A Dose Escalation Study Evaluating the Safety and Tolerability of GDC-0032 in Patients With Locally Advanced or Metastatic Solid Tumors And in Combination With Endocrine Therapy in Patients With Locally Advanced or Metastatic Hormone Receptor-Positive Breast Cancer

• Incidence of adverse events by NCI CTCAE v4.0 grade and associated dose of GDC-0032 [ Time Frame: Up to 2 years ] [ Designated as safety issue: No ]
• Incidence of dose-limiting toxicities (DLTs) by NCI CTCAE v4.0 grade and associated dose of GDC-0032 [ Time Frame: Days 1-35 ] [ Designated as safety issue: No ]
• Incidence of Grade 3 and 4 abnormalities in safety related laboratory parameters and associated dose of GDC-0032 [ Time Frame: Up to 2 years ] [ Designated as safety issue: No ]
• Safety in combination with letrozole: incidence of adverse events [ Time Frame: Up to 2 years ] [ Designated as safety issue: No ]
• Safety in combination with fulvestrant: Incidence of adverse events [ Time Frame: Up to 2 years ] [ Designated as safety issue: No ]

• Best overall response for patients with measurable disease according to RECIST v1.1 [ Time Frame: Up to 2 years ] [ Designated as safety issue: No ]
• Duration of objective response for patients with measurable disease according to RECIST v1.1 [ Time Frame: Up to 2 years ] [ Designated as safety issue: No ]
• Progression free survival (PFS) for patients with measurable disease according to RECIST v1.1 [ Time Frame: Up to 2 years ] [ Designated as safety issue: No ]

This is an open-label, multicenter, Phase I, dose-escalation study to assess the safety, tolerability, and pharmacokinetics of GDC-0032 administered every day orally (PO).

• Drug: GDC-0032
  Oral repeating dose
• Drug: letrozole
  Repeating dose
• Drug: fulvestrant
  Repeating dose

• Experimental: Single-Agent Cohorts
  Intervention: Drug: GDC-0032
• Experimental: Combination expansion cohorts
  Interventions:

  • Drug: GDC-0032
  • Drug: letrozole
  • Drug: fulvestrant

Inclusion Criteria:

• Histologically documented, locally advanced or metastatic solid malignancy that has progressed or failed to respond to at least one prior regimen and/or are not candidates for regimens known to provide clinical benefit
• Evaluable or measurable disease per RECIST v1.1
• Life expectancy of >= 12 weeks
• Adequate hematologic and organ function within 14 days prior to initiation of study treatment
• Documented willingness to use an effective means of contraception for both men and women while participating in the study

Exclusion Criteria:

• Known untreated central nervous system (CNS) malignancies or treated brain metastases that are not radiographically stable for >= 3 months prior to initiation of study treatment
• Type 1 or 2 diabetes requiring daily anti-hyperglycemic medication
• Grade >=2 peripheral neuropathy
• Active congestive heart failure or ventricular arrhythmia requiring medication
• Patients requiring any daily supplemental oxygen
• Clinically significant history of liver disease, including viral or other hepatitis, current alcohol abuse, or cirrhosis
• Treatment with chemotherapy <= 4 weeks before study treatment
• Treatment with investigational drug <= 4 weeks before study treatment
• Treatment with biologic therapy <= 4 weeks before study treatment
• Treatment with kinase inhibitors <= 2 weeks before study treatment
• Radiation therapy <= 4 weeks before study treatment
• Radiation therapy for bony metastases <= 2 weeks before study treatment; other radiation for cancer therapy <= 4 weeks before study treatment
• Major surgery <= 4 weeks before study treatment
• Any other diseases, active or uncontrolled pulmonary dysfunction, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug, that may affect the interpretation of the results, or renders the patients at high risk from treatment complications