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.
• 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.
- 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.
• 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
- 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
- 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
- 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
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.
- History or current evidence/risk of retinal vein occlusion (RVO) or central serous
- 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
- 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
- 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
- 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