A Phase II, Open-label, Multicenter, Randomized Study to Assess the Efficacy and Safety of GSK1120212 Compared with Docetaxel in 2nd Line Subjects with Targeted Mutations (KRAS, NRAS, BRAF, MEK1) in Locally Advanced or Metastatic Nonsmall Cell Lung Cancer (MEK114653)

In de US 220,000 (NL: 9,000) newly diagnosed cases and over 150,000 deaths are
predicted in 2010, lung cancer is by far the leading cause of cancer-related
death worldwide. The vast majority of lung cancer cases (up to 85%) are
commonly described as Non-small cell lung cancer (NSCLC). In advanced-stage and
metastatic NSCLC, systemic chemotherapy with four to six courses of a
platinum-based doublet is widely regarded as the standard first-line therapy.
Upon disease progression second-line treatment options, including single agent
pemetrexed, erlotinib, or docetaxel, are approved and can be selected based on
the previous treatment and the patient*s performance status. The clinical
activity of these second-line therapies in a general NSCLC patient population
are limited with response rates <=10% and thus, there remains to be a high unmet
medical need for more efficacious treatments.
Significant progress in the understanding of the molecular pathology of NSCLC
and major advances in pharmacogenomics and high-throughput molecular
diagnostics have enabled the identification of distinct patient sub-populations
and the successful implementation of novel targeted therapies directed against
cancer-cell specific attributes essential for growth and survival. The *proof-
of-principle* that a targeted therapy in a molecularly-defined NSCLC population
can achieve superior response rates and allow better clinical management with
less toxic side effects when compared to established and effective chemotherapy
has recently been demonstrated in the IPASS phase III trial with gefitinib.
KRAS-mutation is among the most frequent genetic aberrations in NSCLC and
identifies a sub-population of patients with distinct clinical characteristics.
Demographic and clinical outcome data derived from multiple NSCLC studies
indicate that KRAS mutations are more frequent in patients with a smoking
history and may be associated with an overall poor prognosis when compared to
matched cohorts of KRAS wild-type NSCLC patients. Although KRAS-mutation
testing has not yet been widely established as a standard in NSCLC in contrast
to colorectal cancer, the finding that KRAS- and EGFR-activating mutations are
mutually exclusive in NSCLC has significant clinical relevance excluding
EGFR-TKI as a preferred therapeutic option in the second-line therapy of
KRAS-mutated disease.
With the second line treatment options in KRAS-mutant NSCLC limited to
single-agent chemotherapy, and with retrospective data indicating that this
chemotherapy may be less effective in patients with activating mutations in the
RAS/RAF/MAPK signal transduction pathway, the urgent need for clinical testing
of new treatments targeting this activation, such as GSK1120212, is warranted.

Primary: progression-free survival in the GSK1120212-group in comparison with
the docetaxel group. Secondary: safety and tolerability, response rate,
duration of response, overall survival, PK.

Multicenter randomized open-label phase II parallel group study.
Randomization (2:1) to treatment with:
3. GSK1120212, 2 mg orally daily
4. Docetaxel 75 mg/m2 i.v. every 3 weeks.
Treatment untill disease progression. Thereafter option for cross-over.
Follow-up for survival.
Stratification according to KRAS-mutation, gender and previous best response.
Approx 120 patients with KRAS mutation and 21 patients with NRAS, BRAF, MEK1
mutation. Approx 500 patients to be screened.

Treatment with GSK1120212 or docetaxel.

Risk: Adverse effects of study medication.
Burden: Study duration varies (untill disease progression). Burden compared to
standard treatment:
Screening (1 visit approx. 6 h). Visits day 8 and 15 of 1st cycle (0,5 and 4-8
h).
Blood draw: frequency not different, volume larger (approx. 10-20 ml/occasion).
Ophthalmic investigation: at screening and if needed during study.
ECG: every 9 weeks.
Echocardiogram or MUGA scan: every 9 weeks.
Tumor measurements: same frequency (every 6 weeks), but in some cases more
extensive (CT scan of abdomen and pelvis and brain CT/MRI required for study).
Optional substudies: pharmacogenetic research (10 ml blood), biomarker research
(tumor tissue from previous biopsy), biomarker research (extra tumor biopsy
after discontinuation study treatment).