Abstract

SummaryBackground Combinations of molecularly targeted agents may provide optimal anti-tumor activity and improve clinical outcomes for patients with advanced cancers. Selumetinib (AZD6244, ARRY-142886) is an oral, potent and highly selective, allosteric inhibitor of MEK1/2, a component of the RAS/RAF/MEK/ERK pathway which is constitutively activated in many cancers. We investigated the safety, tolerability, and pharmacokinetics (PK) of selumetinib in combination with molecularly targeted drugs erlotinib or temsirolimus in patients with advanced solid tumors. Methods Two-part study: dose escalation, to determine the maximum tolerated dose (MTD) of selumetinib in combination with erlotinib 100 mg once daily (QD) or temsirolimus 25 mg once weekly, followed by dose expansion at the respective combination MTDs to further investigate safety and anti-tumor effects. Results 48 patients received selumetinib plus erlotinib and 32 patients received selumetinib plus temsirolimus. The MTD with erlotinib 100 mg QD was selumetinib 100 mg QD, with diarrhea being dose limiting. The most common all grade adverse events (AEs): diarrhea, rash, nausea, and fatigue. Four (8.3%) patients had ≥12 weeks stable disease. The MTD with temsirolimus 25 mg once weekly was selumetinib 50 mg twice daily (BID), with mucositis and neutropenia being dose limiting. The most commonly reported AEs: nausea, fatigue, diarrhea, and mucositis. Ten (31.3%) patients had ≥12 weeks stable disease. The combination PK profiles were comparable to previously observed monotherapy profiles. Conclusions MTDs were established for selumetinib in combination with erlotinib or temsirolimus. Overlapping toxicities prevented the escalation of selumetinib to its recommended phase II monotherapy dose of 75 mg BID. Trial registration:ClinicalTrials.gov NCT00600496; registered 8 July 2009.

Highlights

  • The intracellular RAS/RAF/MEK/ERK (RAS-ERK) pathway converges on MEK1/2, whose only known substrates are ERK1/2

  • Patients eligible for the study were those with advanced solid tumors for whom erlotinib or temsirolimus would be an appropriate standard of care, or those who might benefit from erlotinib or temsirolimus combined with a novel agent such as selumetinib

  • Patients with any of the following were excluded from the study: prior treatment with a MEK inhibitor; received an investigational drug within 30 days of entering the study, or had not recovered from the adverse events (AEs) of an investigational study drug; received radiotherapy or standard chemotherapy within 21 days of study entry; use of strong cytochrome 1A2 or 3A4 inducers and/or inhibitors; brain metastases or spinal cord compression unless treated and stable (>1 month) and off steroids; factors that increased the risk of QT prolongation or arrhythmic events or QTc interval of >450 ms for males or >470 ms for females; inadequate bone marrow, hepatic, cardiac, or renal function; current smoker or user of any tobacco

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Summary

Introduction

The intracellular RAS/RAF/MEK/ERK (RAS-ERK) pathway converges on MEK1/2, whose only known substrates are ERK1/2. Constitutive activation of the pathway is implicated in cell proliferation and is central to driving cancer growth and progression [1, 2]. Invest New Drugs (2017) 35:576–588 transduction of the mitogenic signals from multiple pathways, resulting in effects on tumor proliferation, differentiation, and survival. These observations have been translated to the clinic and have improved outcomes for patients with advanced cancer. The MEK inhibitor trametinib is recommended as monotherapy and in combination for patients with BRAF V600 mutant melanoma [3]. Several other MEK inhibitors are currently undergoing clinical investigation [4]

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