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3987 Population Pharmacokinetics of Inotuzumab Ozogamicin (InO) As Single Agent in Pediatric Relapsed/Refractory Acute Lymphoblastic Leukemia – Results from the ITCC-059 Phase IA and Phase II Trial

Program: Oral and Poster Abstracts
Session: 605. Molecular Pharmacology and Drug Resistance: Lymphoid Neoplasms: Poster III
Hematology Disease Topics & Pathways:
ALL, Lymphoid Leukemias, clinical trials, Research, Clinical Research, drug development, Diseases, Therapies, Lymphoid Malignancies
Monday, December 12, 2022, 6:00 PM-8:00 PM

Edoardo Pennesi1,2*, Erica Brivio, MD1,2*, Kathleen B. Pelletier3*, Ying Chen4*, Alwin D. R. Huitema2,5,6*, Yilin Jiang, MSc2*, Anneke C. J. Ammerlaan1,2*, Barbara Sleight, MD3*, Franco Locatelli, MD7, Inge M. Van Der Sluis, MD, PhD2, Claudia Rossig8*, Christiane Chen-Santel, MD9*, Bella Bielorai, MD10*, Arnaud Petit, MD, PhD11*, Jan Stary, MD12*, Lucie Sramkova, MD12*, Cristina Díaz de Heredia Rubio, MD13*, Susana Rives14*, Aengus O'Marcaigh, MD15*, Carmelo Rizzari, MD16*, Gernot Engstler, MD17*, Karsten Nysom, MD, PhD18*, Alba Rubio-San-Simón19*, Francisco J. Bautista Sirvent2*, Bénédicte Bruno, MD20*, Yives Bertrand, MD21*, Benoit Brethon, MD22*, Fanny Rialland, MD23*, Genevieve Plat24*, Uta Dirksen25*, May Garrett26* and Christian M. Zwaan, Prof, MD, PhD1,2*

1Department of Pediatric Oncology, Erasmus MC-Sophia Children’s Hospital, Rotterdam, Netherlands
2Princess Máxima Center for Pediatric Oncology, Utrecht, Netherlands
3Pfizer Inc, Groton, CT
4Pfizer Inc, La Jolla, CA
5University Medical Center Utrecht, Utrecht, Netherlands
6The Netherlands Cancer Institute, Amsterdam, Netherlands
7IRCCS Ospedale Pediatrico Bambino Gesú, Catholic University of the Sacred Heart, Rome, Italy
8Department of Pediatric Hematology and Oncology, University Children's Hospital Münster, Münster, Germany
9Rostock Medical Center, Rostock, Germany
10Division of Pediatric Hematology and Oncology, Sheba Medical Center, Ramat-Gan, Israel
11Pediatric Hematology and Oncology Department, Trousseau Hospital, Hopital Armand Trousseau, APHP, Sorbonne Université, Paris, France
12Department of Pediatric Hematology and Oncology, University Hospital Motol, Prague, Czech Republic
13Division of Pediatric Hematology and Oncology, Hospital Universitario Vall d´Hebron, Barcelona, Spain
14Department of Pediatric Hematology and Oncology, Hospital Sant Joan de Déu de Barcelona, Barcelona, Spain
15The Hospital for Sick Children, Dublin, IRL
16Pediatric Hematology-Oncology Unit, University of Milano-Bicocca, MBBM Foundation, San Gerardo Hospital, Monza, Italy
17St Anna Children's Hospital, Medical University of Vienna, Vienna, Austria
18Department of Paediatrics and Adolescent Medicine, Rigshospitalet, Copenhagen, Denmark
19Department of Pediatric Oncology and Hematology, Hospital Niño Jesús, Madrid, Spain
20Pediatric Hematology, Hôpital Jeanne de Flandre, CHRU de Lille, Lille, France
21Institute of Pediatric Hematology and Oncology, Civil Hospital of Lyon - Claude Bernard University, Lyon, France
22Department of Pediatric Hematology and Immunology, Robert-Debré Hospital, AP-HP, University of Paris, Paris, France
23Service Onco-Hématologie Pédiatrique, Hôpital Mère-Enfant, Nantes University Hospital, Nantes, France
24Service d’Hématologie-Immunologie-Oncologie, Hôpital des Enfants - CHU Toulouse, Toulouse, France
25Pediatrics III, West German Cancer Center, German Cancer Consortium (DKTK), Essen University Hospital, Essen, Germany
26Pfizer Oncology, La Jolla, CA

INTRODUCTION: This population pharmacokinetics (PopPK) analysis assessed the disposition of InO, a CD22 directed antibody conjugated with calicheamicin, as single agent in pediatric subjects with relapsed/refractory (R/R) B-cell precursor CD22+ acute lymphoblastic leukemia (BCP-ALL). Pooled data from the phase IA and II of the trial ITCC-059 (EudraCT:2016-000227-71) are presented. Clinical results from the Phase IA and Phase II were reported previously (Brivio et al., 2021; Pennesi et al., 2022). The trial was sponsored by Erasmus MC and financed by Pfizer.

