LungcancerPhase 1MEK162NCT02185690
A Phase I/Ib Study of MEK162, a MEK Inhibitor, in Combination With Carboplatin and Pemetrexed in Patients With Non-squamous Carcinoma of the Lung
A Phase 1 study testing Binimetinib, Pemetrexed and Carboplatin in people with Lungcancer, run by University Health Network, Toronto at 4 sites in Canada.
Trial summary
MEK162 has shown significant inhibition of tumor growth as a single agent in NSCLC xenograft models in mice and human cancer cells in vitro, which have KRAS and/or other mutations. These data suggest that MEK162 may provide a potential benefit in cancer indications harboring these mutations. Read more about this study
- Who is it for?
- Ages 18 to 90 years
- Conditions the study is for
- Lungcancer
- What is being tested?
- Binimetinib, Pemetrexed and Carboplatin
- Type of treatment
- Pill or oral medicine, Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 13 participants
- Where
- 4 sitesCanada
- Study dates
- 7 Mar 2017to 4 Jul 2019
- Phase
- Phase 1
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 90 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Subjects eligible for enrolment on the study must meet all of the following criteria:
- Patients with histologically confirmed non-squamous EGFR wild-type, ALK-rearrangement negative carcinoma of lung. Patients with neuroendocrine carcinoma, mixed small and non-small cell carcinoma or squamous carcinoma are not eligible.
- Tissue available for KRAS mutation status analysis.
- Patients must have metastatic disease (Incurable stage IIIB/stage IV).
- Patients must have clinically and/or radiographically documented measurable disease. At least one site of disease must be unidimensionally measurable by RECIST v1.1 as follows (Eisenhauer et al.):
- CT-scan, physical exam ≥10 mm Chest X-ray ≥20 mm Lymph node short axis ≥15 mm
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- All radiology studies must be performed within 28 days prior to registration (35 days if negative).
- Lesions in previously irradiated areas should not be selected unless there is clear evidence of progression in such lesions.
- Patients may not have received any prior systemic treatment for metastatic NSCLC. Patients who have received adjuvant treatment or chemoradiation for stage III disease should have completed this ≥12 months prior to study enrollment.
- Patients with stable CNS metastases are permitted if stability of disease is documented with imaging ≥28 days after treatment completion, are and off corticosteroids by day 1 of study treatment.
- Patients may have had prior malignancy if definitively treated and/or, in the opinion of the investigator, the only active malignancy is NSCLC. Patients with mixed small cell lung cancer histology are excluded. Patients who have received radiotherapy to >30% bone marrow are excluded. Consult PI if unsure whether second malignancies meet requirements specified above.
- In patients treated for other malignancy, all prior treatment-related toxicities must be CTCAE v4.0 ≤ Grade 1 (except alopecia) at the time of enrollment.
- Able to swallow and retain oral medication and does not have any clinically significant gastrointestinal abnormalities that may alter absorption such as malabsorption syndrome or major resection of the stomach or bowels.
- Patients receiving medications or substances that are inhibitors or inducers of CYP1A2, CYP2A19, CYP2B6, CYP3A4 and/or UGT1A1 and UGT1A9 are eligible but these drugs must be used with caution (Appendix C).
- Because the lists of these agents are constantly changing, it is important to regularly consult a frequently-updated list such as http://medicine.iupui.edu/clinpharm/ddis/table.aspx;
- Patients must be aged ≥18 years.
- Eastern Cooperative Oncology Group (ECOG) performance status ≤1
- Adequate organ and laboratory parameters, defined below.
- Laboratory Requirements - within 7 days prior to enrollment:
- Haematology: absolute granulocytes ≥1.5 × 109/L platelets ≥100 × 109/L Biochemistry: bilirubin ≤1.25 × institutional upper limit of normal AST(SGOT) ≤2.5 × institutional upper limit of normal /ALT(SGPT) or ≤5 × institutional upper limit of normal in the presence of liver metastases
- creatinine clearance ≥45 mL/min/1.73 m2
- -Patients must be able to provide Informed Consent based on the details below:
- absence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial
- before patient registration/randomization, written informed consent must be given according to ICH/GCP, and national/local regulations.
