A Study of Vemurafenib And GDC-0973 in Patients With BRAF-Mutation Positive Metastatic Melanoma

• Dose-limiting toxicity of vemurafenib in combination with GDC-0973 [ Time Frame: Cycle 1: Day 28 ] [ Designated as safety issue: Yes ]
• Maximum tolerated dose of vemurafenib in combination with GDC-0973 [ Time Frame: Cycle 1: Day 28 ] [ Designated as safety issue: Yes ]
• Safety (Incidence of adverse events) [ Time Frame: Approximately 2 years ] [ Designated as safety issue: No ]
• Steady state plasma concentrations [ Time Frame: Cycle 1: Predose, Days 1, 2, 8, 14, 15, 16, 17; Cycle 2: Day 1, 8; Cycle 3: Day 8; at disease progression ] [ Designated as safety issue: No ]

• Dose-limiting toxicity of RO5185426 in combination with GDC-0973 [ Time Frame: Day 28 ] [ Designated as safety issue: No ]
• Maximum tolerated dose of RO5185426 in combination with GDC-0973 [ Time Frame: Day 28 ] [ Designated as safety issue: No ]
• Safety (Incidence of adverse events) [ Time Frame: Approximately 2 years ] [ Designated as safety issue: No ]

• Objective response [ Time Frame: Approximately 2 years ] [ Designated as safety issue: No ]
• Progression-free survival [ Time Frame: Approximately 2 years ] [ Designated as safety issue: No ]
• Duration of response [ Time Frame: Approximately 2 years ] [ Designated as safety issue: No ]
• Overall survival [ Time Frame: Approximately 2 years ] [ Designated as safety issue: No ]
• Pharmacodynamics: Change in fluorodeoxyglucose-positron emission tomography (FDG-PET) [ Time Frame: At baseline; Cycle 1, Day 14: Cycle 2, Day 14; at disease progression ] [ Designated as safety issue: No ]
• Pharmacodynamics: Immunohistochemical assessment of biopsies (MAP kinase) [ Time Frame: At baseline; Cycle 1: Day 14; at disease progression ] [ Designated as safety issue: No ]

• Objective response [ Time Frame: Approximately 2 years ] [ Designated as safety issue: No ]
• Progression-free survival [ Time Frame: Approximately 2 years ] [ Designated as safety issue: No ]
• Duration of response [ Time Frame: Approximately 2 years ] [ Designated as safety issue: No ]
• Steady state plasma concentrations [ Time Frame: Approximately 2 years ] [ Designated as safety issue: No ]

This open-label, dose-escalation study of vemurafenib in combination with GDC-0973 will evaluate the safety, tolerability and pharmacokinetics in patients with BRAF V600 mutation-positive metastatic melanoma. Patients with previously untreated, BRAFV600E mutation-positive, locally advanced/unresectable or metastatic melanoma or those who have progressed on vemurafenib monotherapy immediately prior to enrolling in this trial are eligible. Patients will be assigned to different cohorts with escalating oral doses of vemurafenib and GDC-0973. The anticipated time on study treatment is until disease progression, unacceptable toxicity or any other discontinuation criterion.

• Drug: vemurafenib
  Oral repeated dose
• Drug: GDC-0973
  Oral repeated dose

Inclusion Criteria:

• Adult patients, age >/=18 years
• Patients with histologically confirmed metastatic melanoma (unresectable Stage IIIc and Stage IV, American Joint Committee on Cancer (AJCC) metastatic melanoma)
• Measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
• Eastern Cooperative Oncology Group (ECOG) Performance Status of </=1

• Patients must

  1. be previously untreated for locally advanced/unresectable or metastatic melanoma or
  2. previously treated but without prior exposure to any BRAF or MEK inhibitor therapy or
  3. progressed on vemurafenib while participating in a Phase I (including clinical pharmacology studies), II, or III clinical study or EAP immediately prior to enrollment in this study or
  4. progressed on vemurafenib administered in a postmarketing setting immediately prior to enrollment in this study.
• Life expectancy >/=12 weeks

Exclusion Criteria:

• History of prior significant toxicity from another RAF or MEK pathway inhibitor requiring discontinuation of treatment
• Palliative radiotherapy within 2 weeks prior to first dose of study drug treatment
• Experimental therapy within 4 weeks prior to first dose of study drug treatment except vemurafenib
• Major surgery within 4 weeks of first dose of study drug treatment or planning a major surgery during the study