A Phase III, Double-Blind, Randomised, Placebo-Controlled Study to Assess the Efficacy and Safety of Selumetinib (AZD6244; ARRY142886) (Hyd-Sulfate) in Combination with Docetaxel, in Patients receiving second line treatment for KRAS Mutation-Positive Locally Advanced or Metastatic Non Small Cell Lung Cancer (Stage IIIB-IV).

Patients with advanced non-small cell lung cancer (NSCLC) have a very poor
prognosis. Therefore, there is a strong medical need for medicines that have
more benefit for the patient than the current standard treatment. Selumetinib
(AZD6244) is a new agent that inhibits a protein called MEK. MEK is part of the
RAS/RAF/MEK/ERK kinase cascade. This cascade plays a pivotal role in cell
proliferation and survival. Over-activation of this pathway has been implicated
in numerous cancers, including NSCLC with KRAS mutations.
Selumetinin can be effective as monotherapy or when given in combination with
chemotherapy.
Pre-clinical experiments demonstrated that a KRAS mutation in a tumour leads to
a better response on treatment with selumetinib in combination with
chemotherapy compared to chemotherapy alone.
A previous clinical trial has shown that the combination of selumetinib with
docetaxel provided potential clinical benefit as second-line therapy in
patients with NSCLC.
Further studies are necessary to assess the efficacy and safety of Selumitinib
in combination with docetaxel in patients with KRAS mutation-positive NSCLC.

To assess the efficacy, measured as progression free survival, and safety of
Selumetinib in combination with docetaxel, compared to docetaxel alone, in
patients receiving second line treatment for KRAS mutation-positive, locally
advanced or metastatic non small cell lung cancer.

Phase III, double-blind, randomised, placebo-controlled study
Randomised in a ratio of 1:1
- Selumetinib (75 mg dd on every day of a cycle of 21 days) in combination with
75 mg/m2 docetaxel (given on day 1 of every 21 day cycle)
- Placebo in combination with 75 mg/m2 docetaxel (given on day 1 of every 21
day cycle)

Patient will be dosed twicedaily with a oral dose (capsules) of Selumetinib or
placebo in combination with 75 mg/m2 docetaxel iv, administered on day 1 of
each 21 day cycle.

On several days during the study patients will undergo the following
assessments:
- anamnesis (at screening also medical history)
- physical examination
- WHO performance status
- vital signs (blood pressure, pulse)
- length
- weight
- CT or MRI scan
- ECG
- eye assessment
- blood and urine assessments
- MUGA/echocardiogram
- questionnaires (LSCC (specific voor lung cancer symptoms) en SF-36v2)
- pregnancy test

Adverse events of Selumetinib (AZD6244), docetaxel or the combination:
Adverse events that may be caused by Selumetinib are: diarrhea, nausea,
vomiting, fever, difficulty breathing or shortness of breath, blurring of
vision, decrease in the pumping performance of the heart, swelling of the face
or extremities, rash, dry skin, nail changes, tiredness, increase in blood
pressure, stomatitis, increase in phosphate level, increase in some liver
proteins, low albumin level.
Adverse events, that probably may be caused by selumetinib are: weakness of
neck muscles, cough, eye problems, increase in blood level of CPK.
The most common side effects that may be caused by docetaxel are: decrease in
number of white blood cells, rash, diarrhea, nausea, vomiting, stomatitis,
hair loss, tiredness, burning or tingling sensation in hands or feet, muscle
pain, elevated tear production, allergic reaction and nail changes.
When selumetinib was used in combination with docetaxel, the number of patients
with side effects, and or the severity of side effects was increased.
Female patients cannot become pregnant during this study.