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Invest New Drugs. 2017 Oct;35(5):576-588. doi: 10.1007/s10637-017-0459-7. Epub 2017 Apr 19.

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

Author information

1
Sarah Cannon Research Institute, 93 Harley St, Marylebone, London, W1G 6AD, UK. jinfante@tnonc.com.
2
Tennessee Oncology, PLLC, 250 25th Ave North, Nashville, TN, 37203, USA. jinfante@tnonc.com.
3
Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111, USA.
4
California Pacific Medical Center (Sutterhealth), 475 Brannan Street, Suite 220, San Francisco, CA, 94107, USA.
5
Sarah Cannon Research Institute, 93 Harley St, Marylebone, London, W1G 6AD, UK.
6
Tennessee Oncology, PLLC, 250 25th Ave North, Nashville, TN, 37203, USA.
7
AstraZeneca, 1800 Concord Pike, Wilmington, DE, 19850, USA.
8
AstraZeneca, Charter Way, Macclesfield, SK10 2NA, UK.
9
Yale Cancer Center, 55 Park Street, Ste First Floor, New Haven, CT, 06519, USA.

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

PMID:
28424891
PMCID:
PMC5613062
DOI:
10.1007/s10637-017-0459-7
[Indexed for MEDLINE]
Free PMC Article

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