A first-in-human phase 1/2 dose-escalation study of MAK683 (EED inhibitor) in patients with advanced malignancies

Vincent Ribrag; Lara Iglesias; Filippo De Braud; Brigette Ma; Tomoya Yokota; Thomas Zander; Anna Spreafico; Vivek Subbiah; Anna L Illert; Daniel Tan; Armando Santoro; Pamela N Munster; Youko Suehiro; Yongsheng Wang; Dong-Mei Ji; Shuqi Chen; Karen Beltz; Naoko Suenaga; Thiruvamoor Ramkumar; Fangjun Luo; Clinton Lai; Zev A Wainberg

doi:10.1016/j.ejca.2024.115122

A first-in-human phase 1/2 dose-escalation study of MAK683 (EED inhibitor) in patients with advanced malignancies

Eur J Cancer. 2024 Nov 16:216:115122. doi: 10.1016/j.ejca.2024.115122. Online ahead of print.

Authors

Vincent Ribrag¹, Lara Iglesias², Filippo De Braud³, Brigette Ma⁴, Tomoya Yokota⁵, Thomas Zander⁶, Anna Spreafico⁷, Vivek Subbiah⁸, Anna L Illert⁹, Daniel Tan¹⁰, Armando Santoro¹¹, Pamela N Munster¹², Youko Suehiro¹³, Yongsheng Wang¹⁴, Dong-Mei Ji¹⁵, Shuqi Chen¹⁶, Karen Beltz¹⁷, Naoko Suenaga¹⁸, Thiruvamoor Ramkumar¹⁹, Fangjun Luo¹⁶, Clinton Lai¹⁶, Zev A Wainberg²⁰

Affiliations

¹ Gustave Roussy, Villejuif, France. Electronic address: vincent.ribrag@gustaveroussy.fr.
² Hospital Universitario 12 de Octubre, Madrid, Spain.
³ IRCCS National Cancer Institute of Milan Foundation, Milan, Italy.
⁴ The Chinese University of Hong Kong, Phase 1 Clinical Trial Centre, Department of Clinical Oncology, Hong Kong SAR.
⁵ Division of Gastrointestinal Oncology, Shizuoka Cancer Center, Shizuoka, Japan.
⁶ Klinik I für Innere Medizin, Universitätsklinikum Köln, Centrum für Integrierte Onkologie Aachen Bonn Köln Düsseldorf, Köln, Germany.
⁷ Drug Development Program, Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, ON, Canada.
⁸ Sarah Cannon Research Institute, Nashville, TN, USA.
⁹ Clinic of Internal Medicine I, Medical Center, University of Freiburg Faculty of Medicine, University of Freiburg, Freiburg, Germany; German Cancer Consortium (DKTK), Partner Site Technical University of Munich, Germany; Center for Personalized Medicine, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany; Clinic of Internal Medicine III, Hematology & Oncology, Klinikum rechts der Isar, Technical University of Munich, Germany.
¹⁰ Cancer Therapeutics Research Laboratory, National Cancer Centre, Singapore, Singapore.
¹¹ Department of Medical Oncology and Hematology, Humanitas Clinical and Research Center, Rozzano, Milan, Italy.
¹² Division of Hematology and Oncology, University of California, San Francisco, CA, USA.
¹³ Department of Hematology and Cell Therapy, Kyushu Cancer Center, Fukuoka, Japan.
¹⁴ GCP Center/Institute of Drug Clinical Trials, West China Hospital of Sichuan University, Sichuan, China.
¹⁵ Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, China; Shanghai Medical College, Fudan University, Shanghai, China.
¹⁶ Novartis Institutes for BioMedical Research, Shanghai, China.
¹⁷ Novartis Institutes for BioMedical Research, Basel, Switzerland.
¹⁸ Novartis Pharma K.K., Tokyo, Japan.
¹⁹ Novartis Institutes for BioMedical Research, Cambridge, MA, USA.
²⁰ David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA.

PMID: 39793445
DOI: 10.1016/j.ejca.2024.115122

Abstract

Purpose: MAK683, a first-in-class and highly selective allosteric inhibitor of the embryonic ectoderm development subunit of polycomb repressive complex 2, has shown sustained antitumor activity in tumor xenograft models. This first-in-human phase 1/2 study evaluated the safety, pharmacokinetics (PK), and clinical activity of single-agent MAK683 in advanced malignancies.

Methods: MAK683 was administered fasted once daily or twice daily continuously in 28-day treatment cycles. Safety assessments included the nature of dose-limiting toxicities (DLTs) and the incidence and severity of adverse events (AEs) and serious AEs. The PK profile of MAK683 was assessed in sequential blood samples of cycles 1-6, and pharmacodynamic profiles were measured by H3K27me3 changes from baseline.

Results: Overall, 139 patients (clear cell carcinoma of the ovary [CCCO], 9 [6.5%]; castration-resistant prostate cancer [CRPC], 22 [15.8 %]; diffuse large B-cell lymphoma [DLBCL], 31 [22.3%]; epithelioid sarcoma [ES], 17 [12.2 %]; gastric cancer [GC], 37 [26.6 %]; nasopharyngeal carcinoma [NPC], 17 [12.2 %]; SWI/SNF-mutated sarcoma, 6 [4.3 %]) received MAK683. Median duration of exposure was 57 days (range: 4-1006). Fifteen patients experienced 22 DLTs including thrombocytopenia (4.9 %) and febrile neutropenia (3.3 %). MAK683-related AEs were reported in 98 patients (70.5 %); 43 patients had grade 3/4 drug-related AEs, including neutropenia, thrombocytopenia, and anemia. MAK683 was quickly absorbed, with peak plasma concentrations ranging from 0.975 to 4.08 h. Median progression-free survival was 1.9 months (90 % confidence interval [CI]: 1.8-2.3), and overall response rate was 5.8 % (90 % CI: 2.52-11.03 %). Clinical activity was observed in patients with advanced DLBCL and ES.

Conclusion: Overall, MAK683 treatment was well tolerated, and clinical activity was observed in patients with advanced DLBCL and ES.

Clinical trial information: NCT02900651.

Keywords: DLBCL; EED; ES; MAK683; PRC2.

Associated data

ClinicalTrials.gov/NCT02900651