Study of GDC-0973/XL518 in Patients With Solid Tumors

• Stage I-II: Safety, tolerability, and maximum tolerated dose of GDC-0973/XL518 [ Time Frame: Through study completion or early study discontinuation ] [ Designated as safety issue: No ]
• Stage III: Maximum plasma concentration of midazolam [ Time Frame: Cycle 1: Days 1 and 15 ] [ Designated as safety issue: No ]
• Area under the concentration time curve of midazolam [ Time Frame: Cycle 1: Days 1 and 15 ] [ Designated as safety issue: No ]
• Stage III: Maximum plasma concentration of dextromethorphan [ Time Frame: Cycle 1: Days 1 and 15 ] [ Designated as safety issue: No ]
• Stage III: Area under the concentration time curve of dextromethorphan [ Time Frame: Cycle 1: Days 1 and 15 ] [ Designated as safety issue: No ]
• Stage I-II: Maximum tolerated dose of GDC-0973 [ Time Frame: 2 years ] [ Designated as safety issue: No ]

• Stage I-II: Plasma pharmacokinetics and pharmacodynamic effects of GDC-0973/XL518 [ Time Frame: Through study completion or early study discontinuation ] [ Designated as safety issue: No ]
• Stage III: Safety: incidence of adverse events [ Time Frame: 1 year ] [ Designated as safety issue: No ]

This non-randomized, open-label, study will determine the highest safe dose of GDC-0973/XL518, how often it should be taken, how well patients with cancer tolerate GDC-0973/XL518 and will assess the pharmacokinetic effect of midazolam and dextromethorphan on the study drug.

• Drug: GDC-0973/XL518
  Repeating oral dose
• Drug: midazolam
  In Stage III only: single dose of midazolam
• Drug: dextromethorphan
  In Stage III only: single dose of dextromethorphan

Inclusion Criteria:

• Histologically confirmed solid tumor that is metastatic or unresectable, and for which standard curative or palliative measures do not exist or are no longer effective, and there are no known therapies to prolong survival
• Disease that is measurable according to Response Evaluation Criteria in Solid Tumors (RECIST)
• Adequate organ and marrow function
• Sexually active patients must use medically acceptable methods of contraception during the course of the study and at least 11 days after the last dose of study treatment
• Female patients of childbearing potential must have a negative serum pregnancy test at screening
• No other history of/or ongoing malignancy that would potentially interfere with the interpretation of the pharmacodynamic or efficacy assays

Exclusion Criteria:

• Anticancer treatment (e.g., chemotherapy, radiotherapy, cytokines, or hormones) within 28 days (6 weeks for nitrosoureas or mitomycin C, or 14 days for hormonal therapy or kinase inhibitors) before the first dose of study drug
• The patient has not recovered to Grade </=1 from adverse events (AEs) or to within 10% of baseline values due to investigational or other agents administered more than 28 days prior to study enrollment
• The patient has received another investigational agent within 28 days of the first dose of study drug
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, diabetes, symptomatic congestive heart failure, unstable angina pectoris, or cardiac arrhythmia
• The patient is pregnant or breastfeeding
• The patient is known to be positive for the human immunodeficiency virus (HIV)
• Allergy or hypersensitivity to components of the GDC-0973/XL518 formulation