Population Pharmacokinetics of Inotuzumab Ozogamicin in Pediatric Relapsed/Refractory Acute Lymphoblastic Leukemia – results of study ITCC-059
Jen-Hao Wu (1,2)*, Edoardo Pennesi (1,2)*, Francisco Bautista Sirvent (2), May Garrett (3), Kei Fukuhara (4), Erica Brivio (1,2), Anneke C J Ammerlaan (1,2), Franco Locatelli (5), Inge M van der Sluis (1), Claudia Rössig (6), Christiane Chen-Santel (7), Bella Bielorai (8), Arnaud Petit (9), Jan Starý (10), Cristina Díaz-de-Heredia (11), Susana Rives (12), Aengus O'Marcaigh (13), Carmelo Rizzari (14), Gernot Engstler (15), Karsten Nysom (16), Alba Rubio-San-Simón (17), Benedicte Bruno (18), Yves Bertrand (19), Benoit Brethon (20), Fanny Rialland (21), Geneviève Plat (22), Uta Dirksen (23), Lucie Sramkova (24), C Michel Zwaan (1,2)**, Alwin D.R. Huitema (2,25,26)**; (*Shared first authorship; **Shared last authorship)
(1) Department of Pediatric Oncology, Erasmus MC-Sophia Children’s Hospital, Rotterdam, the Netherlands; (2) Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands; (3) Pfizer Global Pharmacometrics, San Diego, CA, USA.; (4) Pfizer R&D Japan, Tokyo, Japan; (5) Department of Hematology, Oncology and of Cell and Gene Therapy, IRCCS Ospedale Pediatrico Bambino Gesú, Catholic University of the Sacred Heart, Rome, Italy; (6) Pediatric Hematology and Oncology, University Children's Hospital Muenster, Münster, Germany; (7) Department of Pediatrics, Division of Oncology and Hematology, Charité – Universitätsmedizin Berlin, Berlin, Germany; (8) Division of Pediatric Hematology and Oncology, Sheba Medical Center, Ramat-Gan, Israel; (9) Department of pediatric Hematology and Oncology, Hopital Armand Trousseau, APHP, Sorbonne Université, Paris, France; (10) Department of Pediatric Hematology and Oncology, University Hospital Motol, Prague, Czech Republic; (11) Division of Pediatric Hematology and Oncology . Hospital Universitari Vall D'Hebron, Barcelona, Spain; Institut de Recerca Vall d’Hebron (VHIR), Barcelona, Spain; (12) Pediatric Oncology and Hematology Department, Hospital Sant Joan de Déu de Barcelona, Barcelona, Spain; (13) Children’s Health Ireland at Crumlin, Dublin, Ireland; (14) Pediatric Hematology-Oncology Unit, Department of Pediatrics, MBBM Foundation, ASST Monza, University of Milano-Bicocca, Monza, Italy; (15) St Anna Children's Hospital, Medical University of Vienna, Vienna, Austria; (16) Department of Paediatrics and Adolescent Medicine, Juliane Marie Centre, Rigshospitalet, Copenhagen, Denmark; (17) Department of Pediatric Oncology and Hematology, Hospital Niño Jesús, Madrid, Spain; (18) Pediatric Hematology, Hôpital Jeanne de Flandre, CHRU de Lille, Lille, France; (19) Institute of Pediatric Hematology and Oncology, Civil Hospital of Lyon, Claude Bernard University, Lyon, France; (20) Department of Pediatric Hematology, Hôpital Robert-Debré, Assistance Publique-Hôpitaux de Paris, Paris, France; (21) Service Onco-Hématologie Pédiatrique, Hôpital Mère-Enfant, Nantes University Hospital, Nantes, France; (22) Service d’Hématologie-Immunologie-Oncologie, Hôpital des Enfants, CHU Toulouse, Toulouse, France; (23) Department of Pediatric Oncology, Essen University Hospital, Essen, Germany; (24) Department of Paediatric Haematology and Oncology, 2nd Faculty of Medicine, Charles University in Prague and Motol University Hospital, Prague, Czech Republic; (25) Department of Pharmacy & Pharmacology, Netherlands Cancer Institute, Amsterdam, the Netherlands; (26) Department of Clinical Pharmacy, University Medical Center Utrecht, Utrecht, The Netherlands
Objectives:
In pediatric acute lymphoblastic leukemia (ALL), a poor prognosis is observed with refractory disease, early 1st relapse, and ≥ 2 relapses, especially after a prior allograft (1–4). Novel therapeutic agents are needed for relapsed or refractory (R/R) ALL in children. Inotuzumab Ozogamicin (InO) is a CD22 directed antibody-drug conjugate (ADC) linked to calicheamicin, approved for the treatment of adults with R/R B-cell precursor ALL (BCP-ALL). The pharmacokinetics (PK) of InO in adults has been well characterized (5), but studies in the pediatric population are limited. This study aims to evaluate the population PK (POPPK) of InO as a single agent and identify significant covariates that influence InO disposition in pediatric R/R BCP-ALL patients, using pediatric (ITCC-059) and adult trial data. Study ITCC-059 was an open label phase I/II InO study sponsored by Erasmus MC, and financed by Pfizer.