METHODS: Patients aged 1-18 years, in M2 or M3 marrow status, and either ≥ 2nd relapsed, transplanted after 1st relapse, or with refractory disease were enrolled. In Phase I, InO (fractionated in 3 doses/cycle at day 1, 8 and 15) was initially administered at 1.4 mg/m2/cycle (0.6 + 0.4 + 0.4 mg/m2, dose level 1 (DL1)), then escalated to 1.8 mg/m2 (0.8 + 0.5 + 0.5 mg/m2, DL2). In Phase II, patients received 1.8 mg/m2/cycle of InO, or 1.5 mg/m2/cycle (0.5 + 0.5 + 0.5 mg/m2) once remission was achieved. A maximum of 6 cycles were allowed, except for patients proceeding to transplant, for which maximum 2-3 cycles were recommended. A sparse sampling schedule was applied (on day 1, 8, 15 and 22 (cycle 1) or 28 (cycles 2-3)). The PopPK of InO was developed using nonlinear mixed-effects analysis and combining pediatric data from the trial ITCC-059 with data from 11 trials in 765 adult patients with R/R ALL (n=234) or non-Hodgkin’s lymphoma (NHL) (n=531) provided by Pfizer. A prior PopPK model developed for adults (Garrett et al., 2019) was used as a basis for pediatric data. This model had two-compartments with both a linear clearance (CL1) and time-dependent clearance (CLt) that includes a decay coefficient (kdes). Covariates included in that analysis, based on Garret et al., were baseline body surface area (BSA) on CL1, CLt, and volume of distribution in the central compartment; diagnosis (ALL/NHL) and/or bioanalytical assay method on CL1, and the decay coefficient associated with time-dependent clearance (kdes); absence of concomitant rituximab (RITXI) on CL1; and baseline percentage of blasts in the peripheral blood (BLSTPB) as a covariate on kdes of CLt. Simulations were performed to predict InO exposures in both pediatric and adult patients at a fixed dosing regimen of 1.8 mg/m2/cycle.

RESULTS: Pharmacokinetic pediatric data were collected from 53 patients (See table 1 for baseline characteristics); 13 treated at DL1, and 40 at DL2; in total 563 serum PK observations were collected. When combined with adult data, the final analysis included a total of 818 patients and 8924 serum PK observations, of which 3394 (38.0%) below the lower limit of quantitation (LLOQ); and hence the M3 method (maximizing the likelihood for data ≥ LLOQ and treating PK data < LLOQ as censored) was selected. Overall, the previous model developed for adults described the pediatric patients’ PK well. Besides the covariates identified in the adult model (BSA, RTX, diagnosis and BLSTPB), the current model also identified the effect of pediatric patients on kdes as a significant covariate. In the final model, InO typical value of CL1 was estimated to be 0.113 L/hr with 40% inter-individual variability (IIV); CL2 was estimated to be 0.384 L/hr with 74% IIV; and central volume of distribution (V1) was estimated to be 6.56 L with 41% IIV. The kdes was estimated to be 0.036 h-1 with 54% IIV. The inter-compartmental CL and peripheral volume of distribution were estimated to be 0.045 L/hr and 4.70 L, respectively. The simulated median Cmax and the accumulated area under the curve (AUC) at end of cycle 1 were 191 ng/mL and 24550 ng.hr/mL; 155 ng/mL and 18200 ng.hr/mL for pediatric and adult patients with ALL, respectively. The simulated median Cmax and accumulated AUC at end of cycle 2 were 284 ng/mL and 117830 ng.hr/mL; 217 ng/mL and 90270 ng.hr/mL for children and adults, respectively.

CONCLUSIONS: InO PK is generally comparable between pediatric and adult patients with R/R ALL. This supports the same dosing regimen in these two populations at 1.8 mg/m2/cycle until remission then 1.5 mg/m2/cycle, the same as per our phase I and II trials.

Disclosures: Pelletier: Pfizer Inc: Current Employment. Chen: Pfizer Inc: Current Employment. Sleight: Pfizer Inc: Current Employment. Locatelli: Neovii: Speakers Bureau; Medac: Speakers Bureau; SOBI: Speakers Bureau; Miltenyi: Speakers Bureau; Jazz Pharmaceuticals: Honoraria; Novartis: Honoraria, Speakers Bureau; BlueBird bio: Speakers Bureau; Amgen: Speakers Bureau. Van Der Sluis: Jazz: Consultancy; Servier: Consultancy, Research Funding. Rossig: novartis: Other: consulting fees; Roche: Other: Consulting Fees; Amgen: Other: Consulting Fees; Pfizer Inc: Other: consulting fee. Sramkova: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Rives: Amgen: Other: Advisory Board; Novartis: Other: Advisory Board. Rizzari: Agmen: Honoraria; Jazz: Honoraria; Servier: Honoraria. Bautista Sirvent: Roche: Other: Consulting Fees; Amgen: Other: Consulting Fees; Bayer: Other: Consulting Fees. Garrett: Pfizer Inc: Current Employment. Zwaan: Pfizer Inc: Honoraria; Novartis: Honoraria; Abbvie: Honoraria; Abbvie: Honoraria; JAZZ: Honoraria.

*signifies non-member of ASH