Who cannot join
- History or current evidence/risk of retinal vein occlusion (RVO) or central serous retinopathy (CSR):
- History of RVO or CSR, or predisposing factors to RVO or CSR (e.g., uncontrolled glaucoma or ocular hypertension, uncontrolled systemic disease such as hypertension, diabetes mellitus, or history of hyperviscosity or hypercoagulability syndromes). Patients with prior deep venous thrombosis or pulmonary embolism are permitted.
- Visible retinal pathology as assessed by ophthalmologic exam that is considered a risk factor for RVO or CSR such as:
- Evidence of new optic disc cupping
- Evidence of new visual field defects on automated perimetry
- Intraocular pressure >21mmHg as measured by tonography
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- Any serious and/or unstable pre-existing medical (aside from malignancy exception), psychiatric disorder, or other conditions that could interfere with subjects' safety, obtaining informed consent or compliance to the study procedures, in the opinion of the PI.
- History of interstitial lung disease or pneumonitis.
- Evidence of severe or uncontrolled systemic diseases (e.g., unstable or uncompensated respiratory, hepatic, renal metabolic or cardiac disease).
- Any factors that increase the risk of QTc prolongation or risk of arrhythmic events (e.g. congenital long QT syndrome, family history of long QT syndrome, hypokalemia) or baseline QTcB interval ≥480 msec.
- History of acute coronary syndromes (including myocardial infarction and unstable angina), coronary angioplasty, or stenting within the past 6 months or cardiac metastases.
- History or evidence of current clinically significant uncontrolled arrhythmias.
- History or evidence of current ≥Class II congestive heart failure as defined by New York Heart Association (NYHA).
- Known positivity for Hepatitis B surface antigen or Hepatitis C antibody.
- Known Human Immunodeficiency Virus (HIV) infection.
- Treatment refractory hypertension defined as a blood pressure systolic >140 mmHg and/or diastolic >90 mmHg which cannot be controlled by anti-hypertensive therapy.
- Subjects with intra-cardiac defibrillators or permanent pacemakers.
- Pregnant or nursing (lactating) women are excluded.
- Female patient of child bearing potential must have a negative serum or urine pregnancy test.
- Women of child-bearing potential must agree to use of appropriate contraceptive methods throughout the study and for 120 days after, These methods include
- Total abstinence or 2 barrier methods or a barrier method plus hormonal method from visit 1 to 120 days after the last dose of treatment.
- Men must agree to use an appropriate method of contraception starting with first dose of study drug through 120 days after the last dose of treatment (see above).
- Whilst not excluded, patients with significant impaired hearing must be made aware of potential ototoxicity and may choose not to be included. If included, baseline audiograms are recommended and should be followed by repeat audiograms prior to cycle 2.
Trial locations and contacts
4 sites in 1 country.
Canada4 sites
Cross Cancer Institute
Edmonton, Alberta, T6G1Z2
Juravinski Cancer Centre
Hamilton, Ontario, L8V 5C2
The Ottawa Hospital Regional Cancer Centre
Ottawa, Ontario, K1G 3Y9
Princess Margaret Cancer Centre
Toronto, Ontario, M5G2M9
About this study
MEK162 has shown significant inhibition of tumor growth as a single agent in NSCLC xenograft models in mice and human cancer cells in vitro, which have KRAS and/or other mutations. These data suggest that MEK162 may provide a potential benefit in cancer indications harboring these mutations. MEK162 is currently being investigated in phase I clinical testing and has been well tolerated up to an MTD of 45mg BID in cancer patients.
There has been little change in survival benefit for patients with non-small cell lung cancer in recent years. Emerging new treatment options relying on molecular and genetic markers are being studied extensively. Thus, there has been a shift to manage non-small cell lung cancer with molecular targeted therapies in combination with standard chemotherapy. This study will be targeting patients with KRAS mutations.
Read the detailed description
OBJECTIVES
1.1 Primary Objectives
- To assess the safety of MEK162 administered in combination with carboplatin and pemetrexed as first line treatment in advanced non-small cell lung cancer (NSCLC).
