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Mini oral session - Sarcoma

1525MO - Phase I/II study of MAK683 in patients (pts) with advanced malignancies including epithelioid sarcoma

Date

17 Sep 2021

Session

Mini oral session - Sarcoma

Presenters

Rastislav Bahleda

Citation

Annals of Oncology (2021) 32 (suppl_5): S1111-S1128. 10.1016/annonc/annonc712

Authors

R. Bahleda1, Z.A. Wainberg2, A. Spreafico3, B. Ma4, V. Subbiah5, V. Ribrag6, M. Duca7, Y.Y. Fan8, Y. Cheng9, C. Lai8, F. De Braud7

Author affiliations

  • 1 Drug Development Department, Gustave Roussy - Cancer Campus, 94805 - Villejuif/FR
  • 2 Medicine, Hematology & Oncology, Ronald Reagan UCLA Medical Center, Los Angeles/US
  • 3 Princess Margaret Cancer Centre, University Health Network, Toronto/CA
  • 4 Department Of Clinical Oncology, Prince of Wales Hospital, Chinese University of Hong Kong, New Territories/HK
  • 5 Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston/US
  • 6 Department Of Hematology, Gustave Roussy, Villejuif/FR
  • 7 Medical Oncology Department, Fondazione IRCCS Istituto Nazionale Tumori, Milan/IT
  • 8 Translational Clinical Oncology, Novartis Institutes for BioMedical Research Co., Ltd., Shanghai/CN
  • 9 Global Drug Development And Clinical Development Analytics, Novartis Institutes for Biomedical Research Co. Ltd., Shanghai/CN
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Resources

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Abstract 1525MO

Background

EED is a core component of PRC2 which modifies the epigenetic status of target genes, including cell cycle control genes. Loss of SNF5 function in epithelioid sarcoma drives oncogenesis by imbalanced PRC2 activity. MAK683 is a potent, S-adenosyl-l-methionine, non-competitive PRC2 inhibitor that impairs EED binding to tri-methylated lysine 27 on histone H3 (H3K27me3), preventing allosteric activation of this complex. This is a phase I/II study of MAK683, in adult pts with advanced malignancies who have exhausted or have no effective standard treatment. The primary objective was to characterize safety and tolerability and determine the maximum tolerated dose and/or recommended phase II dose.

Methods

Pts received escalating doses of MAK683 in fasted conditions where appropriate. Eligible pts had specified advanced/metastatic hematological or solid malignancies. Here, we present data from a subset of pts with advanced epithelioid sarcoma. Pts were administered MAK683 120–300 mg twice daily (BID) or 500–800 mg once daily (QD) orally until unacceptable or dose-limiting toxicities (DLT) had developed, disease progression or death.

Results

As of Jan 15, 2021, 14 pts with a median of 1.5 prior lines of therapy (range: 0–5) had been treated. Four (29%) were ongoing and 10 (71%) discontinued, primarily due to progressive disease (PD) (43%). Nine (64%) pts reported ≥1 treatment-related adverse event (TRAE) of any grade, with the most common (≥20%) being alopecia (36%), nausea, neutropenia, thrombocytopenia (29% each), and diarrhea (21%). Grade 3/4 TRAEs were reported in 50% pts, with ≥20% reporting neutropenia and thrombocytopenia (21% each). DLT were reported in 2 pts receiving 120 and 300 mg BID, respectively. There were no treatment-related deaths. Partial response was observed in 2 pts (14%) receiving 120 mg BID and 500 mg QD respectively. Six (43%) pts had stable disease and 3 (21%) had PD. The overall response rate was 14% (95% CI: 1.8–42.8) and the disease control rate was 57% (95% CI: 28.9–82.3). Duration of response of the two responders were 16.5+ and 5.2+ months.

Conclusions

MAK683 was generally well-tolerated and there were preliminary signs of activity in pts with advanced epithelioid sarcoma.

Clinical trial identification

NCT02900651; Protocol number: CMAK683X2101; Release date: 27 June 2018.

Editorial acknowledgement

Writing and editorial assistance was provided by Sivanjaa Manoj of ArticulateScience, UK.

Legal entity responsible for the study

Novartis Pharmaceutical Corporation.

Funding

Novartis Pharmaceutical Corporation.

Disclosure

Z.A. Wainberg: Financial Interests, Personal, Other, Honoraria: Amgen, Astra Zeneca, Daiichi, Bayer, BMS, Merck, Ipsen, Five Prime, Gilead, Arcus, Astellas, Molecular Templates, Array; Financial Interests, Personal, Advisory Board: Amgen, Astra Zeneca, Daiichi, Bayer, BMS, Merck, Ipsen, Five Prime, Gilead, Arcus, Astellas, Molecular Templates, Array; Financial Interests, Institutional, Research Grant: Amgen, Astra Zeneca, Daiichi, Bayer, BMS, Merck, Ipsen, Five Prime, Gilead, Arcus, Astellas, Molecular Templates, Roche/Genentech, Array/Pfizer. A. Spreafico: Financial Interests, Institutional, Funding, Research Funding to support clinical trials: Novartis, Bristol-Myers Squibb, Symphogen AstraZeneca/Medimmune, Merck, Bayer, Surface Oncology, Northern Biologics, Janssen Oncology/Johnson & Johnson, Roche, Regeneron, Alkermes, Array Biopharma/Pfizer, GSK, Treadwell; Financial Interests, Personal, Advisory Board: Merck, Bristol-Myers Squibb, Oncorus, Janssen. B. Ma: Financial Interests, Personal, Invited Speaker: MSD, Taiho, Daichi; Financial Interests, Personal, Advisory Board: BMS; Financial Interests, Personal, Other, Pre-clinical: Boehringer Ingelheim, Novartis; Financial Interests, Personal, Other, Consultancy : Y-biologics. V. Subbiah: Financial Interests, Personal, Research Grant: Novartis; Financial Interests, Personal, Research Grant: LOXO Oncology; Financial Interests, Personal, Research Grant: BluePrint Medicines; Financial Interests, Personal, Advisory Board: Helsinn, Loxo Oncology/Eli Lilly, R-Pharma US, INCYTE, QED Pharma, Medimmune,and Novartis; Financial Interests, Personal, Other: Loxo Oncology/Eli Lilly, Novartis, Bayer, Berghealth, Incyte, Fujifilm, Pharmamar, D3, Pfizer, Multivir, Amgen, Abbvie, Alfa-sigma, Agensys, Boston Biomedical, Idera Pharma, Inhibrx, Exelixis, Blueprint Medicines, Medimmune, Altum, Dragonfly Therapeutics,. V. Ribrag: Financial Interests, Personal, Advisory Board: Gilead, Infinity, MSD, BMS, Nanostring, Incyte, Roche, AstraZeneca; Financial Interests, Personal, Other, Consulting: Servier; Non-Financial Interests, Personal, Research Grant: Astex. Y.Y. Fan: Financial Interests, Personal, Full or part-time Employment: Novartis. Y. Cheng: Financial Interests, Personal, Full or part-time Employment: Novartis. C. Lai: Financial Interests, Personal, Full or part-time Employment: Novartis; Financial Interests, Personal, Stocks/Shares: Novartis. F. De Braud: Financial Interests, Personal, Other, Honoraria: Roche, EMD Serono, NMS Nerviano Medical Science, Sanofi, Novartis, Incyte, Bristol-Myers Squibb, MSD, Servier, Merck Group, Amgen, Pfizer, Tesaro, Celgene. All other authors have declared no conflicts of interest.

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