Clinical Study

A phase Ib dose-escalation and expansion study of the oral MEK inhibitor pimasertib and PI3K/MTOR inhibitor voxtalisib in patients with advanced solid tumours

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Abstract

Background

This phase Ib study evaluated the safety, maximum-tolerated dose (MTD), pharmacokinetics, pharmacodynamics, and preliminary efficacy of pimasertib (MSC1936369B), a MEK1/2 inhibitor, in combination with voxtalisib (SAR245409), a pan-PI3K and mTORC1/mTORC2 inhibitor, in patients with advanced solid tumours.

Methods

This study included a dose escalation and expansion in patients with select tumour types and alterations in the MAPK or PI3K pathways. A 3 + 3 design was used to determine MTD. Patients were evaluated for adverse events and tumour response.

Results

146 patients were treated, including 63 in dose escalation and 83 in expansion. The MTD was pimasertib 90 mg and voxtalisib 70 mg daily. Based on the safety profile, the recommended phase 2 dose (RP2D) was pimasertib 60 mg and voxtalisib 70 mg. The most frequent treatment-emergent adverse events (TEAEs) were diarrhoea (75%), fatigue (57%), and nausea (50%). Responses included a complete response in one patient (1%), partial response in five (5%), and stable disease in 51 (46%). At the RP2D, 74 patients required dose interruption (73%), 20 required dose reduction (20%), and 26 discontinued treatment due to TEAEs (26%).

Conclusions

The combination of pimasertib and voxtalisib showed poor long-term tolerability and limited anti-tumour activity in patients with advanced solid tumours.

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Acknowledgements

We thank all the patients, their families and investigators who participated in this study.

Author information

L.G., M.M., L.D., F.C., M.H., E.G., D.H., and R.H. participated in the study design. L.G., M.M., M.H., E.G., D.H., and R.H. recruited the patients. A.S., D.H., and R.H. participated in statistical analyses, discussion of the results, and writing of the manuscript. All authors read and approved the final manuscript.

Correspondence to Alison M. Schram.

Ethics declarations

Competing interests

L.G.: Research Fuding: Merck. Advisory Role: Merck, Genentech/Roche, Pfizer, Ignyta, Syndax, AbbVie, AstraZeneca, Bristol-Myers Squibb; L.D.: Employee of Merck KGaA; F.C.: Employee of Sanofi; D.M.H.: Research Funding: NIH R01 CA204749, AstraZeneca, Puma Biotechnology, Loxo Oncology. Consulting or Advisory Role: AstraZeneca, Atara Biotherapeutics, Chugai Pharma, CytomX Therapeutics, Boehringer Ingelheim, Pfizer, Genetech, Bayer, Debiopharm, ArQule; R.S.H.: Consulting: Boehringer Ingelheim. Research funding (to institution): Novartis, Celgene, Corvus, Genentech/Roche, Millenium, Mirati, ABBVie, Incyte, Exelixis, Daichi, Agios.

Data availability:

Available through EMD Serono.

Ethical approval and consent to participate:

All patients signed an informed consent prior to participation in the study. Ethical approval was given by the Institutional Review Boards at all participating institutions. The study was conducted according to the Declaration of Helsinki.

Funding:

Provided by EMD Serono.

Note:

This work is published under the standard license to publish agreement. After 12 months the work will become freely available and the license terms will switch to a Creative Commons Attribution 4.0 International (CC BY 4.0).

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