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

Brivio, Erica ; Locatelli, Franco ; Lopez-Yurda, Marta ; Malone, Andrea ; Diaz de Heredia, Cristina ; Bielorai, Bella ; Rossig, Claudia ; van der Velden, Vincent H J ; Ammerlaan, Anneke Cj and Thano, Adriana , et al. (2020) In Blood
Abstract

This Phase I study investigated the recommended Phase II dose (RP2D) of inotuzumab ozogamicin (InO), a CD22-directed antibody-drug conjugate, in pediatric patients with multiple-relapsed/refractory (R/R) CD22-positive acute lymphoblastic leukemia (ALL). Patients (≥1-<18 years) received three InO doses (Days 1, 8, 15) per course. Dose-escalation was based on dose-limiting toxicities (DLT) during Course 1 . Dose level 1 (DL1)=1.4 mg/m2 (0.6-0.4-0.4 mg/m2); DL2=1.8 mg/m2 (0.8-0.5-0.5 mg/m2). Secondary endpoints included safety, anti-leukemic activity, and pharmacokinetics. Twenty-five patients (23 evaluable for DLT) were enrolled. In Course 1, first cohort, 1/6 (DL1) and 2/5 (DL2) patients experienced DLTs; subsequent review considered... (More)

This Phase I study investigated the recommended Phase II dose (RP2D) of inotuzumab ozogamicin (InO), a CD22-directed antibody-drug conjugate, in pediatric patients with multiple-relapsed/refractory (R/R) CD22-positive acute lymphoblastic leukemia (ALL). Patients (≥1-<18 years) received three InO doses (Days 1, 8, 15) per course. Dose-escalation was based on dose-limiting toxicities (DLT) during Course 1 . Dose level 1 (DL1)=1.4 mg/m2 (0.6-0.4-0.4 mg/m2); DL2=1.8 mg/m2 (0.8-0.5-0.5 mg/m2). Secondary endpoints included safety, anti-leukemic activity, and pharmacokinetics. Twenty-five patients (23 evaluable for DLT) were enrolled. In Course 1, first cohort, 1/6 (DL1) and 2/5 (DL2) patients 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, where 0/6 (DL1) and 1/6 (DL2) patients had a DLT. Twenty-three patients experienced Grade 3-4 adverse events; hepatic sinusoidal obstruction syndrome was reported in two patients after subsequent chemotherapy. Overall response rate after Course 1 was 80% [95% CI: 59-93%] (20/25 patients; DL1=75% [43-95%], DL2=85% [55-98%]); 84% [60-97%] of responders obtained minimal residual disease-negative CR; 12-month overall survival was 40% [95% CI: 25-66%]. Nine patients received hematopoietic stem cell transplant or chimeric-antigen receptor T-cells after InO. InO median maximum concentrations were comparable to simulated adult concentrations. InO was well tolerated, demonstrating anti-leukemic activity in heavily pre-treated children with CD22-positive R/R ALL. RP2D was established as 1.8 mg/m2/course, as in adults.

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Contribution to journal
publication status
published
subject
in
Blood
publisher
American Society of Hematology
external identifiers
  • scopus:85097392477
  • pmid:33067614
ISSN
1528-0020
DOI
10.1182/blood.2020007848
language
English
LU publication?
no
id
01537799-1937-43df-a9e9-f64abca1731f
date added to LUP
2021-03-16 10:28:47
date last changed
2025-01-24 08:17:58
@article{01537799-1937-43df-a9e9-f64abca1731f,
  abstract     = {{<p>This Phase I study investigated the recommended Phase II dose (RP2D) of inotuzumab ozogamicin (InO), a CD22-directed antibody-drug conjugate, in pediatric patients with multiple-relapsed/refractory (R/R) CD22-positive acute lymphoblastic leukemia (ALL). Patients (≥1-&lt;18 years) received three InO doses (Days 1, 8, 15) per course. Dose-escalation was based on dose-limiting toxicities (DLT) during Course 1 . Dose level 1 (DL1)=1.4 mg/m2 (0.6-0.4-0.4 mg/m2); DL2=1.8 mg/m2 (0.8-0.5-0.5 mg/m2). Secondary endpoints included safety, anti-leukemic activity, and pharmacokinetics. Twenty-five patients (23 evaluable for DLT) were enrolled. In Course 1, first cohort, 1/6 (DL1) and 2/5 (DL2) patients 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, where 0/6 (DL1) and 1/6 (DL2) patients had a DLT. Twenty-three patients experienced Grade 3-4 adverse events; hepatic sinusoidal obstruction syndrome was reported in two patients after subsequent chemotherapy. Overall response rate after Course 1 was 80% [95% CI: 59-93%] (20/25 patients; DL1=75% [43-95%], DL2=85% [55-98%]); 84% [60-97%] of responders obtained minimal residual disease-negative CR; 12-month overall survival was 40% [95% CI: 25-66%]. Nine patients received hematopoietic stem cell transplant or chimeric-antigen receptor T-cells after InO. InO median maximum concentrations were comparable to simulated adult concentrations. InO was well tolerated, demonstrating anti-leukemic activity in heavily pre-treated children with CD22-positive R/R ALL. RP2D was established as 1.8 mg/m2/course, as in adults.</p>}},
  author       = {{Brivio, Erica and Locatelli, Franco and Lopez-Yurda, Marta and Malone, Andrea and Diaz de Heredia, Cristina and Bielorai, Bella and Rossig, Claudia and van der Velden, Vincent H J and Ammerlaan, Anneke Cj and Thano, Adriana and van der Sluis, Inge Margriet and Den Boer, Monique L and Chen, Ying and Sleight, Barbara and Brethon, Benoit and Nysom, Karsten and Sramkova, Lucie and Øra, Ingrid and Vinti, Luciana and Chen-Santel, Christiane and Zwaan, Christian Michel}},
  issn         = {{1528-0020}},
  language     = {{eng}},
  month        = {{10}},
  publisher    = {{American Society of Hematology}},
  series       = {{Blood}},
  title        = {{A Phase I study of inotuzumab ozogamicin in pediatric relapsed/refractory acute lymphoblastic leukemia (ITCC-059 study)}},
  url          = {{http://dx.doi.org/10.1182/blood.2020007848}},
  doi          = {{10.1182/blood.2020007848}},
  year         = {{2020}},
}