Japan PhI/II of GSK2118436 and GSK1120212 Combination in Subjects With BRAF V600E/K Mutation Positive Advanced Solid Tumors (Phase I Part) or Cutaneous Melanoma (Phase II Part)

A Japanese Open-label Phase I/II Study to Assess the Safety, Tolerability, Pharmacokinetics and Efficacy of GSK2118436 and GSK1120212 Combination Therapy in Subjects With BRAF V600E/K Mutation Positive Advanced Solid Tumors (Phase I Part) and BRAF V600E/K Mutation Positive Cutaneous Melanoma (Phase II Part).

This is a Japanese Phase I/II, open-label, non-controlled study to evaluate the safety, tolerability, pharmacokinetic profile, and efficacy of the combination of GSK2118436 and GSK1120212 in subjects with BRAF V600E/K mutation positive advanced solid tumors (Phase I part) and BRAF V600E/K mutation positive cutaneous melanoma (Phase II part).

This is a Japanese Phase I/II, open-label, non-controlled study to evaluate the safety, tolerability, pharmacokinetic profile, and efficacy of the combination of GSK2118436 and GSK1120212 in subjects with BRAF V600E/K mutation positive advanced solid tumors (Phase I part) and BRAF V600E/K mutation positive cutaneous melanoma (Phase II part). Phase I part is designed to primarily assess the safety and tolerability of GSK2118436 and GSK1120212 combination therapy in subjects with BRAF V600E/K mutation positive advanced solid tumors. Six evaluable subjects will be enrolled into Phase I part and receive the combination therapy of GSK2118436 (150 mg, twice daily) and GSK1120212 (2 mg, once daily). A decision for starting Phase II part will be made by careful review based on available safety, tolerability and pharmacokinetic data in Phase I part. Phase II part is designed to primarily evaluate ORR of the combination as first-line therapy in subjects with unresectable (Stage IIIC) or metastatic (Stage IV) BRAF V600E/K mutation positive cutaneous melanoma. Subjects who have had prior systemic anti-cancer treatment in the advanced or metastatic setting will not be eligible for Phase II part although prior systemic treatment in the adjuvant setting will be allowed. Six evaluable subjects will be enrolled in Phase II part.

Inclusion Criteria:

• Capable of given written informed consent, which includes compliance with the requirements and restrictions listed in the consent form.
• Male or female age 20 years or greater; able to swallow and retain oral medication.
• BRAF mutation positive advanced solid tumor ( Phase I part). BRAF mutation positive melanoma (Phase II part).
• Measurable disease according to RECIST version 1.1.
• Eastern Cooperative Oncology Group Performance Status of 0 or 1
• Agree to contraception requirements.
• Adequate organ system function.

Exclusion Criteria:

• Currently receiving cancer therapy (chemotherapy, radiation therapy, immunotherapy, or biologic therapy).
• Phase II part ONLY: Prior systemic anti-cancer treatment (chemotherapy, immunotherapy, biologic therapy, vaccine therapy, or investigational treatment) for Stage IIIC (unresectable) or Stage IV (metastatic) melanoma. Prior systemic treatment in the adjuvant setting is allowed.
• Any major surgery, extensive radiotherapy, chemotherapy with delayed toxicity, biologic therapy, or immunotherapy within 28 days prior to the study treatment (6 weeks for prior nitrosourea or mitomycin C), or daily or weekly chemotherapy without the potential for delayed toxicity within 14 days prior to the study treatment. Limited radiotherapy within the last 2 weeks. (Note: Ipilimumab treatment must end at least 8 weeks prior to the study treatment.)
• Taken an investigational drug within 28 days or 5 half-lives (minimum 14 days), whichever is shorter, prior to the study treatment.
• Current use of a prohibited medication or requires any of these medications during treatment with the study drugs.
• A history of another malignancy. Subjects who have been disease-free for 5 years, or subjects with a history of completely resected non-melanoma skin cancer, or successfully treated in situ carcinoma are eligible.
• Any serious or unstable pre-existing medical conditions (aside from malignancy exceptions specified above), psychiatric disorders, or other conditions that could interfere with the subject's safety, obtaining informed consent, or compliance with study procedures (e.g., uncontrolled diabetes).
• Presence of active gastrointestinal disease or other condition that will interfere significantly with the absorption, distribution, metabolism, or excretion of drugs.
• History of pneumonitis or interstitial lung disease.
• Known HIV infection.
• Certain cardiac abnormality
• A history or current evidence/risk of retinal vein occlusion or central serous retinopathy.
• Pregnant or lactating female.