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Investigational New Drugs
Published in: Investigational New Drugs 5/2017

Open Access 01-10-2017 | PHASE I STUDIES

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

Authors: Jeffrey R. Infante, Roger B. Cohen, Kevin B. Kim, Howard A. Burris III, Gregory Curt, Ugochi Emeribe, Delyth Clemett, Helen K. Tomkinson, Patricia M. LoRusso

Published in: Investigational New Drugs | Issue 5/2017

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Summary

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.
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Literature
1.
Davies BR, Logie A, McKay JS et al (2007) AZD6244 (ARRY-142886), a potent inhibitor of mitogen-activated protein kinase/extracellular signal-regulated kinase kinase 1/2 kinases: mechanism of action in vivo, pharmacokinetic/pharmacodynamic relationship, and potential for combination in preclinical models. Mol Cancer Ther 6(8):2209–2019CrossRef
2.
Roberts PJ, Stinchcombe TE (2013) KRAS mutation: should we test for it, and does it matter? J Clin Oncol 31(8):1112–1121CrossRef
3.
4.
Akinleye A, Furqan M, Mukhi N, Ravella P, Liu D (2013) MEK and the inhibitors: from bench to bedside. J Hematol Oncol 6:27CrossRef
5.
Banerji U, Camidge DR, Verheul HM et al (2010) The first-in-human study of the hydrogen sulfate (Hyd-sulfate) capsule of the MEK1/2 inhibitor AZD6244 (ARRY-142886): a phase I open-label multicenter trial in patients with advanced cancer. Clin Cancer Res 16(5):1613–1623CrossRef
6.
Yeh TC, Marsh V, Bernat BA et al (2007) Biological characterization of ARRY-142886 (AZD6244), a potent, highly selective mitogen-activated protein kinase kinase 1/2 inhibitor. Clin Cancer Res 13(5):1576–1583CrossRef
7.
Denton CL, Gustafson DL (2011) Pharmacokinetics and pharmacodynamics of AZD6244 (ARRY-142886) in tumor-bearing nude mice. Cancer Chemother Pharmacol 67(2):349–360CrossRef
8.
Ho AL, Grewal RK, Leboeuf R et al (2013) Selumetinib-enhanced radioiodine uptake in advanced thyroid cancer. N Engl J Med 368(7):623–632CrossRef
9.
Widemann BC, Marcus LJ, Fisher MJ et al (2014) Phase I study of the MEK1/2 inhibitor selumetinib (AZD6244) hydrogen sulfate in children and young adults with neurofibromatosis type 1 (NF1) and inoperable plexiform neurofibromas (PNs). J Clin Oncol 32(suppl 15):abstract 10018–10018CrossRef
10.
Bennouna J, Lang I, Valladares-Ayerbes M et al (2011) A Phase II, open-label, randomised study to assess the efficacy and safety of the MEK1/2 inhibitor AZD6244 (ARRY-142886) versus capecitabine monotherapy in patients with colorectal cancer who have failed one or two prior chemotherapeutic regimens. Investig New Drugs 29(5):1021–1028CrossRef
11.
Bodoky G, Timcheva C, Spigel DR et al (2012) A Phase II open-label randomized study to assess the efficacy and safety of selumetinib (AZD6244 [ARRY-142886]) versus capecitabine in patients with advanced or metastatic pancreatic cancer who have failed first-line gemcitabine therapy. Investig New Drugs 30(3):1216–1223CrossRef
12.
Hainsworth JD, Cebotaru CL, Kanarev V et al (2010) A Phase II, open-label, randomized study to assess the efficacy and safety of AZD6244 (ARRY-142886) versus pemetrexed in patients with non-small cell lung cancer who have failed one or two prior chemotherapeutic regimens. J Thorac Oncol 5(10):1630–1636CrossRef
13.
Kirkwood JM, Bastholt L, Robert C et al (2012) Phase II, open-label, randomized trial of the MEK1/2 inhibitor selumetinib as monotherapy versus temozolomide in patients with advanced melanoma. Clin Cancer Res 18(2):555–567CrossRef
14.
Yoon YK, Kim HP, Han SW et al (2009) Combination of EGFR and MEK1/2 inhibitor shows synergistic effects by suppressing EGFR/HER3-dependent AKT activation in human gastric cancer cells. Mol Cancer Ther 8(9):2526–2536CrossRef
15.
Ma BB, Lui VW, Cheung CS et al (2013) Activity of the MEK inhibitor selumetinib (AZD6244; ARRY-142886) in nasopharyngeal cancer cell lines. Investig New Drugs 31(1):30–38CrossRef
16.
Chang Q, Chen E, Hedley DW (2009) Effects of combined inhibition of MEK and mTOR on downstream signaling and tumor growth in pancreatic cancer xenograft models. Cancer Biol Ther 8(20):1893–1901CrossRef
17.
Huynh H (2010) AZD6244 (ARRY-142886) enhances the antitumor activity of rapamycin in mouse models of human hepatocellular carcinoma. Cancer 116(5):1315–1325CrossRef
18.
Moore MJ, Goldstein D, Hamm J et al (2007) Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a Phase III trial of the National Cancer Institute of Canada clinical trials group. J Clin Oncol 25(15):1960–1966CrossRef
19.
20.
