608 Phase I Dose-escalation Trial of a Selective Oral MEK1/2 Inhibitor, Pimasertib (MSC1936369B), Combined with an mTOR Inhibitor, Temsirolimus, in Patients with Advanced Solid Tumors

Naing, Aung; Mita, Masayuki; Komarnitsky, Philip; Milner, Alvin; Richter, Oliver von; Ogden, Julia; Piha-Paul, S. A.; Fu, Sidney W.; Asatiani, Ekaterine; Kurzrock, Razelle

doi:10.1016/s0959-8049(12)72405-x

Cited by 7 publications

(4 citation statements)

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“…Common MEK inhibitor-related AEs, such as skin, gastrointestinal and ocular events, 28,29 were observed more frequently with the combination therapy, but the majority of these were reversible on discontinuation of treatment. These AEs have been observed previously with pimasertib monotherapy 22,30 and in combination with FOL-FIRI 31 and temsirolimus, 32 and with other MEK inhibitors, such as trametinib and selumetinib. 27,28,33 However, with pimasertib therapy, more patients withdrew due to AEs, more serious AEs were observed, and time on treatment was decreased compared to placebo plus gemcitabine.…”

Section: Cancer Therapy and Preventionsupporting

confidence: 65%

Phase I/II trial of pimasertib plus gemcitabine in patients with metastatic pancreatic cancer

Cutsem

Hidalgo²,

Canon

et al. 2018

Intl Journal of Cancer

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The selective MEK1/2 inhibitor pimasertib has shown anti-tumour activity in a pancreatic tumour model. This phase I/II, two-part trial was conducted in patients with metastatic pancreatic adenocarcinoma (mPaCa) (NCT01016483). In the phase I part, oral pimasertib was given once daily discontinuously (5 days on/2 days off treatment) or twice daily continuously (n = 53) combined with weekly gemcitabine (1,000 mg/m ) in 28-day cycles to identify the recommended phase II dose (RP2D) of pimasertib. In the phase II part, patients were randomised to pimasertib (RP2D) or placebo plus weekly gemcitabine (n = 88) to investigate progression-free survival (PFS), overall survival (OS) and safety. The RP2D was determined to be 60 mg BID. PFS and OS outcomes did not indicate any treatment benefit for pimasertib over placebo in combination with gemcitabine (median PFS 3.7 and 2.8 months, respectively, HR = 0.91, 95% CI: 0.58-1.42: median OS 7.3 vs. 7.6 months, respectively). KRAS status did not influence PFS or OS. The incidence of grade ≥3 adverse events was 91.1% and 85.7% for pimasertib/gemcitabine and placebo/gemcitabine respectively, but there was a higher incidence of ocular events with pimasertib/gemcitabine (28.9% vs. 4.8% for placebo/gemcitabine). In conclusion, no clinical benefit was observed with first-line pimasertib plus gemcitabine compared with gemcitabine alone in patients with mPaCa.

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Section: Cancer Therapy and Preventionsupporting

confidence: 65%

Phase I/II trial of pimasertib plus gemcitabine in patients with metastatic pancreatic cancer

Cutsem

Hidalgo²,

Canon

et al. 2018

Intl Journal of Cancer

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“…Pimasertib showed a favourable PK profile in patients with solid tumours, and target action was shown by a decrease of phospho-ERK (pERK) in peripheral blood mononuclear cells (PBMCs). 90,91 Clinical trials with pimasertib revealed a dosedependent target-inhibitory impact. In melanomas with BRAF or NRAS mutations, sustained responses were primarily seen.…”

Section: Gdc-0623 [(1-(5-((2-fluoro-4-iodophenyl)amino) Imidazo[15-a]...mentioning

confidence: 99%

MEK inhibitors in cancer treatment: structural insights, regulation, recent advances and future perspectives

et al. 2023

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“…TARGETS Enzymes [2] Introduction Pimasertib (MSC1936369B/AS703026) is a highly selective, orally bioavailable, small molecule inhibitor of mitogenactivated protein kinases 1 and 2 (MEK1/2) of the MAPK pathway (the chemical structure and synthesis of pimasertib are available [3][4][5]). Pimasertib has demonstrated potent antitumour activity either alone or in combination with other agents in cell lines and xenograft models [3,6,7] and is currently undergoing phase I/II clinical trials in patients with different tumour types; it has demonstrated clinical activity both as monotherapy and in combination with gemcitabine, the PI3K inhibitor SAR245409, and the HDM-2 inhibitor SAR405838 [8][9][10].…”

Section: What This Study Addsmentioning

confidence: 99%

Pimasertib, a selective oral MEK1/2 inhibitor: absolute bioavailability, mass balance, elimination route, and metabolite profile in cancer patients

Richter

Massimini

Scheible

et al. 2016

Brit J Clinical Pharma

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Keywords14 C, absolute bioavailability, elimination route, mass balance, pimasertib AIMThis trial (NCT: 01713036) investigated the absolute bioavailability, mass balance and metabolite profile of pimasertib in a new design combining these investigations in a single group of patients. METHODSSix male patients with pathologically confirmed, locally advanced or metastatic solid tumours were enrolled. Exclusion criteria included Eastern Cooperative Oncology Group performance status >1. In Part A of the trial, patients received a 60 mg oral dose of unlabelled pimasertib followed by an intravenous (i.v.) RESULTS Following i.v. administration, [14 C]pimasertib exhibited a geometric mean total body clearance of 45.7 l h À1 (geometric coefficient of variation [geometric CV]: 47.2%) and a volume of distribution of 229 l (geometric CV: 42.0%). Absolute bioavailability was 73%. The majority of the oral [ 14 C] dose (85.1%) was recovered in excreta. Total radioactivity was mainly excreted into urine (52.8%) and faeces (30.7%) with 78.9% of the [ 14 C] dose recovered as metabolites. Two major circulating metabolites were identified in plasma: a carboxylic acid (M445) and a phosphoethanolamine conjugate (M554). The safety profile was in line with the published pimasertib trials. CONCLUSIONPimasertib showed a favourable pharmacokinetic profile with high absolute bioavailability and a unique metabolic pathway (conjugation with phosphoethanolamine). British Journal of Clinical Pharmacology WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Pimasertib is a new selective, oral inhibitor of mitogen-activated protein kinases 1 and 2 (MEK1/2).• Comprehensive information about the pharmacokinetics, including absolute bioavailability, metabolism and elimination routes, of cancer drugs is often incomplete. WHAT THIS STUDY ADDS• Description of a trial design combining investigation of absolute bioavailability and mass balance/metabolite identification in a single group of six male cancer patients.• Identification of a new metabolic pathway for drugs, i.e. conjugation with phosphoethanolamine.• Information about key pharmacokinetic parameters and the drug disposition of pimasertib in cancer patients. Tables of Links

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608 Phase I Dose-escalation Trial of a Selective Oral MEK1/2 Inhibitor, Pimasertib (MSC1936369B), Combined with an mTOR Inhibitor, Temsirolimus, in Patients with Advanced Solid Tumors

Cited by 7 publications

References 0 publications

Phase I/II trial of pimasertib plus gemcitabine in patients with metastatic pancreatic cancer

Phase I/II trial of pimasertib plus gemcitabine in patients with metastatic pancreatic cancer

MEK inhibitors in cancer treatment: structural insights, regulation, recent advances and future perspectives

Pimasertib, a selective oral MEK1/2 inhibitor: absolute bioavailability, mass balance, elimination route, and metabolite profile in cancer patients

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