A phase 1 study of inotuzumab ozogamicin in pediatric relapsed/refractory acute lymphoblastic leukemia (ITCC-059 study)

Erica Brivio; Franco Locatelli; Marta Lopez-Yurda; Andrea Malone; Cristina Díaz-de-Heredia; Bella Bielorai; Claudia Rossig; Vincent H.J. van der Velden; Anneke C.J. Ammerlaan; Adriana Thano; Inge M. van der Sluis; Monique L. den Boer; Ying Chen; Barbara Sleight; Benoit Brethon; Karsten Nysom; Lucie Sramkova; Ingrid Øra; Luciana Vinti; Christiane Chen-Santel; Christian Michel Zwaan

doi:10.1182/blood.2020007848

A phase 1 study of inotuzumab ozogamicin in pediatric relapsed/refractory acute lymphoblastic leukemia (ITCC-059 study)

Erica Brivio, Franco Locatelli, Marta Lopez-Yurda, Andrea Malone, Cristina Díaz-de-Heredia, Bella Bielorai, Claudia Rossig, Vincent H.J. van der Velden, Anneke C.J. Ammerlaan, Adriana Thano, Inge M. van der Sluis, Monique L. den Boer, Ying Chen, Barbara Sleight, Benoit Brethon, Karsten Nysom, Lucie Sramkova, Ingrid Øra, Luciana Vinti, Christiane Chen-SantelChristian Michel Zwaan^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

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Abstract

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. Key Points: • The recommended phase 2 dose of InO for pediatric patients with ALL was established at 1.8 mg/m² per course. • Of the patients with multiple R/R ALL, 85% reached CR after 1 course of single-agent InO at the RP2D, 100% of whom had MRD negativity.

Original language	English
Pages (from-to)	1582-1590
Number of pages	9
Journal	Blood
Volume	137
Issue number	12
DOIs	https://doi.org/10.1182/blood.2020007848
Publication status	Published - 25 Mar 2021

Bibliographical note

Acknowledgments
The authors thank the Innovative Therapies for Children with Cancer (ITCC) Consortium and the International-BFM study group for providing the infrastructure and the collaborative environment to run early clinical trials in pediatric oncology, and Pfizer Inc for providing funding and a clinical research collaboration to implement the study. The authors also thank Berna Beverloo and the Department of Clinical Genetics, Erasmus Medical Center (Erasmus MC), for the central review of cytogenetic data. Medical writing support, under the direction of the authors, was provided by Juliet George, on behalf of CMC AFFINITY, McCann Health Medical Communications, in accordance with Good Publication Practice guidelines.

This study was sponsored by Erasmus MC Sophia Children’s Hospital, Department of Pediatrics, Rotterdam, The Netherlands, and was performed in a Clinical Research Collaboration and financially supported by Pfizer Inc. The KiKa Foundation provided infrastructural funding for the trial office at Erasmus MC and later at the Princess Máxima Center.

Publisher Copyright: © 2021 American Society of Hematology

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10.1182/blood.2020007848

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Brivio, E., Locatelli, F., Lopez-Yurda, M., Malone, A., Díaz-de-Heredia, C., Bielorai, B., Rossig, C., van der Velden, V. H. J., Ammerlaan, A. C. J., Thano, A., van der Sluis, I. M., den Boer, M. L., Chen, Y., Sleight, B., Brethon, B., Nysom, K., Sramkova, L., Øra, I., Vinti, L., ... Zwaan, C. M. (2021). A phase 1 study of inotuzumab ozogamicin in pediatric relapsed/refractory acute lymphoblastic leukemia (ITCC-059 study). Blood, 137(12), 1582-1590. https://doi.org/10.1182/blood.2020007848

@article{a4954ea7e4ba4d89a44be037efeeaf80,

title = "A phase 1 study of inotuzumab ozogamicin in pediatric relapsed/refractory acute lymphoblastic leukemia (ITCC-059 study)",

abstract = "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. Key Points: • The recommended phase 2 dose of InO for pediatric patients with ALL was established at 1.8 mg/m2 per course. • Of the patients with multiple R/R ALL, 85% reached CR after 1 course of single-agent InO at the RP2D, 100% of whom had MRD negativity.",

author = "Erica Brivio and Franco Locatelli and Marta Lopez-Yurda and Andrea Malone and Cristina D{\'i}az-de-Heredia and Bella Bielorai and Claudia Rossig and {van der Velden}, {Vincent H.J.} and Ammerlaan, {Anneke C.J.} and Adriana Thano and {van der Sluis}, {Inge M.} and {den Boer}, {Monique L.} and Ying Chen and Barbara Sleight and Benoit Brethon and Karsten Nysom and Lucie Sramkova and Ingrid {\O}ra and Luciana Vinti and Christiane Chen-Santel and Zwaan, {Christian Michel}",

