PMID- 28424891 OWN - NLM STAT- MEDLINE DCOM- 20180711 LR - 20190827 IS - 1573-0646 (Electronic) IS - 0167-6997 (Print) IS - 0167-6997 (Linking) VI - 35 IP - 5 DP - 2017 Oct TI - A phase I dose-escalation study of Selumetinib in combination with Erlotinib or Temsirolimus in patients with advanced solid tumors. PG - 576-588 LID - 10.1007/s10637-017-0459-7 [doi] AB - 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. FAU - Infante, Jeffrey R AU - Infante JR AD - Sarah Cannon Research Institute, 93 Harley St, Marylebone, London, W1G 6AD, UK. jinfante@tnonc.com. AD - Tennessee Oncology, PLLC, 250 25th Ave North, Nashville, TN, 37203, USA. jinfante@tnonc.com. FAU - Cohen, Roger B AU - Cohen RB AD - Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111, USA. FAU - Kim, Kevin B AU - Kim KB AD - California Pacific Medical Center (Sutterhealth), 475 Brannan Street, Suite 220, San Francisco, CA, 94107, USA. FAU - Burris, Howard A 3rd AU - Burris HA 3rd AD - Sarah Cannon Research Institute, 93 Harley St, Marylebone, London, W1G 6AD, UK. AD - Tennessee Oncology, PLLC, 250 25th Ave North, Nashville, TN, 37203, USA. FAU - Curt, Gregory AU - Curt G AD - AstraZeneca, 1800 Concord Pike, Wilmington, DE, 19850, USA. FAU - Emeribe, Ugochi AU - Emeribe U AD - AstraZeneca, 1800 Concord Pike, Wilmington, DE, 19850, USA. FAU - Clemett, Delyth AU - Clemett D AD - AstraZeneca, Charter Way, Macclesfield, SK10 2NA, UK. FAU - Tomkinson, Helen K AU - Tomkinson HK AD - AstraZeneca, Charter Way, Macclesfield, SK10 2NA, UK. FAU - LoRusso, Patricia M AU - LoRusso PM AD - Yale Cancer Center, 55 Park Street, Ste First Floor, New Haven, CT, 06519, USA. LA - eng SI - ClinicalTrials.gov/NCT00600496 GR - UL1 TR001863/TR/NCATS NIH HHS/United States PT - Clinical Trial, Phase I PT - Journal Article PT - Multicenter Study PT - Research Support, Non-U.S. Gov't DEP - 20170419 PL - United States TA - Invest New Drugs JT - Investigational new drugs JID - 8309330 RN - 0 (AZD 6244) RN - 0 (Antineoplastic Agents) RN - 0 (Benzimidazoles) RN - 0 (Protein Kinase Inhibitors) RN - 624KN6GM2T (temsirolimus) RN - DA87705X9K (Erlotinib Hydrochloride) RN - W36ZG6FT64 (Sirolimus) SB - IM EIN - Invest New Drugs. 2017 Jul 5;:. PMID: 28676972 MH - Antineoplastic Agents/administration & dosage MH - Antineoplastic Combined Chemotherapy Protocols/*therapeutic use MH - Benzimidazoles/administration & dosage MH - Dose-Response Relationship, Drug MH - Erlotinib Hydrochloride/administration & dosage MH - Female MH - Humans MH - Male MH - Maximum Tolerated Dose MH - Middle Aged MH - Neoplasms/*drug therapy MH - Protein Kinase Inhibitors/administration & dosage MH - Sirolimus/administration & dosage/analogs & derivatives PMC - PMC5613062 OTO - NOTNLM OT - Advanced solid tumors OT - Dose-escalation OT - Erlotinib OT - Selumetinib OT - Temsirolimus COIS- Author JI declares that he has no conflict of interest. Author RC declares that he has no conflict of interest. Author KK declares that he has no conflict of interest. Author HB declares that he has no conflict of interest. Author GC declares that at the time of the study he was an employee of AstraZeneca and held stock/share options. Author UE declares that he is an employee of AstraZeneca and holds stock/share options. Author HT declares that she is an employee of AstraZeneca and holds stock/share options. Author DC declares that she is a former employee of AstraZeneca and holds stock/share options. Author PL declares that she has no conflict of interest. EDAT- 2017/04/21 06:00 MHDA- 2018/07/12 06:00 PMCR- 2017/04/19 CRDT- 2017/04/21 06:00 PHST- 2017/02/21 00:00 [received] PHST- 2017/03/17 00:00 [accepted] PHST- 2017/04/21 06:00 [pubmed] PHST- 2018/07/12 06:00 [medline] PHST- 2017/04/21 06:00 [entrez] PHST- 2017/04/19 00:00 [pmc-release] AID - 10.1007/s10637-017-0459-7 [pii] AID - 459 [pii] AID - 10.1007/s10637-017-0459-7 [doi] PST - ppublish SO - Invest New Drugs. 2017 Oct;35(5):576-588. doi: 10.1007/s10637-017-0459-7. Epub 2017 Apr 19.