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Clinical Trial
. 2024 May;19(3):321-332.
doi: 10.1007/s11523-024-01054-z. Epub 2024 Apr 29.

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

Michael Maris  1 , Gilles Salles  2 , Won Seog Kim  3 , Tae Min Kim  4 , Roger M Lyons  5 , Martha Arellano  6 , Reem Karmali  7 , Gary Schiller  8 , Elizabeth Cull  9 , Camille N Abboud  10 , Connie Batlevi  11 , Ioannis Kagiampakis  12 , Marlon C Rebelatto  13 , Young Lee  13 , Lyndon C Kirby  13 , Fujun Wang  14 , John Bothos  13 , Danielle M Townsley  13 , Amir T Fathi #  15 , Vincent Ribrag #  16
Affiliations
Clinical Trial

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

Michael Maris et al. Target Oncol. 2024 May.

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 (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).

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Conflict of interest statement

Michael Maris: None. Gilles Salles: Financial compensation for participating in advisory boards or consulting from: Abbvie, BMS/Celgene, Debiopharm, Epizyme, Genentech/Roche, Incyte, Janssen, Kite/Gilead, Epizyme, Miltenyi, Morphosys, Novartis, VelosBio; and for participation in educational events from: Kite Pharma/Gilead Sciences. Won Seog Kim: Nothing to disclose. Tae Min Kim: Advisory or consultant roles for AstraZeneca, Novartis, Takeda, Sanofi, Roche/Genentech, and Boryung. Research funding from AstraZeneca and Korea Health Industry Development Institute outside this work. Roger Lyons: Consultancy and Advisory boards for ABBVie, Argenx, AstraZeneca, BriGene, Celgene, INCYTE, IQVIA, Karyopharm, Taiho, and Takeda. Martha Arellano: Advisory board member for Kite Pharma, Inc, Gilead Sciences, Inc, and Syndax Pharmaceuticals, Inc. Reem Karmali: Consulting Fees: Celgene Corporation, Gilead Sciences, Inc, Juno Therapeutics, Kite Pharma, OncLive, Verastem, Janssen, Karyopharm, Morphosys; Grants/Research; Support: Celgene Corporation, Juno Therapeutics, BMS, Takeda, BeiGene, AstraZeneca; Speakers Bureau: Celgene Corporation, Gilead Sciences, Inc, Juno Therapeutics, Kite Pharma, AstraZeneca, BeiGene, Morphosys. Gary Schiller: Stock and Other Ownership Interests: Bristol Myers Squibb, Amgen, Johnson & Johnson; Consulting or Advisory Role: Ono Pharmaceutical, Agios, Celgene, Incyte, Jazz Pharmaceuticals, Novartis, AbbVie, Astellas Pharma; Speakers' Bureau: Astellas Pharma, Kite, a Gilead Company, Jazz Pharmaceuticals, Stemline Therapeutics, Bristol Myers Squibb, Sanofi, Karyopharm Therapeutics, Incyte, AbbVie; Research Funding: AbbVie, Actinium Pharmaceuticals, Actuate Therapeutics, Arog, Astellas Pharma, Bristol Myers Squibb/Celgene, Celator, Constellation Pharmaceuticals, Daiichi Sankyo, Deciphera, Delta-Fly Pharma, FORMA Therapeutics, Fujifilm, Gamida Cell, Genentech/Roche, Geron, Incyte, Karyopharm Therapeutics, Kite, a Gilead Company, Mateon Therapeutics, Onconova Therapeutics, Pfizer, Precog, REGiMMUNE, Samus Therapeutics, Sangamo Bioscience, SELLAS Life Sciences, Stemline Therapeutics, Takeda, Tolero Pharmaceuticals, Trovagene, Agios, Amgen, Jazz Pharmaceuticals, ElevateBio, Ono Pharmaceutical, Novartis, Sanofi, AVM Biotechnology, Syros Pharmaceuticals. Elizabeth Cull: Speaker for Bristol Myers Squibb. Camille N. Abboud: Clinical research support from Novartis, Gilead, and Ryvu. Connie Batlevi: Research Funding: Janssen, Novartis, Epizyme, Xynomics, Bayer, Autolus, Roche; Consulting/Advisory Boards: Life Sci, GLG, Juno/Celgene, Seattle Genetics, Kite Pharma, Karyopharm, TG Therapeutics, ADC Therapeutics; Honorarium: Dava Oncology, TouchIME, Medscape; Stock ownership: BMS, Pfizer, Viatris, Regeneron, Moderna, Novavax. Ioannis Kagiampakis: Employee of AstraZeneca and may own stock or stock options. Marlon C. Rebelatto: Employee of AstraZeneca and may own stock or stock options. Young Lee: Employee of AstraZeneca and may own stock or stock options. Lyndon C. Kirby: Employee of AstraZeneca and may own stock or stock options. Fujun Wang: Employee of AstraZeneca and may own stock or stock options. Current equity holder in a publicly traded company. John Bothos: Employee of AstraZeneca and may own stock or stock options. Danielle M Townsley: Employee of AstraZeneca and may own stock or stock options. Amir T. Fathi: Consulting/Advisory Fees: Celgene/BMS, Foghorn, Kite Pharma, Morphosys, Abbvie, Agios, Genentech, Takeda, Pfizer, Trillium, Kura Oncology, Blueprint, Astellas; Grants/Research Support: Celgene/BMS, Abbvie, Agios. Vincent Ribrag: Advisory boards for Gilead, Infinity, MSD, BMS, Nanostring, Incyte, Roche, AstraZeneca, Servier; Research support from Argen-X and Astex.

Figures

Fig. 1
Fig. 1
Patient flow diagram. ADA anti-drug antibody, AML acute myeloid leukemia, DLBCL diffuse large B-cell lymphoma, DLT dose-limiting toxicity, MM multiple myeloma, PK pharmacokinetic. See Online Supplementary Material Table 3 for patient disposition
Fig. 2
Fig. 2
MEDI7247 treatment response for patients with AML (A), MM (B), and DLBCL (C). For AML, PD includes PD and TF. AML acute myeloid leukemia, CR complete remission, CRi complete response with incomplete hematologic recovery, DLBCL diffuse large B-cell lymphoma, MM multiple myeloma, MLFS morphologic leukemia-free state, MR minimal response, PD progressive disease, SD stable disease, TF treatment failure
See this image and copyright information in PMC

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