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A first-in-human phase 1/2 dose-escalation study of MAK683 (EED inhibitor) in patients with advanced malignancies
Vincent Ribrag1, Lara Iglesias2, Filippo De Braud3
1Gustave Roussy, Villejuif, France.
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.
Insights
MAK683, an allosteric inhibitor of polycomb repressive complex 2, demonstrated clinical activity in advanced diffuse large B-cell lymphoma and epithelioid sarcoma. This first-in-human study found MAK683 to be generally well-tolerated in patients with advanced malignancies.
Area of Science:
- Oncology
- Pharmacology
- Clinical Trials
Background:
- MAK683 is a novel, selective allosteric inhibitor targeting the embryonic ectoderm development subunit of polycomb repressive complex 2.
- Preclinical studies showed sustained antitumor activity of MAK683 in tumor xenograft models.
Purpose of the Study:
- To evaluate the safety, pharmacokinetics (PK), and clinical activity of single-agent MAK683 in patients with advanced malignancies.
- To assess adverse events, dose-limiting toxicities, and PK profiles in a first-in-human phase 1/2 study.
Main Methods:
- MAK683 was administered orally once or twice daily in 28-day cycles.
- Safety was assessed through dose-limiting toxicities (DLTs) and adverse events (AEs).
- Pharmacokinetic profiles and pharmacodynamic changes (H3K27me3) were measured throughout the study.
Main Results:
- 139 patients with various advanced malignancies received MAK683.
- Common DLTs included thrombocytopenia and febrile neutropenia. Grade 3/4 drug-related AEs involved neutropenia, thrombocytopenia, and anemia.
- Clinical activity was observed in patients with advanced diffuse large B-cell lymphoma (DLBCL) and epithelioid sarcoma (ES).
Conclusions:
- MAK683 treatment was generally well-tolerated in patients with advanced cancers.
- Clinical activity was noted in specific patient populations, particularly advanced DLBCL and ES.
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