Methods:
This POPPK analysis is based on clinical data from 11 InO studies in adults with either R/R B-cell ALL or R/R B-cell non-Hodgkin’s lymphoma (NHL), and a study of single-agent InO in pediatric R/R BCP-ALL patients (ITCC-059 Phase IA and Phase II Trial). In the phase I trial, pediatric patients aged 1 to 17 years, received an initial fractionated InO dosing regimen of 1.4 mg/m2/cycle, that was reduced to fractionated 1.2 mg/m2/cycle once remission was achieved (dose level 1, DL1). The dose was then escalated to 1.8 mg/m2/cycle and reduced to 1.5 mg/m2/cycle after remission (DL2). DL2 was selected as the recommended phase II dose (6) and further tested in the phase II trial (7). In pediatric patients, InO was fractioned in three doses/cycle, and PK samples were taken during cycle 1–3 from 13 patients treated at DL1, and 40 at DL2. InO serum concentration was measured by LCMS. The basis of model development was a prior InO POPPK model for adult ALL patients, a 2-compartment model with linear and time-dependent clearance, with covariates effect of baseline body size and the percentage of blasts in the peripheral blood (BLSTPB) (5). The adult POPPK model was adapted to describe pediatric data by further examining the changes in the structural model and covariate effect (body size, age, etc.). POPPK analysis was performed using NONMEM.
Results:
PK data from 765 adults (8361 PK observations) and 53 children (563 PK observations) were analyzed. InO disposition was described by a two-compartment model with a linear (CL1) and a time-dependent clearance (CLt); where CLt is described as CLt = CL2*e(-kdes*Time), CL2 is the initial value of CLt, and kdes is the first-order decay coefficient. CL1 is thought to reflect the Fc receptors and neonatal Fc receptor-mediated monoclonal antibodies clearance; while CLt relates to the target-mediated clearance, which decreases over time as tumor burden reduces, indicated by complete remissions were achieved by most patients after the first cycle (7). The estimated typical value (SE) of CL1 was 0.10 (0.003) L/h; the central (V1) and peripheral (V2) volume of distribution was 5.74 (0.12) L and 7.35 (0.81) L, respectively; CL2 was 0.43 (0.03) L/h; kdes was 0.005 (0.0003) h-1; intercompartment clearance was 0.16 (0.03) L/h. For pediatric R/R ALL patients, covariates (normalized to median/ a standard value), identified in the model include i) body size, as represented by lean body mass, on V1 (exponent of power function (SE): 1.05 (0.05)), CL1 (0.90 (0.06)), and CL2 (0.77 (0.16)); ii) age on kdes (-0.45 (0.08)); iii) blasts in peripheral blood on kdes (-0.06 (0.01)). Compared to the adult R/R ALL model from prior study (5), an additional age effect on kdes was identified as statistically significant.
Conclusions:
PK of InO in pediatric R/R BCP-ALL patients was well characterized by a two-compartment model with linear and time-dependent clearance. In comparison to the POPPK analysis conducted on adult ALL patients (5), similar body size (larger body size was related to a lower exposure) and BLSTPB (higher peripheral blood blasts was related to a lower exposure) effect were identified, while an additional smaller kdes value (i.e., CLt decay slower, related to a lower exposure) was observed with an increasing age. Of note, given that CLt reduce by 53% after 7 days, the effect of peripheral blood blasts and age on kdes were not considered clinically relevant; therefore, the findings support the current body surface area-based dosing strategy for pediatric R/R BCP-ALL patients.
References:
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