Pharmacokinetic and pharmacodynamic activity evaluation of MAK683, a selective oral embryonic ectoderm development (EED) inhibitor, in adults with advanced malignancies in a first-in-human study.

Authors

Vincent Ribrag

Vincent Ribrag

Gustave Roussy, Villejuif, France

Vincent Ribrag , Zev A. Wainberg , Lara Iglesias Docampo , Thiruvamoor Ramkumar , Louise Barys , Shuqi Chen , Marc Raccuglia , Mélanie Wilbaux , Karen Beltz , Amy Luyt , Yu Yun Fan , Naoko Suenaga , Fangjun Luo , Xuan Dai , Clinton Lai , Jia Chen

Organizations

Gustave Roussy, Villejuif, France, Ronald Reagan UCLA Medical Center, Los Angeles, CA, Hospital Universitario 12 de Octubre, Madrid, Spain, Novartis Institutes for BioMedical Research, Cambridge, MA, Novartis Institutes for BioMedical Research, Basel, Switzerland, Novartis Institutes for BioMedical Research Co. Ltd, Shanghai, China, Novartis Pharma K.K., Tokyo, Japan

Research Funding

Pharmaceutical/Biotech Company

Background: Polycomb Repressive Complex 2 (PRC2) regulates transcription via trimethylation of histone H3 at lysine 27 (H3K27me3). Its dysregulation and over-expression are associated with tumorigenesis in several conditions. MAK683 is a potent oral inhibitor of PRC2 activation, allosterically targeting the EED–H3K27me3 binding site. Methods: NCT02900651 is an ongoing first-in-human dose-escalation study of MAK683 in adults with advanced malignancies. MAK683 was administered fasted once (QD) or twice daily (BID) on a continuous schedule in 28-day treatment cycles. The pharmacokinetic (PK) profile of MAK683 was assessed in sequential blood samples on Days 1, 8 and/or 15 of Cycles 1–6. MAK683 pharmacodynamic activity in Cycle 1, measured by change in H3K27me3, was evaluated in peripheral blood monocytes on Days 1, 8, and 15 by flow cytometry and in tumor biopsies at baseline and Day 15 by H-score. Results: As of Aug 30, 2021, 125 patients had received MAK683 at doses of 10–800 mg QD or 60–450 mg BID. MAK683 was well absorbed with a median Tmax of ̃1-4 hours across cohorts. PK exposure (Cmax, AUC) increased generally with dose over the entire dose range with no major deviation from dose proportionality, taking into account the sample size and PK variability. Apparent terminal half-life (geometric mean) was 2.5–6.6 hours across cohorts and constant over time. MAK683 accumulation of ̃0.9-2.2-fold (QD) or ̃1.3-2.0-fold (BID) was seen with repeat dosing. Peripheral monocytes showed substantial on-treatment reductions from baseline in the H3K27me3/H3 ratio across doses. Maximum percentage reduction was proportional to cumulative MAK683 AUC, with a trend towards greater reductions at higher baseline H3K27me3. H3K27me3 H-score reductions from baseline > 40 were observed in 7/10 patients with diffuse large B-cell lymphoma (n = 4) or epithelioid sarcoma (n = 6) and paired baseline–Day 15 biopsies. RNA-seq characterization of biopsy samples is ongoing. Conclusions: MAK683 has a PK profile supportive of QD or BID dosing in patients with advanced malignancies. Analysis of H3K27me3 in blood monocytes and tumor biopsy confirm the in vivo pharmacodynamic activity of MAK683. Clinical trial information: NCT02900651.

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Abstract Details

Meeting

2022 ASCO Annual Meeting

Session Type

Poster Session

Session Title

Developmental Therapeutics—Molecularly Targeted Agents and Tumor Biology

Track

Developmental Therapeutics—Molecularly Targeted Agents and Tumor Biology

Sub Track

New Targets and New Technologies (non-IO)

Clinical Trial Registration Number

NCT02900651

Citation

J Clin Oncol 40, 2022 (suppl 16; abstr 3083)

DOI

10.1200/JCO.2022.40.16_suppl.3083

Abstract #

3083

Poster Bd #

75

Abstract Disclosures