BRF113928: A Phase II study of the BRAF inhibitor dabrafenib as a single agent and in combination with the MEK inhibitor trametinib in subjects with BRAF V600E mutation positive metastatic (stage IV) non-small cell lung cancer

For patients diagnosed with advanced non-small cell lung cancer (NSCLC),
conventional cytotoxic chemotherapy remains the standard treatment and offers
only a modest survival benefit. Therefore, more innovative approaches are
needed to improve the therapy of this deadly disease. One approach is to
identify specific genomic changes in different lung cancer patients and treat
them with agents directed against those genetic changes. One specific genomic
change present in approximately 2% of lung cancers is a BRAF mutation. BRAF is
a serine/threonine kinase that lies downstream of RAS in the RAS/RAF/MEK/ERK
signaling pathway, a key molecular cascade that regulates cell growth,
proliferation and differentiation. Mutations in the BRAF gene, the vast
majority of which are V600E missense mutations, are most commonly seen in
melanoma, but are also detected in approximately 2% of NSCLC. Importantly, most
cancer cells harboring a V600E BRAF mutation display a critical dependence on
the activity of this oncogene for their growth and survival, and are extremely
sensitive to selective BRAF and MEK inhibitors, irrespective of tissue of
origin. This study will investigate the effects of GSK2118436 administered as a
single agent to subjects with stage IV NSCLC whose tumors carry a V600E BRAF
mutation.

In protocol amendment 8 an extra arm is introduced: dabrafenib plus trametinib,
while subjects with disease progression when on dabrafenib monotherapy are
given the option to continue treatment with dabrafenib in combination with
trametinib.

In protocol amendment 9 another extra arm is introduced: 25-40 first line
patients. They will betreated with the combination therapy.

Primary: overall response rate.
Secondary: progression free survival, duration of response, overall survival,
safety, tolerability, pharmacokinetics (PK).

Phase II, non-comparative, open-label, study. Treatment with dabrafenib 150 mg
twice daily lus or minus trametinib 2 mg twice daily until disease progression
or unacceptable adverse events. Th last 40 subjects to be included will be
treated with the combination therapy.
Subjects enrolled in the primary study cohort will be required to have relapsed
or progressed on one or more platinum based chemotherapy prior to
enrolment (i.e., dabrafenib will be no less than second line treatment for
metastatic disease). The expansion cohort will allow subjects that have
received prior treatment as well as treatment naive subjects where dabrafenib
will be first line treatment in the metastatic setting.
Interim-analysis after 20 subjects have either withdrawn from the study before
response is assessed or have at least 2 post-baseline scans.
The study will be considered completed when a minimum of 70% of subjects have
died or 5 years have passed since the last subject was entered on the study,
whichever comes first. Subjects who are still benefiting from dabrafenib at the
time of study completion may have the option to enter a follow-up study.
Approx. 140 patients.

Cohort A: Monotherapy (dabrafenib 150 mg BID) approximately 60 at least 2nd
line subjects with BRAF V600E NSCLC centrally confirmed.
Cohort B: Combination therapy (dabrafenib 150 mg BID and trametinib 2 mg once
daily); approximately 40 at least 2nd line subjects with BRAF V600E NSCLC
subjects centrally confirmed.
Cohort C: Combination therapy (dabrafenib 150 mg BID and trametinib 2 mg once
daily); approximately 25-40 1st line subjects with BRAF V600E NSCLC centrally
confirmed:

Treatment with dabrafenib plus or minus trametinib.

Risk: adverse events of study treatment.
Burden: Visits screening, start, week 3, 6, 9 and thereafter every 3 weeks.
After disease progression: follow-up for survival (by phone if needed).
Tests etc. until progression:
Physical examination every visit (2 times incl. rectal/vaginal examination),
regular skin inspection. Eye examination twice and more frequently in case of
signs or symptoms.
Blood tests every visit ,10-15 mL.
CT/MRI scan chest and abdomen (if indicated: more extensive) every 6 weeks
until week 36, thereafter every 12 weeks (as during regular treatment).
Pregnancy tests at screening.
Tumor biopsy (from prior procedure, if needed fresh sample) for assessment BRAF
mutation at screening.
ECG 3x in first 6 weeks, thereafter every 9 weeks.
Echocardiogram 2x in First 6 weeks, thereafter every 9 weeks.
Optional sub-studies:
- pharmacogenetic (1x, 6 mL blood).
- Tumor biopsy at screening, after 6 week and at progression.
- Skin biopsy in case of skin lesions.
- Tumor biopsy in case of new tumor.
Most tests are not different from regular treatment in nature and frequency.
Extra are the echocardiography, theskin examinations and the optional tests.