- To determine the recommended phase II dose (RP2D) of MEK162 to be used when given in a continuous dosing schedule together with pemetrexed and carboplatin administered on a 3-weekly schedule as first line treatment in advanced NSCLC.
- To explore the efficacy (as measured by tumor response in the Phase Ib portion) of the combination of MEK162 in addition to pemetrexed and carboplatin in treatment-naïve patients with EGFR wild-type, ALK-rearrangement negative NSCLC of the lung.
1.2 Secondary Objectives
- To characterize the population pharmacokinetics of MEK162 administered in combination with carboplatin and pemetrexed (Phase I).
- To explore relationships between KRAS mutation (and sub-types) and additional genomic mutations and objective clinical response.
1.3 Trial End-points Primary Phase I • Development of dose-limiting toxicity (DLT), (defined in section 4.3) as measured with NCI CTC AE v4.
Phase Ib
- Objective response rate (ORR) as per RECIST v1.1.
Secondary Phase I • Adverse events, serious adverse events, changes in hematology and chemistry values, vital signs, ECGs.
Phase Ib
- Evaluation of response rate (RR), progression-free survival (PFS) and disease control rate (DCR) for patients with and without KRAS mutation in tumor tissue.
- Exploratory analysis of KRAS mutation sub-type.
Exploratory end-points
- A limited sampling strategy pharmacokinetic model will be used to ensure that the clearance of MEK162 is not influenced by the concurrent administration of pemetrexed-based chemotherapy.
- Conditions
- Lungcancer
- Being tested
- Binimetinib, Pemetrexed, Carboplatin
- Keywords
- Lung cancer, Non small cell lung cancer, non squamous, pemetrexed, carboplatin, binimetinib, chemotherapy, combination chemotherapy, Phase 1, Princess Margaret Cancer Centre, carcinoma
- Medical subject headings
- Lung Neoplasms, Carcinoma, Non-Small-Cell Lung, Carcinoma
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
BinimetinibDrug
Also called MEK162
Continuous MEK162 with dose escalation until the Recommended Phase 2 dose (RP2D) one dose level below the Maximum administered dose (MAD) or progression of disease.
MEK162 tablets 15 mg strength will be taken orally on a BID dose schedule.
PemetrexedDrug
Also called Alimta
4-6 cycles given intravenously in combination with carboplatin as per standard therapy.
CarboplatinDrug
Also called Paraplatin AG
4-6 cycles of intravenous Carboplatin in combination with Pemetrexed as per standard therapy.
| Study group | Role | What they receive |
|---|---|---|
| Binimetinib efficacy/safety | Other | This is a Phase I/Ib, open-label, dose-escalation, multi-center, non-randomized study designed to evaluate the safety and tolerability of oral Binimetinib in combination with carboplatin and pemetrexed.
Phase I part A standard 3+3 dose-escalation will be used to determine the maximum administered dose (MAD) and the RP2D for the combination in subjects with advanced non-squamous lung carcinoma.
Phase Ib part Once RP2D has been identified, an expansion cohort will be accrued; these patients will be stratified by KRAS genotype.
The RP2D will be expanded by enrolling additional patients, stratified by KRAS genotype, to a total of 30 patients eligible for the safety set (including those treated at the same dose combination in the dose-escalation phase of the study who are eligible for the safety set) to be evaluated for safety, tolerability, pharmacokinetics and biologic activity of MEK162. Receives: Drug: Binimetinib; Drug: Pemetrexed; Drug: Carboplatin |
What is being measured
The primary outcome is the main question the study is designed to answer.
Recommended Dose in Milligrams Per Day for Binimetinib.
To determine the recommended dose in milligrams per day of the combination of MEK162 with standard therapy pemetrexed and carboplatin as determined by toxicity.
Measured: 22 weeks
Secondary outcomes (1)
Objective Response Rate (ORR) as Per RECIST v1.1.
The size of tumors in centimeters before and after treatment. The measurements will be compared against the RECIST v1.1 criteria to ascertain response as defined in the protocol.
