A Study Evaluating the Safety, Tolerability, and Pharmacokinetics of GDC-0973 in Combination With GDC-0068 When Administered in Patients With Locally Advanced or Metastatic Solid Tumors

• Incidence of dose-limiting toxicities [ Time Frame: approximately 24 months ] [ Designated as safety issue: No ]
• Nature of dose-limiting toxicities [ Time Frame: approximately 24 months ] [ Designated as safety issue: No ]
• Estimation of the maximum tolerated dose [ Time Frame: approximately 24 months ] [ Designated as safety issue: No ]
• Incidence of adverse events, graded according to National Cancer Institute Common Terminology Criteria for Adverse Events, Version 4.0 [ Time Frame: approximately 24 months ] [ Designated as safety issue: No ]
• Nature of adverse events, graded according to National Cancer Institute Common Terminology Criteria for Adverse Events, Version 4.0 [ Time Frame: approximately 24 months ] [ Designated as safety issue: No ]
• Severity of adverse events, graded according to National Cancer Institute Common Terminology Criteria for Adverse Events, Version 4.0 [ Time Frame: approximately 24 months ] [ Designated as safety issue: No ]
• Incidence of serious adverse events, graded according to National Cancer Institute Common Terminology Criteria for Adverse Events, Version 4.0 [ Time Frame: approximately 24 months ] [ Designated as safety issue: No ]
• Nature of serious adverse events, graded according to National Cancer Institute Common Terminology Criteria for Adverse Events, Version 4.0 [ Time Frame: approximately 24 months ] [ Designated as safety issue: No ]
• Severity of serious adverse events, graded according to National Cancer Institute Common Terminology Criteria for Adverse Events, Version 4.0 [ Time Frame: approximately 24 months ] [ Designated as safety issue: No ]

• Pharmacokinetic parameters of GDC-0973 and GDC-0068: total exposure [ Time Frame: Days 1, 8, and 15 pre-dose and up to 24 h post-dose for Cycle 1 and Day 1 on Cycles 2 and 3 ] [ Designated as safety issue: No ]
• Pharmacokinetic parameters of GDC-0973 and GDC-0068: maximum plasma concentration [ Time Frame: Days 1, 8, and 15 pre-dose and up to 24 h post-dose for Cycle 1 and Day 1 on Cycles 2 and 3 ] [ Designated as safety issue: No ]
• Pharmacokinetic parameters of GDC-0973 and GDC-0068: minimum concentration [ Time Frame: Days 1, 8, and 15 pre-dose and up to 24 h post-dose for Cycle 1 and Day 1 on Cycles 2 and 3 ] [ Designated as safety issue: No ]
• Objective response for patients with measurable disease according to RECIST criteria [ Time Frame: approximately 24 months ] [ Designated as safety issue: No ]
• Duration of objective response for patients with measurable disease according to RECIST criteria [ Time Frame: approximately 24 months ] [ Designated as safety issue: No ]
• Progression-free survival for patients with measurable disease according to RECIST criteria [ Time Frame: approximately 24 months ] [ Designated as safety issue: No ]

This open-label, multicenter, Phase Ib dose-escalation study will evaluate the safety, tolerability and pharmacokinetics of oral dosing of GDC-0973 and GDC-0068 administered in combination in patients with locally advanced or metastatic solid tumors. Cohorts of patients will receive multiple ascending doses of GDC-0973 and GDC-0068. Anticipated time on study treatment is until disease progression or unacceptable toxicity occurs.

• Drug: GDC-0973
  multiple doses
• Drug: GDC-0068
  multiple doses

• Experimental: A
  Interventions:

  • Drug: GDC-0973
  • Drug: GDC-0068
• Experimental: B
  Interventions:

  • Drug: GDC-0973
  • Drug: GDC-0068

Inclusion Criteria:

• Histologically or cytologically documented locally advanced or metastatic solid tumors for which standard therapies either do not exist or have proven ineffective or intolerable
• Evaluable disease or disease measurable per Response Evaluation Criteria in Solid Tumors (RECIST)
• Life expectancy >/= 12 weeks
• Adequate hematologic and end organ function

Exclusion Criteria:

• History of prior significant toxicity from another MEK pathway inhibitor requiring discontinuation of treatment
• History of prior significant toxicity from another PI3K or Akt pathway or mTOR inhibitor requiring discontinuation of treatment
• Anti-cancer therapy within 28 days prior to first dose of study drug, except as stated in protocol
• History of type I or type II diabetes mellitus requiring insulin
• Current severe, uncontrolled systemic disease (e.g. clinically significant cardiovascular, pulmonary, or metabolic disease)
• Clinically significant history of liver disease, current alcohol abuse, or current known active infection with HIV, hepatitis B or hepatitis C virus
• Active autoimmune disease
• Pregnant or lactating women
• Known brain metastases that are untreated, symptomatic, or require therapy to control symptoms
• History of glaucoma
• History of retinal vein occlusion