Patient case: 54-year-old male with Gastric cancer. Genetic variant: PIK3CA (E545K). Other conditions: Depression.

Clinical trial: To Evaluate the Safety, Tolerability, and Pharmacokinetics of GDC-0077 Single Agent in Participants With Solid Tumors and in Combination With Endocrine and Targeted Therapies in Participants With Breast Cancer

Summary: This is an open-label, multicenter, Phase I study designed to evaluate the safety, tolerability, and pharmacokinetics of GDC-0077 administered orally as a single agent in participants with locally advanced or metastatic Phosphatidylinositol-4,5-Bisphosphate 3-Kinase Catalytic Subunit Alpha (PIK3CA)-mutant solid tumors, including breast cancer, and in combination with standard-of-care endocrine and targeted therapies for the treatment of locally advanced or metastatic PIK3CA-mutant hormone receptor-positive (HR+)/human epidermal growth factor receptor 2 negative (HER2-) breast cancer. Participants will be enrolled in two stages: a dose-escalation stage (Stage I) and an expansion stage (Stage II). Participants will be assigned to one of four regimens: GDC-0077 as a single agent (Arm A), GDC-0077 in combination with palbociclib and letrozole (Arm B), GDC-0077 in combination with letrozole (Arm C), or GDC-0077 in combination with fulvestrant (Arm D).


Eligibility: Inclusion Criteria:
  -  Evaluable or measurable disease per RECIST, Version 1.1
  -  Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
  -  Life expectancy of greater than or equal to (≥) 12 weeks
  -  Adequate hematologic and organ function, including blood counts, liver and kidney function
  Stage I Arm A (GDC-0077):
  -  Locally advanced, recurrent, or metastatic, PIK3CA mutant, incurable solid tumor malignancy, including breast cancer
  Stages I and II, Arm B:
  -  Postmenopausal female participants with histologically documented locally advanced or metastatic PIK3CA-mutant HR+/HER2- breast cancer
  -  Absolute neutrophil count ≥ 1500 per microliter
  Stages I and II, Arm C or Stage II Arm D:
  -  Postmenopausal female participants with locally advanced or metastatic PIK3CA-mutant HR+/HER2− breast cancer
  Stages I and II:
  -  All participants must provide tumor tissue from the primary or metastatic tumor site obtained from a prior or new biopsy or surgical procedure for detection of PIK3CA mutation by central laboratory test. Confirmation of adequate tissue is required prior to enrollment. For participants enrolled to biopsy cohorts or who consent to optional tumor biopsies, the pretreatment tumor biopsy may be used
  Exclusion Criteria:
  -  Inflammatory or metaplastic breast cancer
  -  History of leptomeningeal disease
  -  Type 1 or 2 diabetes requiring anti-hyperglycemic medication
  -  Inability or unwillingness to swallow pills
  -  Malabsorption syndrome or other condition that would interfere with enteral absorption
  -  Known and untreated, or active central nervous system metastases
  -  Uncontrolled pleural effusion or ascites
  -  Serious infection requiring antibiotics
  -  Concurrent ocular or intraocular condition that requires medical or surgical intervention to prevent or treat vision loss
  -  Active inflammatory or infectious conditions in either eye or history of idiopathic or autoimmune-associated uveitis
  -  Daily supplemental oxygen
  -  History of or active inflammatory disease or active bowel inflammation
  -  Symptomatic hypercalcemia requiring bisphosphonate or denosumab therapy
  -  Significant traumatic injury or major surgical procedure within 4 weeks prior to starting study treatment
  -  Clinically significant history of liver disease, including viral or other hepatitis, current alcohol abuse, or cirrhosis
  -  Treatment with chemotherapy, immunotherapy, or biologic therapy as anti-cancer therapy within 3 weeks, or treatment with endocrine therapy or kinase inhibitors within 2 weeks, prior to starting study treatment, except for premenopausal participants with breast cancer who may continue Gonadotropin-releasing hormone agonist therapy
  -  Radiation therapy as cancer therapy within 4 weeks, or palliative radiation to bony metastases within 2 weeks, prior to starting study treatment
  -  History of other malignancy within 5 years, except for treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, or Stage I uterine cancer
  -  History of or active ventricular dysrhythmias or congestive heart failure requiring medication or symptomatic coronary heart disease
  -  Congenital long QT syndrome, prolonged QT interval, or family history of sudden unexplained death or long QT syndrome
  -  Current treatment with medications known to prolong the QT interval
  Stage I:
  -  History of significant toxicity related to another phosphatidylinositol 3-kinase (PI3K) inhibitor or mammalian target of rapamycin (mTOR) inhibitor requiring treatment discontinuation
  -  Stage I Arm A: Pregnancy, lactation, or intention to become pregnant or fathering a child during the study
  -  Stage I Arm B: history of significant toxicity related to cyclin-dependent kinase (CDK)4/6 inhibitor, bone marrow transplant or extensive radiotherapy to ≥25 percent (%) of bone marrow
  Stage II:
  -  Prior treatment with >1 chemotherapy regimen for metastatic disease
  -  Prior treatment with PI3K inhibitor
  -  History of significant toxicity related to mTOR inhibitor requiring treatment discontinuation
  -  Stage II Arm B: prior CDK4/6 inhibitor treatment, bone marrow transplant or extensive radiotherapy to ≥25% of bone marrow

Relevance to patient case: possibly relevant