A phase I dose-escalation study of Selumetinib in combination with Erlotinib or Temsirolimus in patients with advanced solid tumors

Abstract

Background 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.

Keywords: Advanced solid tumors; Dose-escalation; Erlotinib; Selumetinib; Temsirolimus.

Fig. 1

Patient disposition at the time of data cut-off in the a selumetinib plus erlotinib and b selumetinib plus temsirolimus arms. BID, twice daily; QD, once daily

Fig. 2

Waterfall plots for best change in target lesion size from baseline for the a selumetinib plus erlotinib and b selumetinib plus temsirolimus arms. Lower reference line indicates the point below which best response is partial response (>30% reduction). Upper reference line indicates the point above which best response is progressive disease (>20%). Response Evaluation Criteria In Solid Tumors best response: N, not evaluable; P, progressive disease; R, partial response; S, stable disease. BID, twice daily; QD, once daily. Population: Measurable disease at baseline and underwent follow-up scan (Figures created in Adobe Illustrator CC 2015)