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Phase I trial of MEK 1/2 inhibitor pimasertib combined with mTOR inhibitor temsirolimus in patients with advanced solid tumors

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Summary

Background Dual inhibition of activated MAPK and mTOR signaling pathways may enhance the antitumor efficacy of the MEK 1/2 inhibitor pimasertib and the mTOR inhibitor temsirolimus given in combination. Methods In this phase I study, patients with refractory advanced solid tumors (NCT01378377) received once-weekly temsirolimus plus once-daily oral pimasertib in 21-day cycles in a modified 3 + 3 dose-escalation design. The maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of pimasertib in combination with temsirolimus, safety and pharmacokinetics (PK) were investigated. Results Of 33 patients evaluated, all experienced ≥1 treatment-emergent adverse event (TEAE) and 31 had treatment-related TEAEs, most frequently stomatitis and thrombocytopenia. TEAEs were reversible. No deaths were attributed to treatment. Nine patients had dose-limiting toxicities (stomatitis, thrombocytopenia, serum creatinine phosphokinase increase, visual impairment) and the MTD was determined as 45 mg/day pimasertib plus 25 mg/week temsirolimus. However, due to overlapping toxicities no further investigations were performed and the RP2D was not defined. PK profiles of both agents were not adversely affected. Seventeen patients (17/26 patients) had a best response of stable disease; five had stable disease lasting >12 weeks. Conclusions The RP2D was not defined and the pimasertib plus temsirolimus combination investigated did not warrant further study.

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Acknowledgements

The authors would like to thank patients and their families, investigators, co-investigators and the study teams at the participating centers and at Merck KGaA, Darmstadt, Germany and EMD Serono, Billerica, USA (an affiliate of Merck KGaA, Darmstadt, Germany). Our thanks also to Ekaterine Asatiani for her contribution to the study and guidance on this manuscript. Wei Guo’s current affiliation is TESARO Inc. Waltham, USA. This study was sponsored by Merck KGaA, Darmstadt, Germany and EMD Serono Inc., Billerica, USA. Medical writing assistance was provided by Helen Swainston, Bioscript Science, Macclesfield, UK and funded by Merck KGaA, Darmstadt, Germany.

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Authors and Affiliations

  1. Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA

    Monica Mita, Alain Mita & Ronald Natale

  2. Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX, 77030, USA

    Siqing Fu, Sarina Anne Piha-Paul, Filip Janku & Aung Naing

  3. Global Biostatistics, EMD Serono Inc., Billerica, MA, 01821, USA

    Wei Guo

  4. Clinical Oncology Early Development, EMD Serono Inc., Billerica, MA, 01821, USA

    Charles Zhao

  5. Division of Hematology and Oncology, University of California San Diego (UCSD) School of Medicine and UCSD Moores Cancer Center, La Jolla, CA, 92093, USA

    Razelle Kurzrock

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Correspondence to Aung Naing.

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Conflict of interest

M Mita has no conflicts of interest to declare.

S Fu has no conflicts of interest to declare.

SA Piha-Paul has no conflicts of interest to declare.

F Janku has no conflicts of interest to declare.

A Mita has no conflicts of interest to declare.

R Natale has no conflicts of interest to declare.

W Guo was an employee of EMD Serono Inc, Billerica, USA who sponsored this trial.

C Zhao is an employee of EMD Serono Inc., Billerica, USA who sponsored this trial.

R Kurzrock has research funding from Genentech, Merck Serono, Pfizer, Sequenom, Foundation Medicine, and Guardant, as well as consultant/advisory board fees from Sequenom, Actuate Therapeutics, and Xbiotech, and an ownership interest in Novena, Inc. and Curematch, Inc.

A Naing has no conflicts of interest to declare.

Funding

This study was sponsored by Merck KGaA, Darmstadt, Germany and EMD Serono Inc., Billerica, USA.

Ethical approval

Written informed consent was obtained from all patients prior to study initiation. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institution of the participating centers and with the 1964 Helsinki declaration and its later amendments.

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Mita, M., Fu, S., Piha-Paul, S.A. et al. Phase I trial of MEK 1/2 inhibitor pimasertib combined with mTOR inhibitor temsirolimus in patients with advanced solid tumors. Invest New Drugs 35, 616–626 (2017). https://doi.org/10.1007/s10637-017-0442-3

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