 1 (DL1) was 1.4 mg/m2 (0.6, 0.4, 0.4 mg/m2) and DL2 was 1.8 mg/m2 (0.8, 0.5, 0.5 mg/m2). Secondary end points included safety, antileukemic activity, and pharmacokinetics. Twenty-five patients (23 evaluable for DLTs) were enrolled. In course 1, the first cohort had 1 of 6 (DL1) and 2 of 5 (DL2) patients who experienced DLTs; subsequent review considered DL2 DLTs to be non-dose-limiting. Dose was de-escalated to DL1 while awaiting protocol amendment to re-evaluate DL2 in a second cohort, in which 0 of 6 (DL1) and 1 of 6 (DL2) patients had a DLT. Twenty-three patients experienced grade 3 to 4 adverse events; hepatic sinusoidal obstruction syndrome was reported in 2 patients after subsequent chemotherapy. Overall response rate after course 1 was 80% (95% confidence interval [CI], 59% to 93%) (20 of 25 patients; DL1: 75% [95% CI, 43% to 95%], DL2: 85% [95% CI, 55% to 98%]). Of the responders, 84% (95% CI, 60% to 97%) achieved minimal residual disease (MRD)-negative complete response, and 12-month overall survival was 40% (95% CI, 25% to 66%). Nine patients received hematopoietic stem cell transplantation or chimeric antigen receptor T cells after InO. InO median maximum concentrations were comparable to simulated adult concentrations. InO was well tolerated, demonstrating antileukemic activity in heavily pretreated children with CD22+ R/R ALL. RP2D was established as 1.8 mg/m2 per course, as in adults. This trial was registered at https://www.clinicaltrialsregister.eu as EUDRA-CT 2016-000227-71.

Children's Health Ireland at Crumlin Dublin Ireland

Department of Immunology Erasmus MC University Medical Center Rotterdam Rotterdam The Netherlands

Department of Paediatric Haematology and Oncology 2nd Faculty of Medicine Charles University Prague and Motol University Hospital Prague Czech Republic

Department of Paediatrics and Adolescent Medicine Juliane Marie Centre Rigshospitalet Copenhagen Denmark

Department of Pediatric Hematology and Oncology University Children's Hospital Münster Germany

Department of Pediatric Hematology and Oncology University Hospital Vall d'Hebron Barcelona Spain

Department of Pediatric Hematology Hôpital Robert Debré Assistance Publique Hôpitaux de Paris Paris France

Department of Pediatric Hematology Oncology and Cell and Gene Therapy Ospedale Pediatrico Bambino Gesù Sapienza University of Rome Rome Italy

Department of Pediatric Hematology Oncology The Edmond and Lily Safra Children's Hospital Sheba Medical Center Ramat Gan Israel

Department of Pediatric Oncology and Hematology Childhood Cancer Research Unit Lund University Hospital Lund Sweden

Department of Pediatric Oncology Erasmus Medical Center Sophia Children's Hospital Rotterdam The Netherlands

Department of Pediatrics Division of Oncology and Hematology Charité Universitätsmedizin Berlin Berlin Germany; and

Netherlands Cancer Institute Amsterdam The Netherlands

Pediatric Oncology and Hematology Karolinska Hospital Stockholm Sweden

Pfizer Global Product Development San Diego CA

Pfizer Inc Groton CT

Princess Máxima Center for Pediatric Oncology Utrecht The Netherlands

The Oncode Institute Utrecht The Netherlands

Universitätsmedizin Rostock Kinder und Jugendklinik Rostock Germany

Blood. 2021 Mar 25;137(12):1563-1564. doi: 10.1182/blood.2020009407. PubMed

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Population Pharmacokinetics of Inotuzumab Ozogamicin in Pediatric Relapsed/Refractory B-Cell Precursor Acute Lymphoblastic Leukemia: Results of Study ITCC-059

Inotuzumab ozogamicin as single agent in pediatric patients with relapsed and refractory acute lymphoblastic leukemia: results from a phase II trial