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A Phase I/II Study to Assess the Safety and Efficacy of MK-3475 in Combination with Trametinib and Dabrafenib in Subjects with Advanced Melanoma

Part 3: To evaluate the efficacy with respect to progression-free survival (PFS) of MK-3475 administered intravenously in combination with oral dabrafenib and trametinib in subjects with advanced (unresectable or metastatic) melanoma with BRAF V600 E or K mutations, compared with placebo administered intravenously in combination with oral dabrafenib and trametinib alone. Secondary a) To evaluate the pharmacokinetics (PK) of MK-3475, dabrafenib, and/or trametinib when MK-3475 is administered intravenously in combination with oral dabrafenib and/or trametinib. b)To evaluate the efficacy of MK-3475 administered intravenously in combination with oral dabrafenib and trametinib in subjects with advanced (unresectable or metastatic) melanoma with BRAF V600 E or K mutations with respect to Objective Response Rate (ORR), Response Duration, and overall survival (OS), compared with oral dabrafenib and trametinib alone. Exploratory To evaluate the use of tumor kinetic parameters including time to growth (TTG) modeling and simulation to evaluate the effect of MK-3475 administered intravenously in combination with oral dabrafenib and trametinib in subjects with advanced (unresectable or metastatic) melanoma with BRAF V600 E or K mutations. These tumor kinetics parameters may be correlated with clinical outcomes. Part 4: To evaluate the safety and tolerability and identify the maximum tolerated dose (MTD) or maximum administered dose (MAD) of MK-3475 administered intravenously in combination with oral trametinib in subjects with advanced (unresectable or metastatic) melanoma without BRAF V600 E or K mutations or advanced (metastatic and/or unresectable) solid tumors, irrespective of BRAF status. Secondary To evaluate the pharmacokinetics (PK) of MK-3475, dabrafenib, and/or trametinib when MK-3475 is administered intravenously in combination with oral dabrafenib and/or trametinib. Exploratory To evaluate the efficacy of MK-3475 administered intravenously in combination with oral dabrafenib and trametinib in subjects with advanced (unresectable or metastatic) melanoma with BRAF V600 E or K mutations with respect to Best Overall Response, 5-Category Best Overall Response, 5-Category Ordinal Response by Week, Percentage of Subjects with Complete Response, Percentage of Subjects with Partial Response, Percentage of Subjects with Deep Response, Best Target Lesion Response, Time to Confirmed Response, Percentage of Subjects with Sustained Response at Week 36 (see Section 8.2.3.1 for endpoint definitions), EuroQol (EQ-5D), and EORTC (QLQ-C30) compared with oral dabrafenib and trametinib alone in Part 3. Part 5 a) To confirm the safety and tolerability of the preliminary maximum tolerated dose (MTD) or maximum administered dose (MAD) of MK -3475 administered intravenously in combination with oral trametinib in subjects with advanced (unresectable or metastatic) melanoma without BRAF V600 E or K mutations or advanced (metastatic and/or unresectable) solid tumors, irrespective of BRAF status. b)To evaluate the efficacy of MK-3475 administered intravenously in combination with oral trametinib in subjects with advanced (unresectable or metastatic) melanoma without BRAF V600 E or K mutations with respect to Objective Response Rate (ORR). Secondary To evaluate the pharmacokinetics (PK) of MK-3475, dabrafenib, and/or trametinib when MK-3475 is administered intravenously in combination with oral dabrafenib and/or trametinib. Exploratory To evaluate the potential for development of anti-drug antibodies (ADA) after administration of MK-3475.

Part 3: To evaluate the efficacy with respect to progression-free survival (PFS) of MK-3475 administered intravenously in combination with oral dabrafenib and trametinib in subjects with advanced (unresectable or metastatic) melanoma with BRAF V600 E or K mutations, compared with placebo administered intravenously in combination with oral dabrafenib and trametinib alone. Secondary a) To evaluate the pharmacokinetics (PK) of MK-3475, dabrafenib, and/or trametinib when MK-3475 is administered intravenously in combination with oral dabrafenib and/or trametinib. b)To evaluate the efficacy of MK-3475 administered intravenously in combination with oral dabrafenib and trametinib in subjects with advanced (unresectable or metastatic) melanoma with BRAF V600 E or K mutations with respect to Objective Response Rate (ORR), Response Duration, and overall survival (OS), compared with oral dabrafenib and trametinib alone. Exploratory To evaluate the use of tumor kinetic parameters including time to growth (TTG) modeling and simulation to evaluate the effect of MK-3475 administered intravenously in combination with oral dabrafenib and trametinib in subjects with advanced (unresectable or metastatic) melanoma with BRAF V600 E or K mutations. These tumor kinetics parameters may be correlated with clinical outcomes. Part 4: To evaluate the safety and tolerability and identify the maximum tolerated dose (MTD) or maximum administered dose (MAD) of MK-3475 administered intravenously in combination with oral trametinib in subjects with advanced (unresectable or metastatic) melanoma without BRAF V600 E or K mutations or advanced (metastatic and/or unresectable) solid tumors, irrespective of BRAF status. Secondary To evaluate the pharmacokinetics (PK) of MK-3475, dabrafenib, and/or trametinib when MK-3475 is administered intravenously in combination with oral dabrafenib and/or trametinib. Exploratory To evaluate the efficacy of MK-3475 administered intravenously in combination with oral dabrafenib and trametinib in subjects with advanced (unresectable or metastatic) melanoma with BRAF V600 E or K mutations with respect to Best Overall Response, 5-Category Best Overall Response, 5-Category Ordinal Response by Week, Percentage of Subjects with Complete Response, Percentage of Subjects with Partial Response, Percentage of Subjects with Deep Response, Best Target Lesion Response, Time to Confirmed Response, Percentage of Subjects with Sustained Response at Week 36 (see Section 8.2.3.1 for endpoint definitions), EuroQol (EQ-5D), and EORTC (QLQ-C30) compared with oral dabrafenib and trametinib alone in Part 3. Part 5 a) To confirm the safety and tolerability of the preliminary maximum tolerated dose (MTD) or maximum administered dose (MAD) of MK -3475 administered intravenously in combination with oral trametinib in subjects with advanced (unresectable or metastatic) melanoma without BRAF V600 E or K mutations or advanced (metastatic and/or unresectable) solid tumors, irrespective of BRAF status. b)To evaluate the efficacy of MK-3475 administered intravenously in combination with oral trametinib in subjects with advanced (unresectable or metastatic) melanoma without BRAF V600 E or K mutations with respect to Objective Response Rate (ORR). Secondary To evaluate the pharmacokinetics (PK) of MK-3475, dabrafenib, and/or trametinib when MK-3475 is administered intravenously in combination with oral dabrafenib and/or trametinib. Exploratory To evaluate the potential for development of anti-drug antibodies (ADA) after administration of MK-3475.