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 Journal Article

   

Authors:	Schram, A. M.; Gandhi, L.; Mita, M. M.; Damstrup, L.; Campana, F.; Hidalgo, M.; Grande, E.; Hyman, D. M.; Heist, R. S.
Article Title:	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
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. © 2018, Cancer Research UK.
Keywords:	adult; controlled study; treatment response; aged; major clinical study; fatigue; advanced cancer; area under the curve; diarrhea; drug dose reduction; drug efficacy; drug safety; drug withdrawal; recommended drug dose; side effect; pancreas cancer; colorectal cancer; melanoma; multiple cycle treatment; ovary cancer; pharmacodynamics; breast cancer; nausea; stomatitis; vomiting; dehydration; cohort analysis; antineoplastic activity; drug dose escalation; dyspnea; fever; drug fatality; hypokalemia; hyponatremia; maculopapular rash; multicenter study; cardiotoxicity; pancreatitis; acne; peripheral edema; retina detachment; time to maximum plasma concentration; drug absorption; maximum tolerated dose; phase 1 clinical trial; drug half life; eye toxicity; non small cell lung cancer; decreased appetite; macular edema; heart ejection fraction; pimasertib; chorioretinopathy; human; male; female; priority journal; article; voxtalisib; solid malignant neoplasm; msc 1936369b
Journal Title:	British Journal of Cancer
Volume:	119
Issue:	12
ISSN:	0007-0920
Publisher:	Nature Publishing Group
Date Published:	2018-12-11
Start Page:	1471
End Page:	1476
Language:	English
DOI:	10.1038/s41416-018-0322-4
PROVIDER:	scopus
PUBMED:	30425349
PMCID:	PMC6288157
DOI/URL:	https://www.scopus.com/inward/record.uri?eid=2-s2.0-85056662306&doi=10.1038%2fs41416-018-0322-4&partnerID=40&md5=6dac5635af5184ab343b412a07d0a4e2
Notes:	Br. J. Cancer -- Export Date: 2 January 2019 -- Article -- CODEN: BJCAA C2 - 30425349 -- Source: Scopus

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