This is an open-label, multicenter, Phase I dose-escalation study to assess the safety, tolerability, and pharmacokinetics of GDC-0623 in patients with locally advanced or metastatic solid tumors. Patients will be enrolled in one of two stages: a dose-escalation stage (Stage I) followed by an expansion stage (Stage II). Stage I will evaluate the safety, tolerability, and pharmacokinetics of increasing doses of GDC-0623 administered orally on a 21 day on/7-day off dosing schedule.

Inclusion Criteria:

• Histologically or cytologically documented, locally advanced or metastatic solid tumors for which standard therapy either does not exist or has proven ineffective or intolerable
• Evaluable disease or disease measurable per RECIST
• Life expectancy >= 12 weeks
• Adequate hematologic and end organ function
• Agreement to use effective form of contraception for the duration of the study
• Consent to provide archival tissue
• For the cohort expansion stage (Stage II): Patients in this cohort must have had no more than four prior systemic therapies for cancer and must have KRAS mutant CRC (Stage II A and B), pancreatic cancer (Stage IIC, or KRAS mutant NSCLC [Stage IID])

Exclusion Criteria:

• History of prior significant toxicity from a MEK pathway inhibitor requiring discontinuation of treatment
• History of parathyroid disorder or history of malignancy-associated hypercalcemia requiring therapy in the last 6 months
• History of retinal vein occlusion (RVO) or predisposing factors to RVO, including uncontrolled hypertension, uncontrolled diabetes, uncontrolled hyperlipidemia, and coagulopathy
• Evidence of visible retinal pathology considered a risk factor for retinal vein thrombosis
• History of glaucoma
• Palliative radiotherapy, experimental therapy, or anti-cancer therapy or major surgical procedure within a specified timeframe prior to first dose of study drug
• Current severe, uncontrolled systemic disease
• History of clinically significant cardiac dysfunction
• History of active gastrointestinal bleeding within 6 months prior to screening
• Clinically significant history of liver disease, current alcohol abuse, or current known active infection with HIV, or hepatitis B or C virus
• Active autoimmune disease
• Uncontrolled ascites
• Pregnancy, lactation, or breastfeeding
• Known brain metastases that are untreated, symptomatic, or require therapy to control symptoms
• For the Exploratory PK Cohorts (Stage IB and Stage IC): Patients who have a history of or ongoing gastro-esophageal reflux disease or peptic ulcer, or who have gastric pathology or history of gastric surgery which could affect absorption of GDC-0623 from the stomach, will be excluded from these cohorts