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A phase I study of inotuzumab ozogamicin as a single agent in pediatric patients in Japan with relapsed/refractory CD22-positive acute lymphoblastic leukemia (INO-Ped-ALL-1)

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Abstract

Inotuzumab ozogamicin (InO) is a CD22-directed antibody conjugated with calicheamicin approved for adult relapsed or refractory CD22-positive acute lymphoblastic leukemia (ALL). This phase 1 study primarily aimed to determine the pediatric recommended doses of InO through the standard 3 + 3 design, and to evaluate the safety, tolerability, pharmacokinetic (PK) profile, immunogenicity and efficacy of InO. Dose level 1 (DL1) was 1.8 mg/m2 (days 1, 8, and 15: 0.8, 0.5, and 0.5 mg/m2, respectively). Six of the seven registered patients were eligible [median age, 7.5 (2–17) years]. Although all six patients started DL1, only five completed the dose. No dose-limiting toxicity was observed. All patients experienced adverse events (AEs), including increased alanine aminotransferase and aspartate aminotransferase in four patients. Three patients experienced serious AEs, which were hepatic veno-occlusive disease (VOD), ALL, and fever. Five patients achieved complete remission (CR) or CR with incomplete blood cell recovery (CRi), among whom 3 (60%) were negative for minimal residual disease. PK findings were similar to those in adults. No patient had anti-drug antibodies to InO. In conclusion, InO was well tolerated in children and promoted similar antileukemic efficacy as in adults. Nonetheless, the risk for VOD requires attention.

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Acknowledgements

The authors thank all the staff at Clinical Research Center in National Hospital Organization Nagoya Medical Center, Kyushu Cancer Center, National Cancer Center Hospital, Osaka City General Hospital, and Hyogo Prefectural Kobe Children’s Hospital for the registration, record, and data management, as well as Pfizer Inc. for providing the study drug, works related to PK analysis, and supplies of safety information.

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Authors and Affiliations

  1. Department of Pediatrics, National Hospital Organization Kyushu Cancer Center, Fukuoka, Japan

    Hideki Nakayama

  2. Department of Pediatric Oncology, National Cancer Center Hospital, Tokyo, Japan

    Chitose Ogawa

  3. Clinical Research Center, National Hospital Organization Nagoya Medical Center, Nagoya, Japan

    Masahiro Sekimizu, Hiroya Hashimoto, Akiko M. Saito & Keizo Horibe

  4. Department of Pediatrics, National Hospital Organization Nagoya Medical Center, Nagoya, Japan

    Masahiro Sekimizu & Keizo Horibe

  5. Department of Pediatric Hematology/Oncology, Osaka City General Hospital, Osaka, Japan

    Hiroyuki Fujisaki

  6. Department of Hematology and Oncology, Hyogo Prefectural Kobe Children’s Hospital, Kobe, Japan

    Yoshiyuki Kosaka

  7. Core Laboratory, Graduate School of Medical Sciences, Nagoya City University, Nagoya, Japan

    Hiroya Hashimoto

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  1. Hideki Nakayama
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Contributions

HK and CO conceived and designed the study; HN, CO, MS, HF and YK collected the data and had responsibility for the study; AMS was responsible for data management and monitoring; HH was responsible for statistical analysis; and all authors helped write the paper and reviewed the final version for submission.

Corresponding author

Correspondence to Hideki Nakayama.

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Conflict of interest

The study related COI would be reviewed and approved by COI review board prescribed by Nagoya Medical Center based on the self-declaration form of the person in charge such as the attending physician. The authors declare that they have no conflict of interest.

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Supplementary Information

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Supplemental Document 1. Inclusion criteria (DOCX 19 KB)

Supplemental Document 2. Exclusion criteria (DOCX 20 KB)

12185_2022_3388_MOESM3_ESM.xlsx

Supplemental Figure. Adverse events in all cycles of all cases. All adverse events observed in this study are shown in grade-based colors from the day they occur to the day of converge in DL1-cycle 1, and the duration of converge in Cycles 2–4. DL1 Dose level 1, DAO day of adverse event, DLT dose-limiting toxicity, N no, NR not related, DIC disseminated intravascular coagulation (XLSX 17 KB)

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Nakayama, H., Ogawa, C., Sekimizu, M. et al. A phase I study of inotuzumab ozogamicin as a single agent in pediatric patients in Japan with relapsed/refractory CD22-positive acute lymphoblastic leukemia (INO-Ped-ALL-1). Int J Hematol 116, 612–621 (2022). https://doi.org/10.1007/s12185-022-03388-8

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