Fumagalli D, Gavin PG, Taniyama Y et al (2010) A rapid, sensitive, reproducible and cost-effective method for mutation profiling of colon cancer and metastatic lymph nodes. BMC Cancer 10:101CrossRef
21.
Robert C, Karaszewska B, Schachter J et al (2015) Improved overall survival in melanoma with combined dabrafenib and trametinib. N Engl J Med 372(1):30–39CrossRef
22.
Adjei AA, Cohen RB, Franklin W et al (2008) Phase I pharmacokinetic and pharmacodynamic study of the oral, small-molecule mitogen-activated protein kinase kinase 1/2 inhibitor AZD6244 (ARRY-142886) in patients with advanced cancers. J Clin Oncol 26(13):2139–2146CrossRef
23.
Hudes G, Carducci M, Tomczak P et al (2007) Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med 356(22):2271–2281CrossRef
24.
25.
Choo SP, Ng QC, Chen WJJ et al (2012) A Phase I/II study of AZD6244 in combination with sorefenib in advanced hepatocellular carcinoma. J Clin Oncol 30(suppl):abstract 4100–4100
26.
Speranza G, Kinders RJ, Khin S et al (2012) Pharmacodynamic biomarker-driven trial of MK-2206, an AKT inhibitor, with AZD6244 (selumetinib), a MEK inhibitor, in patients with advanced colorectal carcinoma (CRC). J Clin Oncol 30(suppl):abstract 3529–3529
27.
Wilky BA, Rudek M, Laheru D et al (2013) A Phase I trial of vertical inhibition of IGF signaling using IMC-A12, an IGF1-R inhibitor, and selumetinib, a MEK 1/2 inhibitor, in patients with advanced solid tumors. Abstract at the AACR-NCI-EORTC, Boston, MA, USA, 19–23 October 2013
28.
Leijen S, Soetekouw PM, Jeffry Evans TR et al (2011) A Phase I, open-label, randomized crossover study to assess the effect of dosing of the MEK 1/2 inhibitor selumetinib (AZD6244; ARRY-142866) in the presence and absence of food in patients with advanced solid tumors. Cancer Chemother Pharmacol 68(6):1619–1628CrossRef
29.
30.
Edgerly M, Fojo T (2008) Is there room for improvement in adverse event reporting in the era of targeted therapies? J Natl Cancer Inst 100(4):240–242CrossRef
31.
Carter CA, Rajan A, Szabo E et al (2013) Two parallel randomized phase II studies of selumetinib (S) and erlotinib (E) in advanced non-small cell lung cancer selected by KRAS mutations. J Clin Oncol 31(suppl 15):abstract 8026–8026
32.
Ko AH, Bekaii-Saab T, van Ziffle J et al (2015) A multicenter, open-label Phase II clinical trial of combined MEK plus EGFR inhibition for chemotherapy-refractory advanced pancreatic adenocarcinoma. Clin Cancer Res 22(1):61–68CrossRef
33.
Carter CA, Rajan A, Keen C et al (2016) Selumetinib with and without erlotinib in KRAS mutant and KRAS wild-type advanced nonsmall-cell lung cancer. Ann Oncol 27(4):693–699CrossRef
34.
Cohen RB (2014) Current challenges and clinical investigations of epidermal growth factor receptor (EGFR)- and ErbB family-targeted agents in the treatment of head and neck squamous cell carcinoma (HNSCC). Cancer Treat Rev 40(4):567–577CrossRef
35.
Cohen MH, Johnson JR, Chen YF, Sridhara R, Pazdur R (2005) FDA drug approval summary: erlotinib (Tarceva) tablets. Oncologist 10(7):461–466CrossRef
36.
Jänne PA, Yang JC, Kim DW et al (2015) AZD9291 in EGFR inhibitor-resistant non-small-cell lung cancer. N Engl J Med 372(18):1689–1699CrossRef
37.
Oxnard GR, Ramalingam SS, Ahn MJ et al (2015) Preliminary results of TATTON, a multi-arm phase Ib trial of AZD9291 combined with MEDI4736, AZD6094 or selumetinib in EGFR-mutant lung cancer. J Clin Oncol 33(suppl 15):abstract 2509–2509CrossRef
38.
Long GV, Stroyakovskiy D, Gogas H et al (2014) Combined BRAF and MEK inhibition versus BRAF inhibition alone in melanoma. N Engl J Med 371(20):1877–1888CrossRef
39.
Long GV, Stroyakovskiy D, Gogas H et al (2015) Dabrafenib and trametinib versus dabrafenib and placebo for Val600 BRAF-mutant melanoma: a multicentre, double-blind, Phase 3 randomised controlled trial. Lancet 386(9992):444–451
40.
Zia Y, Chen L, Daud A (2015) Future of combination therapy with dabrafenib and trametinib in metastatic melanoma. Expert Opin Pharmacother 16(14):2257–2263CrossRef
41.
Flaherty KT, Infante JR, Daud A et al (2012) Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. N Engl J Med 367(18):1694–1703CrossRef
Metadata
Title
A phase I dose-escalation study of Selumetinib in combination with Erlotinib or Temsirolimus in patients with advanced solid tumors
Authors
Jeffrey R. Infante
Roger B. Cohen
Kevin B. Kim
Howard A. Burris III
Gregory Curt
Ugochi Emeribe
Delyth Clemett
Helen K. Tomkinson
Patricia M. LoRusso
Publication date
01-10-2017
Publisher
Springer US
Published in
Investigational New Drugs / Issue 5/2017
Print ISSN: 0167-6997
Electronic ISSN: 1573-0646
DOI
https://doi.org/10.1007/s10637-017-0459-7

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