Objective response rate (ORR) was defined as the percentage of patients who achieved a complete or partial response as the best overall response.
Measured: 22 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted9 Jul 2014 (estimated)
- Study start7 Mar 2017
- Primary completion4 Jul 2019
- Study completion4 Jul 2019
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (21)Papers the sponsor has linked to this study.
- Other trials for LungcancerStudies of the same condition, open and under way.
- More trials run by University Health Network, TorontoThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 13 participants (actual)
Sponsor and investigators
- Lead sponsor
- University Health Network, Toronto
- Sponsor type
- University, hospital or other
- Collaborators
- Novartis Pharmaceuticals
- Responsible party
- Sponsor
- Investigators
- Natasha Leighl, MD, Principal investigator, UHN - Princess Margaret Cancer CentreAmit Oza, MD, Study director, Princess Margaret Cancer Centre Drug Development Program
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02185690
- Sponsor's protocol ID
- CMEK162ACA02T
- Other IDs
- CMEK162ACA02T
- Acronym
- MEK162
- Status last verified
- Aug 2025
- First submitted
- 9 Apr 2014
- Last updated
- 21 Aug 2025
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
Publications
Bos JL. ras oncogenes in human cancer: a review. Cancer Res. 1989 Sep 1;49(17):4682-9.
PubMed 2547513Calvert AH. Dose optimisation of carboplatin in adults. Anticancer Res. 1994 Nov-Dec;14(6A):2273-8.
PubMed 7825958Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S, Teague J, Woffendin H, Garnett MJ, Bottomley W, Davis N, Dicks E, Ewing R, Floyd Y, Gray K, Hall S, Hawes R, Hughes J, Kosmidou V, Menzies A, Mould C, Parker A, Stevens C, Watt S, Hooper S, Wilson R, Jayatilake H, Gusterson BA, Cooper C, Shipley J, Hargrave D, Pritchard-Jones K, Maitland N, Chenevix-Trench G, Riggins GJ, Bigner DD, Palmieri G, Cossu A, Flanagan A, Nicholson A, Ho JW, Leung SY, Yuen ST, Weber BL, Seigler HF, Darrow TL, Paterson H, Marais R, Marshall CJ, Wooster R, Stratton MR, Futreal PA. Mutations of the BRAF gene in human cancer. Nature. 2002 Jun 27;417(6892):949-54. doi: 10.1038/nature00766. Epub 2002 Jun 9.
PubMed 12068308Ding L, Getz G, Wheeler DA, Mardis ER, McLellan MD, Cibulskis K, Sougnez C, Greulich H, Muzny DM, Morgan MB, Fulton L, Fulton RS, Zhang Q, Wendl MC, Lawrence MS, Larson DE, Chen K, Dooling DJ, Sabo A, Hawes AC, Shen H, Jhangiani SN, Lewis LR, Hall O, Zhu Y, Mathew T, Ren Y, Yao J, Scherer SE, Clerc K, Metcalf GA, Ng B, Milosavljevic A, Gonzalez-Garay ML, Osborne JR, Meyer R, Shi X, Tang Y, Koboldt DC, Lin L, Abbott R, Miner TL, Pohl C, Fewell G, Haipek C, Schmidt H, Dunford-Shore BH, Kraja A, Crosby SD, Sawyer CS, Vickery T, Sander S, Robinson J, Winckler W, Baldwin J, Chirieac LR, Dutt A, Fennell T, Hanna M, Johnson BE, Onofrio RC, Thomas RK, Tonon G, Weir BA, Zhao X, Ziaugra L, Zody MC, Giordano T, Orringer MB, Roth JA, Spitz MR, Wistuba II, Ozenberger B, Good PJ, Chang AC, Beer DG, Watson MA, Ladanyi M, Broderick S, Yoshizawa A, Travis WD, Pao W, Province MA, Weinstock GM, Varmus HE, Gabriel SB, Lander ES, Gibbs RA, Meyerson M, Wilson RK. Somatic mutations affect key pathways in lung adenocarcinoma. Nature. 2008 Oct 23;455(7216):1069-75. doi: 10.1038/nature07423.
