Updated the inclusion / exclusion criteria, updated the QTc withdrawal criteria and the Dose Modification section, added an Independent Data Monitoring Committee. In addition, language specific to French sites was added. Throughout the protocol, minor administrative and typographical changes were made.

Increased the frequency of cardiac monitoring from every 12 weeks to every 9 weeks. Other clarifications to the PGx sections in the main text and in Appendix 1, description of physical exam and list of laboratory tests were made. Guidelines for management of renal insufficiency were added. A baseline sample for cytokine profiling was added (in the event a subject develops fever, the baseline cytokine values are available).

Is a country specific amendment that changed the QTc stopping criteria to 500 msec for UK subjects and clarified the definition of abstinence

Changed Inclusion to clarify that the failed chemotherapy regimen must have been a platinum-based chemotherapy; changed Exclusion Criteria #9 regarding the length of time a subject must be disease free from 5 years to 3 years; allowed for continued treatment with GSK2118436 beyond disease progression; updated the Dose Modification Guidelines for Fever and the Renal Insufficiency Guidelines for consistency with the current asset-specific language; added the UK to Appendix 3 (country-specific QTc stopping criteria of 500 msec); clarified restrictions on certain foods known to affect drug metabolism; clarified when an MRI or CT is required at baseline and on-study; removed the requirement for males who choose abstinence as their contraceptive method to begin abstinence 14 days BEFORE administration of GSK2118436; clarified the definition of abstinence; fixed T&E footnotes, lessened the frequency of efficacy assessments beginning at Week 36 and onwards, and removed the ANC measurement on Day 8; clarified SAE language for consistency with current asset language.

Updated the Background section (Section 1.1) to include the currently available safety and efficacy data for GSK2118436; changed Inclusion Criterion (#7) to clarify for the reader that additional details on mutation testing and central confirmation of mutation testing are provided in Section 7.1.1; changes to Section 7.1.1 included clarification onBRAF mutation testing and intent that all subject have tissue available for central confirmation (when testing at inclusion is performed at a local laboratory) (also affected T&E footnote); removed the requirement for men to use contraception (Inclusion Criterion #9 and Section 7.4.2); changed the limit for use of anti-cancer treatment prior to dosing with GSK2118436 from 28 days to 14 days (Exclusion Criteria #2 and #3); added defined safety and efficacy criteria that need to be met in order to allow treatment with GSK2118436 beyond disease progression (Section 4.2.1); updated Section 5.7, Guidelines for Dose Modification and Events of Special Interest, in line with current asset language; clarified QTc Stopping Criteria to delineate QTcF v QTcB and QTc uncorrected stopping values; and clarified protocol-specific SAE language for consistency with current asset language (removed LVEF stopping criteria as a protocol specific SAE).

Is a country specific amendment for France and the UK that specifies QTc stopping criteria in Appendix 3. Footnotes to the Time and Events Table were also renumbered.

Added the study expansion cohort (n=20) increasing total sample size to 60 subjects, updated the eligibility criteria to remove the requirement of disease progression on a platinum-based chemotherapy prior to study enrollment to allow inclusion of first line metastatic patients in the expansion cohort and allow subjects with HCV clearance, updated QTc stopping criteria, removed herbal remedies as a prohibitive medication (St Johns Wort still prohibited), updated the prohibitive and cautionary medication list, increased the frequency of dermatologic assessments to every 9 weeks, changed blood sample for cfDNA at disease progression from optional to required, replaced “GSK2118436” with “dabrafenib” throughout the document and additional administrative level clarifications and edits. Section 1.2.1 deleted, please refer to the Dabrafenib Investigator’s Brochure for all background/clinical trial information on dabrafenib.

Added the dabrafenib/trametinib combination therapy cohort (n=40) increasing the total sample size to 100 subjects, ophthalmic examination added at screening, Week 6 and as clinically necessary thereafter for combination treatment only, combination cohort specific inclusion/exclusion criteria added, combination cohort specific dose modification and toxicity management guidelines added, option to crossover from monotherapy to combination treatment at time of radiologic disease progression added, ECHO and ECG schedule clarified as baseline, Week 6 and every 9 weeks thereafter

Updated secondary medical monitor. Added Cohort C to enroll 25 first line subjects. Additional language added to study rationale in Section 1.2.1. Revised required laboratory value for PT/INR and PTT in Section 4.1.2. Removed HIV from ExclusionCriterion #7 and revised Exclusion Criterion #15 in Section 4.1.3. Additional language added to Section 4.2.1 and Section 4.2.3 to clarify requirements for continuing study treatment post-PD and for crossover requirements. Updated dose modification and toxicity management language throughout Section 5.9. Updated general dose modification guidelines in Section 5.9.2. Updated dose modification guidelines and stopping criteria for LVEF in Section 5.10.1. Updated liver chemistry stopping and follow-up criteria in Section 5.10.3. Guidelines for holding study drug following radiation treatment added to Section 6.1. Specified that body fluid sample (e.g., pleural effusion) is not acceptable for BRAF mutation testing sample in Section 7.1.1. Added confirmation of measurable disease by independent review at baseline prior to enrolment in Section 7.1.2. Updated language regarding ophthalmic examination requirements in Section 7.3.2.3. Added language in Section 7.3.2.9.2 allowing investigator to decide if basal cell carcinoma should be reported as SAE or not. Specified in Section 7.4.1 that females should wait at least 4 months after last dose of the combination therapy before nursing. Specified in Section 7.7 that body fluid sample (e.g., pleural effusion) is not preferred for PD biomarker sample. Added Section 9.1.3 to describe hypothesis and study design for Cohort C. Updated Section 9.2 regarding Cohort C. Updated Investigator Brochures citations to current versions. Appendix 4 added regarding additional monitoring requirements for subjects in France only.