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A phase 1 study of inotuzumab ozogamicin in pediatric relapsed/refractory acute lymphoblastic leukemia (ITCC-059 study)
E. Brivio, F. Locatelli, M. Lopez-Yurda, A. Malone, C. Díaz-de-Heredia, B. Bielorai, C. Rossig, VHJ. van der Velden, ACJ. Ammerlaan, A. Thano, IM. van der Sluis, ML. den Boer, Y. Chen, B. Sleight, B. Brethon, K. Nysom, L. Sramkova, I. Øra, L....
Language English Country United States
Document type Clinical Trial, Phase I, Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't
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- MeSH
- Precursor Cell Lymphoblastic Leukemia-Lymphoma drug therapy MeSH
- Child MeSH
- Inotuzumab Ozogamicin adverse effects therapeutic use MeSH
- Infant MeSH
- Humans MeSH
- Neoplasm Recurrence, Local drug therapy MeSH
- Child, Preschool MeSH
- Antineoplastic Agents, Immunological adverse effects therapeutic use MeSH
- Treatment Outcome MeSH
- Check Tag
- Child MeSH
- Infant MeSH
- Humans MeSH
- Male MeSH
- Child, Preschool MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Clinical Trial, Phase I MeSH
- Multicenter Study MeSH
- Research Support, Non-U.S. Gov't MeSH
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 Pediatric Hematology and Oncology University Children's Hospital Münster Germany
Department of Pediatric Hematology and Oncology University Hospital Vall d'Hebron Barcelona Spain
Netherlands Cancer Institute Amsterdam The Netherlands
Pediatric Oncology and Hematology Karolinska Hospital Stockholm Sweden
Pfizer Global Product Development San Diego CA
Princess Máxima Center for Pediatric Oncology Utrecht The Netherlands
The Oncode Institute Utrecht The Netherlands
Universitätsmedizin Rostock Kinder und Jugendklinik Rostock Germany
References provided by Crossref.org
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