ASCT2-Targeting Antibody-Drug Conjugate MEDI7247 in Adult Patients with Relapsed/Refractory Hematological Malignancies: A First-in-Human, Phase 1 Study

Michael Maris; Gilles Salles; Won Seog Kim; Tae Min Kim; Roger M Lyons; Martha Arellano; Reem Karmali; Gary Schiller; Elizabeth Cull; Camille N Abboud; Connie Batlevi; Ioannis Kagiampakis; Marlon C Rebelatto; Young Lee; Lyndon C Kirby; Fujun Wang; John Bothos; Danielle M Townsley; Amir T Fathi; Vincent Ribrag

doi:10.1007/s11523-024-01054-z

ASCT2-Targeting Antibody-Drug Conjugate MEDI7247 in Adult Patients with Relapsed/Refractory Hematological Malignancies: A First-in-Human, Phase 1 Study

Target Oncol. 2024 Apr 29. doi: 10.1007/s11523-024-01054-z. Online ahead of print.

Authors

Michael Maris¹, Gilles Salles², Won Seog Kim³, Tae Min Kim⁴, Roger M Lyons⁵, Martha Arellano⁶, Reem Karmali⁷, Gary Schiller⁸, Elizabeth Cull⁹, Camille N Abboud¹⁰, Connie Batlevi¹¹, Ioannis Kagiampakis¹², Marlon C Rebelatto¹³, Young Lee¹³, Lyndon C Kirby¹³, Fujun Wang¹⁴, John Bothos¹³, Danielle M Townsley¹³, Amir T Fathi^#¹⁵, Vincent Ribrag^#¹⁶

Affiliations

¹ Colorado Blood Cancer Institute and Sarah Cannon Research Institute, Denver, CO, USA.
² Centre Hospitalier Lyon Sud, Pierre Benite, France.
³ Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea.
⁴ Seoul National University Hospital, Seoul, South Korea.
⁵ Texas Oncology, US Oncology, San Antonio, TX, USA.
⁶ Winship Cancer Institute, Emory University, Atlanta, GA, USA.
⁷ Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
⁸ David Geffen School of Medicine, UCLA Medical Center, Los Angeles, CA, USA.
⁹ Prisma Health, Cancer Institute-Eastside, Greenville, SC, USA.
¹⁰ Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, USA.
¹¹ Memorial Sloan Kettering Cancer Center, New York, NY, USA.
¹² Translational Medicine Bioinformatics, AstraZeneca, Gaithersburg, MD, USA.
¹³ Early Oncology Research and Development, AstraZeneca, Gaithersburg, MD, USA.
¹⁴ Biostatistics, AstraZeneca, Gaithersburg, MD, USA.
¹⁵ Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
¹⁶ Department of Hematology, Drug Development Department (DITEP), Institut Gustave Roussy, 114 rue Edouard Vaillant, 94805, Villejuif Cedex, France. vincent.ribrag@igr.fr.

^# Contributed equally.

PMID: 38683495
DOI: 10.1007/s11523-024-01054-z

Abstract

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 (AUC_inf 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).

Associated data

ClinicalTrials.gov/NCT03106428