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

IF 4.4 3区医学 Q2 ONCOLOGY Targeted Oncology Pub Date : 2024-04-29 DOI:10.1007/s11523-024-01054-z

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

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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).

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成人复发性/难治性血液恶性肿瘤患者的 ASCT2 靶向抗体-药物共轭物 MEDI7247：首次人体1期研究

背景MEDI7247是一种首创的抗体-药物共轭物（ADC），由抗钠盐依赖性丙氨酸-丝氨酸-半胱氨酸转运体2抗体与吡咯并二氮杂卓二聚体结合而成。患者和方法成人急性髓性白血病（AML）、多发性骨髓瘤（MM）或弥漫大B细胞淋巴瘤（DLBCL）标准疗法复发或难治（R/R），或无标准疗法者均符合条件。主要终点是安全性和最大耐受剂量（MTD）的确定。次要终点包括抗肿瘤活性、药代动力学（PK）和免疫原性评估。结果截至2020年3月26日，67名患者接受了治疗（AML：n = 27；MM：n = 18；DLBCL：n = 22）。最常见的MEDI7247相关不良事件（AEs）是血小板减少（41.8%）、中性粒细胞减少（35.8%）和贫血（28.4%）。最常见的治疗相关 3/4 级 AE 为血小板减少（38.8%）、中性粒细胞减少（34.3%）和贫血（22.4%）。在11/67（16.4%）例患者中观察到抗癌活性（应答者人数/接受评估的患者总数）。ASCT2的表达与临床反应之间没有相关性。MEDI7247 ADC和总抗体的全身暴露在患者之间的变异性很高（AUCinf几何CV%分别为62.3-134.2和74.8-126.1）。研究第 8 天后，所有患者的 SG3199（PBD 二聚体）血浆浓度均低于定量限。抗药物抗体 (ADA) 发生率为 7.7%，ADA 发生率为 1.9%，ADA 持续阳性率为 5.8%。该研究已在 ClinicalTrials.gov (NCT03106428) 登记。

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来源期刊

Targeted Oncology 医学-肿瘤学

CiteScore

8.40

自引率

3.70%

发文量

审稿时长

>12 weeks

期刊介绍： Targeted Oncology addresses physicians and scientists committed to oncology and cancer research by providing a programme of articles on molecularly targeted pharmacotherapy in oncology. The journal includes: Original Research Articles on all aspects of molecularly targeted agents for the treatment of cancer, including immune checkpoint inhibitors and related approaches. Comprehensive narrative Review Articles and shorter Leading Articles discussing relevant clinically established as well as emerging agents and pathways. Current Opinion articles that place interesting areas in perspective. Therapy in Practice articles that provide a guide to the optimum management of a condition and highlight practical, clinically relevant considerations and recommendations. Systematic Reviews that use explicit, systematic methods as outlined by the PRISMA statement. Adis Drug Reviews of the properties and place in therapy of both newer and established targeted drugs in oncology.