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First-in-human phase I dose escalation study of MK-8033 in patients with advanced solid tumors

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Summary

Background C-Met, which is frequently activated in multiple cancers, has been implicated in tumor formation, progression, metastasis, angiogenesis, and resistance to multiple therapies. MK-8033 is a small-molecule inhibitor of c-Met that binds preferentially to the activated conformation, and has demonstrated anti-tumor activity in preclinical models. This first-in-human trial was performed to establish the safety and maximum tolerated dose (MTD), as well as preliminary pharmacokinetics (PK) and clinical activity. Methods Forty-seven patients were enrolled in three parts. The primary objective of Parts A and B was safety, whereas Part C evaluated the effect of proton-pump inhibitors on MK-8033 absorption. Dose escalation used an accelerated continual reassessment method, and dose-limiting toxicities (DLTs) were any treatment-related, first course non-hematologic grade ≥ 3 toxicity (except alopecia or inadequately treated nausea/vomiting/diarrhea), grade 4 hematologic toxicity (except grade 3 neutropenic fever and thrombocytopenia), or toxicity where treatment is held >3 weeks. Results Forty-six patients were treated across nine dose levels, and the MTD was 750 mg twice daily. DLTs were fatigue, nausea, vomiting, transaminitis, and hypokalemia. Most frequent toxicities were fatigue (28.3%), nausea (21.7%), and alopecia (19.6%), predominately grade ≤ 2. One patient with endometriod adenocarcinoma achieved a partial response and eight had stable disease. Median progression-free survival (PFS) was 57 days. Strikingly, the PFS for the one responder was 846 days. PK results showed that proton-pump inhibitors have no effect on MK-8033 absorption. Conclusion MK-8033 was well tolerated with no significant toxicity issues, albeit with limited clinical activity. Unfortunately, the company decided to discontinue further clinical development of MK-8033.

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Acknowledgments

The authors would like to thank the patients who participated in this study and their families, the study investigators, and study staff. The authors would also like to thank Jianmin Long from Merck & Co., Inc., Kenilworth, NJ for assistance with the manuscript.

Funding

This first-in-human phase I clinical trial was supported by Merck Research Laboratories.

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Correspondence to Vicki L. Keedy.

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Conflict of interest

VLK is a consultant for Karyopharm and Janssen, and has research funding from Lilly, Plexxicon, CytRx, Daiichi, Threshold, Janssen, Roch, Axtrazeneca, MedPacto, Immune Design, and GSK. HJL has served as consultant for Genentech, Bayer, BMS, Merck KG, Boehringer Ingelheim, Taiho, Symphogen and has clinical trial support from Taiho, Genentech, Incyte, Abbvie, Novartis, Bayer, BMS, Merck, EMD and Boehringer Ingelheim. LS has research funding from Taiho. JB has served as a consultant for Celgene, Genentech, Aduro, Boston Biomedical, Janssen, Cornerstone, Symphogen, and Bayer and has institutional research funding from Genentech, Abbvie, Taiho, Bayer, 5Prime, Phoenix, Incyte, and Vertex. LHC receives research funds from MacroGenics Inc., and serves on the vaccine advisory committee for Merck, Inc. For the remaining author, none were declared.

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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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Informed consent was obtained for all individual participants included in the study.

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Keedy, V.L., Lenz, HJ., Saltz, L. et al. First-in-human phase I dose escalation study of MK-8033 in patients with advanced solid tumors. Invest New Drugs 36, 860–868 (2018). https://doi.org/10.1007/s10637-018-0567-z

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