PubMed 18948947Gervais R, Robinet G, Clement-Duchene C, Denis F, El Kouri C, Martin P, Chouaki N, Bourayou N, Morere JF. Pemetrexed and carboplatin, an active option in first-line treatment of elderly patients with advanced non-small cell lung cancer (NSCLC): a phase II trial. Lung Cancer. 2013 May;80(2):185-90. doi: 10.1016/j.lungcan.2013.01.008. Epub 2013 Feb 21.
PubMed 23434351Hanna N, Shepherd FA, Fossella FV, Pereira JR, De Marinis F, von Pawel J, Gatzemeier U, Tsao TC, Pless M, Muller T, Lim HL, Desch C, Szondy K, Gervais R, Shaharyar, Manegold C, Paul S, Paoletti P, Einhorn L, Bunn PA Jr. Randomized phase III trial of pemetrexed versus docetaxel in patients with non-small-cell lung cancer previously treated with chemotherapy. J Clin Oncol. 2004 May 1;22(9):1589-97. doi: 10.1200/JCO.2004.08.163.
PubMed 15117980Janne PA, Shaw AT, Pereira JR, Jeannin G, Vansteenkiste J, Barrios C, Franke FA, Grinsted L, Zazulina V, Smith P, Smith I, Crino L. Selumetinib plus docetaxel for KRAS-mutant advanced non-small-cell lung cancer: a randomised, multicentre, placebo-controlled, phase 2 study. Lancet Oncol. 2013 Jan;14(1):38-47. doi: 10.1016/S1470-2045(12)70489-8. Epub 2012 Nov 28.
PubMed 23200175Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011 Mar-Apr;61(2):69-90. doi: 10.3322/caac.20107. Epub 2011 Feb 4.
PubMed 21296855Juergens RA, Brahmer JR. Adjuvant treatment in non-small cell lung cancer: Where are we now? J Natl Compr Canc Netw. 2006 Jul;4(6):595-600. doi: 10.6004/jnccn.2006.0049.
PubMed 16813727Kwak EL, Bang YJ, Camidge DR, Shaw AT, Solomon B, Maki RG, Ou SH, Dezube BJ, Janne PA, Costa DB, Varella-Garcia M, Kim WH, Lynch TJ, Fidias P, Stubbs H, Engelman JA, Sequist LV, Tan W, Gandhi L, Mino-Kenudson M, Wei GC, Shreeve SM, Ratain MJ, Settleman J, Christensen JG, Haber DA, Wilner K, Salgia R, Shapiro GI, Clark JW, Iafrate AJ. Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N Engl J Med. 2010 Oct 28;363(18):1693-703. doi: 10.1056/NEJMoa1006448.
PubMed 20979469Maione P, Gridelli C, Troiani T, Ciardiello F. Combining targeted therapies and drugs with multiple targets in the treatment of NSCLC. Oncologist. 2006 Mar;11(3):274-84. doi: 10.1634/theoncologist.11-3-274.
PubMed 16549812Mok TS, Wu YL, Thongprasert S, Yang CH, Chu DT, Saijo N, Sunpaweravong P, Han B, Margono B, Ichinose Y, Nishiwaki Y, Ohe Y, Yang JJ, Chewaskulyong B, Jiang H, Duffield EL, Watkins CL, Armour AA, Fukuoka M. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med. 2009 Sep 3;361(10):947-57. doi: 10.1056/NEJMoa0810699. Epub 2009 Aug 19.
PubMed 19692680Okamoto I, Aoe K, Kato T, Hosomi Y, Yokoyama A, Imamura F, Kiura K, Hirashima T, Nishio M, Nogami N, Okamoto H, Saka H, Yamamoto N, Yoshizuka N, Sekiguchi R, Kiyosawa K, Nakagawa K, Tamura T. Pemetrexed and carboplatin followed by pemetrexed maintenance therapy in chemo-naive patients with advanced nonsquamous non-small-cell lung cancer. Invest New Drugs. 2013 Oct;31(5):1275-82. doi: 10.1007/s10637-013-9941-z. Epub 2013 Mar 10.
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PubMed 21277552