note = "Acknowledgments The authors thank the Innovative Therapies for Children with Cancer (ITCC) Consortium and the International-BFM study group for providing the infrastructure and the collaborative environment to run early clinical trials in pediatric oncology, and Pfizer Inc for providing funding and a clinical research collaboration to implement the study. The authors also thank Berna Beverloo and the Department of Clinical Genetics, Erasmus Medical Center (Erasmus MC), for the central review of cytogenetic data. Medical writing support, under the direction of the authors, was provided by Juliet George, on behalf of CMC AFFINITY, McCann Health Medical Communications, in accordance with Good Publication Practice guidelines. This study was sponsored by Erasmus MC Sophia Children{\textquoteright}s Hospital, Department of Pediatrics, Rotterdam, The Netherlands, and was performed in a Clinical Research Collaboration and financially supported by Pfizer Inc. The KiKa Foundation provided infrastructural funding for the trial office at Erasmus MC and later at the Princess M{\'a}xima Center. Publisher Copyright: {\textcopyright} 2021 American Society of Hematology",

year = "2021",

month = mar,

day = "25",

doi = "10.1182/blood.2020007848",

language = "English",

volume = "137",

pages = "1582--1590",

journal = "Blood",

issn = "0006-4971",

publisher = "Elsevier",

number = "12",

}

Brivio, E, Locatelli, F, Lopez-Yurda, M, Malone, A, Díaz-de-Heredia, C, Bielorai, B, Rossig, C, van der Velden, VHJ, Ammerlaan, ACJ, Thano, A, van der Sluis, IM, den Boer, ML, Chen, Y, Sleight, B, Brethon, B, Nysom, K, Sramkova, L, Øra, I, Vinti, L, Chen-Santel, C & Zwaan, CM 2021, 'A phase 1 study of inotuzumab ozogamicin in pediatric relapsed/refractory acute lymphoblastic leukemia (ITCC-059 study)', Blood, vol. 137, no. 12, pp. 1582-1590. https://doi.org/10.1182/blood.2020007848

TY - JOUR

T1 - A phase 1 study of inotuzumab ozogamicin in pediatric relapsed/refractory acute lymphoblastic leukemia (ITCC-059 study)

AU - Brivio, Erica

AU - Locatelli, Franco

AU - Lopez-Yurda, Marta

AU - Malone, Andrea

AU - Díaz-de-Heredia, Cristina

AU - Bielorai, Bella

AU - Rossig, Claudia

AU - van der Velden, Vincent H.J.

AU - Ammerlaan, Anneke C.J.

AU - Thano, Adriana

AU - van der Sluis, Inge M.

AU - den Boer, Monique L.

AU - Chen, Ying

AU - Sleight, Barbara

AU - Brethon, Benoit

AU - Nysom, Karsten

AU - Sramkova, Lucie

AU - Øra, Ingrid

AU - Vinti, Luciana

AU - Chen-Santel, Christiane

AU - Zwaan, Christian Michel

N1 - Acknowledgments The authors thank the Innovative Therapies for Children with Cancer (ITCC) Consortium and the International-BFM study group for providing the infrastructure and the collaborative environment to run early clinical trials in pediatric oncology, and Pfizer Inc for providing funding and a clinical research collaboration to implement the study. The authors also thank Berna Beverloo and the Department of Clinical Genetics, Erasmus Medical Center (Erasmus MC), for the central review of cytogenetic data. Medical writing support, under the direction of the authors, was provided by Juliet George, on behalf of CMC AFFINITY, McCann Health Medical Communications, in accordance with Good Publication Practice guidelines. This study was sponsored by Erasmus MC Sophia Children’s Hospital, Department of Pediatrics, Rotterdam, The Netherlands, and was performed in a Clinical Research Collaboration and financially supported by Pfizer Inc. The KiKa Foundation provided infrastructural funding for the trial office at Erasmus MC and later at the Princess Máxima Center. Publisher Copyright: © 2021 American Society of Hematology

PY - 2021/3/25

Y1 - 2021/3/25

N2 - 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. Key Points: • The recommended phase 2 dose of InO for pediatric patients with ALL was established at 1.8 mg/m2 per course. • Of the patients with multiple R/R ALL, 85% reached CR after 1 course of single-agent InO at the RP2D, 100% of whom had MRD negativity.

AB - 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. Key Points: • The recommended phase 2 dose of InO for pediatric patients with ALL was established at 1.8 mg/m2 per course. • Of the patients with multiple R/R ALL, 85% reached CR after 1 course of single-agent InO at the RP2D, 100% of whom had MRD negativity.

UR - http://www.scopus.com/inward/record.url?scp=85097392477&partnerID=8YFLogxK

U2 - 10.1182/blood.2020007848

DO - 10.1182/blood.2020007848

M3 - Article

C2 - 33067614

AN - SCOPUS:85097392477

SN - 0006-4971

VL - 137

SP - 1582

EP - 1590

JO - Blood

JF - Blood

IS - 12

ER -

A phase 1 study of inotuzumab ozogamicin in pediatric relapsed/refractory acute lymphoblastic leukemia (ITCC-059 study)

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