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

Lungcancer Clinical Trial

— MEK162  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02185690
• Other study ID #: CMEK162ACA02T
• Secondary ID: CMEK162ACA02T
• Status: Completed
• Phase: Phase 1
• Start date: January 11, 2018
• Est. completion date: July 4, 2019

Study information

• Verified date: April 2021
• Source: University Health Network, Toronto
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical 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. 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 13
• Est. completion date: July 4, 2019
• Est. primary completion date: July 4, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 90 Years

Eligibility

Inclusion Criteria:

• 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

• 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.

Exclusion Criteria:

• 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

• 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.

Related Conditions & MeSH terms

• Carcinoma
• Lung Neoplasms
• Lungcancer

Intervention

Drug:
• Binimetinib
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.
• Pemetrexed
4-6 cycles given intravenously in combination with carboplatin as per standard therapy.
• Carboplatin
4-6 cycles of intravenous Carboplatin in combination with Pemetrexed as per standard therapy.

Locations

Country	Name	City	State
Canada	Cross Cancer Institute	Edmonton	Alberta
Canada	Juravinski Cancer Centre	Hamilton	Ontario
Canada	The Ottawa Hospital Regional Cancer Centre	Ottawa	Ontario
Canada	Princess Margaret Cancer Centre	Toronto	Ontario

Sponsors (2)

Lead Sponsor	Collaborator
University Health Network, Toronto	Novartis Pharmaceuticals

Country where clinical trial is conducted

Canada, 

References & Publications (20)

Bos JL. ras oncogenes in human cancer: a review. Cancer Res. 1989 Sep 1;49(17):4682-9. Review. Erratum in: Cancer Res 1990 Feb 15;50(4):1352. — View Citation

Calvert AH. Dose optimisation of carboplatin in adults. Anticancer Res. 1994 Nov-Dec;14(6A):2273-8. Review. — View Citation

Davies 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. Epub 2002 Jun 9. — View Citation

Ding 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. — View Citation

Gervais R, Robinet G, Clément-Duchêne C, Denis F, El Kouri C, Martin P, Chouaki N, Bourayou N, Morère 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. — View Citation

Hanna 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. — View Citation

Jänne PA, Shaw AT, Pereira JR, Jeannin G, Vansteenkiste J, Barrios C, Franke FA, Grinsted L, Zazulina V, Smith P, Smith I, Crinò 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. — View Citation

Jemal 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. Erratum in: CA Cancer J Clin. 2011 Mar-Apr;61(2):134. — View Citation

Juergens 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. Review. — View Citation

Kwak EL, Bang YJ, Camidge DR, Shaw AT, Solomon B, Maki RG, Ou SH, Dezube BJ, Jänne 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. Erratum in: N Engl J Med. 2011 Feb 10;364(6):588. — View Citation

Maione 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. Review. — View Citation

Mok 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. — View Citation

Okamoto 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-naïve 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. Erratum in: Invest New Drugs. 2013 Oct;31(5):1395-6. — View Citation

Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, Carbone PP. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol. 1982 Dec;5(6):649-55. — View Citation

Pao W, Girard N. New driver mutations in non-small-cell lung cancer. Lancet Oncol. 2011 Feb;12(2):175-80. doi: 10.1016/S1470-2045(10)70087-5. Review. — View Citation

Scagliotti GV, Parikh P, von Pawel J, Biesma B, Vansteenkiste J, Manegold C, Serwatowski P, Gatzemeier U, Digumarti R, Zukin M, Lee JS, Mellemgaard A, Park K, Patil S, Rolski J, Goksel T, de Marinis F, Simms L, Sugarman KP, Gandara D. Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non-small-cell lung cancer. J Clin Oncol. 2008 Jul 20;26(21):3543-51. doi: 10.1200/JCO.2007.15.0375. Epub 2008 May 27. — View Citation

Schiller JH, Harrington D, Belani CP, Langer C, Sandler A, Krook J, Zhu J, Johnson DH; Eastern Cooperative Oncology Group. Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med. 2002 Jan 10;346(2):92-8. — View Citation

Schuette WH, Gröschel A, Sebastian M, Andreas S, Müller T, Schneller F, Guetz S, Eschbach C, Bohnet S, Leschinger MI, Reck M. A randomized phase II study of pemetrexed in combination with cisplatin or carboplatin as first-line therapy for patients with locally advanced or metastatic non-small-cell lung cancer. Clin Lung Cancer. 2013 May;14(3):215-23. doi: 10.1016/j.cllc.2012.10.001. Epub 2013 Jan 16. — View Citation

Spira A, Ettinger DS. Multidisciplinary management of lung cancer. N Engl J Med. 2004 Jan 22;350(4):379-92. Review. Erratum in: N Engl J Med. 2009 Apr 30;360(18):1917. — View Citation

Zukin M, Barrios CH, Pereira JR, Ribeiro Rde A, Beato CA, do Nascimento YN, Murad A, Franke FA, Precivale M, Araujo LH, Baldotto CS, Vieira FM, Small IA, Ferreira CG, Lilenbaum RC. Randomized phase III trial of single-agent pemetrexed versus carboplatin and pemetrexed in patients with advanced non-small-cell lung cancer and Eastern Cooperative Oncology Group performance status of 2. J Clin Oncol. 2013 Aug 10;31(23):2849-53. doi: 10.1200/JCO.2012.48.1911. Epub 2013 Jun 17. — View Citation

* Note: There are 20 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Clearance (millilitres per minute)of MEK162	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.	18 weeks of treatment
Other	Progression Free Survival measured in weeks.	• Evaluation progression-free survival (PFS) for patients with and without KRAS mutation in tumor tissue.; Number of weeks survived before progression or death.	18 weeks of treatment and 30 days of Follow up
Primary	Development of dose-limiting toxicity (DLT) in milligrams per day.	To determine the recommended dose in milligrams per day of the combination of MEK162 with standard therapy pemetrexed and carboplatin as determined by toxicity.	18 weeks of treatment
Secondary	Objective response rate (ORR) as per RECIST v1.1.	The size of tumours in centimetres before and after treatment. The measurements will be compared against the RECIST v1.1 criteria to ascertain response as defined in the protocol.	18 weeks of treatment & 30 days followup