TY - JOUR
T1 - ASCT2-Targeting Antibody-Drug Conjugate MEDI7247 in Adult Patients with Relapsed/Refractory Hematological Malignancies
T2 - A First-in-Human, Phase 1 Study
AU - Maris, Michael
AU - Salles, Gilles
AU - Kim, Won Seog
AU - Kim, Tae Min
AU - Lyons, Roger M.
AU - Arellano, Martha
AU - Karmali, Reem
AU - Schiller, Gary
AU - Cull, Elizabeth
AU - Abboud, Camille N.
AU - Batlevi, Connie
AU - Kagiampakis, Ioannis
AU - Rebelatto, Marlon C.
AU - Lee, Young
AU - Kirby, Lyndon C.
AU - Wang, Fujun
AU - Bothos, John
AU - Townsley, Danielle M.
AU - Fathi, Amir T.
AU - Ribrag, Vincent
N1 - Publisher Copyright:
© The Author(s) 2024.
PY - 2024/5
Y1 - 2024/5
N2 - Background: MEDI7247 is a first-in-class antibody-drug conjugate (ADC) consisting of an anti-sodium-dependent alanine-serine-cysteine transporter 2 antibody-conjugated to a pyrrolobenzodiazepine dimer. Objective: This first-in-human phase 1 trial evaluated MEDI7247 in patients with hematological malignancies. Patients and methods: Adults with acute myeloid leukemia (AML), multiple myeloma (MM), or diffuse large B-cell lymphoma (DLBCL) relapsed or refractory (R/R) to standard therapies, or for whom no standard therapy exists, were eligible. Primary endpoints were safety and determination of the maximum tolerated dose (MTD). Secondary endpoints included assessments of antitumor activity, pharmacokinetics (PK), and immunogenicity. Results: As of 26 March 2020, 67 patients were treated (AML: n = 27; MM: n = 18; DLBCL: n = 22). The most common MEDI7247-related adverse events (AEs) were thrombocytopenia (41.8%), neutropenia (35.8%), and anemia (28.4%). The most common treatment-related grade 3/4 AEs were thrombocytopenia (38.8%), neutropenia (34.3%), and anemia (22.4%). Anticancer activity (number of responders/total patients evaluated) was observed in 11/67 (16.4%) patients. No correlation was observed between ASCT2 expression and clinical response. Between-patient variability of systemic exposure of MEDI7247 ADC and total antibody were high (AUCinf geometric CV%: 62.3–134.2, and 74.8–126.1, respectively). SG3199 (PBD dimer) plasma concentrations were below the limit of quantification for all patients after Study Day 8. Anti-drug antibody (ADA) prevalence was 7.7%, ADA incidence was 1.9%, and persistent-positive ADA was 5.8%. Conclusions: Thrombocytopenia and neutropenia limited repeat dosing. Although limited clinical activity was detected, the dose-escalation phase was stopped early without establishing an MTD. The study was registered with ClinicalTrials.gov (NCT03106428).
AB - Background: MEDI7247 is a first-in-class antibody-drug conjugate (ADC) consisting of an anti-sodium-dependent alanine-serine-cysteine transporter 2 antibody-conjugated to a pyrrolobenzodiazepine dimer. Objective: This first-in-human phase 1 trial evaluated MEDI7247 in patients with hematological malignancies. Patients and methods: Adults with acute myeloid leukemia (AML), multiple myeloma (MM), or diffuse large B-cell lymphoma (DLBCL) relapsed or refractory (R/R) to standard therapies, or for whom no standard therapy exists, were eligible. Primary endpoints were safety and determination of the maximum tolerated dose (MTD). Secondary endpoints included assessments of antitumor activity, pharmacokinetics (PK), and immunogenicity. Results: As of 26 March 2020, 67 patients were treated (AML: n = 27; MM: n = 18; DLBCL: n = 22). The most common MEDI7247-related adverse events (AEs) were thrombocytopenia (41.8%), neutropenia (35.8%), and anemia (28.4%). The most common treatment-related grade 3/4 AEs were thrombocytopenia (38.8%), neutropenia (34.3%), and anemia (22.4%). Anticancer activity (number of responders/total patients evaluated) was observed in 11/67 (16.4%) patients. No correlation was observed between ASCT2 expression and clinical response. Between-patient variability of systemic exposure of MEDI7247 ADC and total antibody were high (AUCinf geometric CV%: 62.3–134.2, and 74.8–126.1, respectively). SG3199 (PBD dimer) plasma concentrations were below the limit of quantification for all patients after Study Day 8. Anti-drug antibody (ADA) prevalence was 7.7%, ADA incidence was 1.9%, and persistent-positive ADA was 5.8%. Conclusions: Thrombocytopenia and neutropenia limited repeat dosing. Although limited clinical activity was detected, the dose-escalation phase was stopped early without establishing an MTD. The study was registered with ClinicalTrials.gov (NCT03106428).
UR - http://www.scopus.com/inward/record.url?scp=85191755557&partnerID=8YFLogxK
U2 - 10.1007/s11523-024-01054-z
DO - 10.1007/s11523-024-01054-z
M3 - Article
C2 - 38683495
AN - SCOPUS:85191755557
SN - 1776-2596
VL - 19
SP - 321
EP - 332
JO - Targeted Oncology
JF - Targeted Oncology
IS - 3
ER -