Faculty Collaboration Database

Phase I trial of MEK 1/2 inhibitor pimasertib combined with mTOR inhibitor temsirolimus in patients with advanced solid tumors. Invest New Drugs 2017 Oct;35(5):616-626

Date

02/15/2017

Pubmed ID

28194539

Pubmed Central ID

PMC5935457

DOI

10.1007/s10637-017-0442-3

Scopus ID

2-s2.0-85012284794 (requires institutional sign-in at Scopus site)   23 Citations

Abstract

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.

Author List

Mita M, Fu S, Piha-Paul SA, Janku F, Mita A, Natale R, Guo W, Zhao C, Kurzrock R, Naing A

Author

Razelle Kurzrock MD Center Associate Director, Professor in the Medicine department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Adult
Aged
Aged, 80 and over
Antineoplastic Combined Chemotherapy Protocols
Female
Humans
MAP Kinase Kinase Kinase 1
MAP Kinase Kinase Kinase 2
Male
Maximum Tolerated Dose
Middle Aged
Neoplasms
Niacinamide
Protein Kinase Inhibitors
Sirolimus
TOR Serine-Threonine Kinases
Young Adult