A Study of BBI503 in Combination With Selected Anti-Cancer Therapeutics in Adult Patients With Advanced Cancer

Major inclusion criteria:

• A histologically or cytologically confirmed solid tumor that is locally advanced, recurrent, or metastatic; for which curative resection is not currently possible; and for which systemic treatment with one of the selected anti-cancer agents is a reasonable therapeutic option.
• Must be ≥ 18 years of age
• Has disease such that progression or response to therapy can be evaluated objectively while on protocol.
• Must have Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
• Male or female patients of childbearing potential must agree to use contraception or avoidance of pregnancy measures during the study and for 30 days after the last dose.
• Females of childbearing potential must have a negative serum pregnancy test.
• Must have aspartate transaminase (AST) ≤ 2.5 × upper limit of normal (ULN) and alanine transaminase (ALT) ≤ 2.5 × ULN. Patients who do not have hepatocellular carcinoma but who have liver lesions or liver metastases may be eligible if AST ≤ 3.5 × ULN and AST ≤ 3.5 × ULN if agreed upon by the investigator and medical monitor for the sponsor.
• Hemoglobin (Hgb) ≥ 9 g/dl
• Total bilirubin ≤ 1.5 × ULN. For patients with liver lesions, total bilirubin ≤ 2.0 × ULN may be enrolled if agreed upon by the investigator and medical monitor for the sponsor
• Creatinine ≤ 1.5 × ULN or creatinine clearance ≥ 60 mL/min/1.73 m^2 for patients with creatinine levels above institutional upper limit of normal (using the Cockcroft-Gault equation).
• Absolute neutrophil count ≥ 1.5 × 10^9/L
• Platelets ≥ 100 × 10^9/L
• Life expectancy ≥ 3 months

Major exclusion criteria:

• Received anti-cancer chemotherapy, radiotherapy, immunotherapy, or investigational agents within 7 days of first dose of protocol therapy. Patients may begin protocol therapy on a date determined by the investigator and medical monitor for the sponsor after a minimum of 7 days since last receiving anti-cancer treatment, provided that all adverse events related to that have resolved or have been deemed irreversible.
• Major surgery within 4 weeks prior to first dose; major surgery is defined as a procedure requiring any of the following: general anesthesia, intubation and mechanical ventilation, or major incision (e.g., thoracotomy, laparotomy)
• Any known, untreated, brain metastases. Patients with treated brain metastases must have no clinical symptoms from the metastases, and must be either off steroids or on a stable dose of steroids ≤ 10 mg prednisone or equivalent for at least 2 weeks prior to protocol enrollment. Patients with known leptomeningeal metastases are excluded, even if treated.
• Pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the study.
• Significant gastrointestinal disorder(s), in the opinion of the Principal Investigator, such as active inflammatory bowel disease, extensive gastric or small intestinal resection (which has resulted in short-gut syndrome or the inability to take oral medications).
• Unable or unwilling to swallow either BBI503 daily or an oral selected anti-cancer therapeutics; or, unwilling to receive intravenous injection of IV anti-cancer therapeutics.
• Positive for Human Immunodeficiency Virus (HIV), Hepatitis B (Hepatitis B Surface Antigen [HBsAg] reactive), or Hepatitis C virus (Hepatitis C Virus Ribonucleic Acid (HCV RNA] (qualitative) is detected).
• Uncontrolled concurrent illness including, but not limited to: ongoing or active infection requiring therapy, clinically significant non-healing or healing wounds, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, significant pulmonary disease (shortness of breath at rest or on mild exertion), uncontrolled infection or psychiatric illness/social situations that would limit compliance with study requirements
• Subjects with a history of another primary cancer with the exception of: a) curatively resected non-melanoma skin cancer; b) curatively treated cervical carcinoma in situ; c) localized prostate cancer not requiring systematic therapy; and d) other primary cancer with no known active disease present, and no treatment administered in the 2 years prior to enrollment.
• For patients to be treated with a regimen containing capecitabine: a) Known hypersensitivity to capecitabine, b) Known dihydropyrimidine dehydrogenase (DPD) deficiency, c) Significant gastrointestinal disorder(s) that would, in the opinion of the Investigator, prevent absorption of an orally available agent
• For patients to be treated with a regimen containing sunitinib: a) Uncontrolled hypertension (systolic blood pressure > 150 mmHg or diastolic pressure > 90 mmHg despite optimal medical management), b) Evidence of bleeding diathesis or a clinically significant coagulopathy (≥ CTCAE Grade 3) within 4 weeks prior to the start of study, c) Recent hypoglycemia, d) Uncontrolled thyroid dysfunction despite optimal medical therapy
• For patients to be treated with a regimen containing doxorubicin: a) Known left ventricular ejection fraction < 50%, b) Hypersensitivity to doxorubicin
• A patient to be treated with a regimen containing nivolumab or pembrolizumab will be excluded if the patient: a) Has an active autoimmune disease requiring immunosuppression with the exception of subjects with isolated vitiligo, resolved childhood asthma or atopic dermatitis, controlled hypoadrenalism or hypopituitarism, and euthyroid patients with a history of Grave's disease, b) Has had a previous life-threatening (CTCAE grade 4) immune-mediated adverse reaction; or, a previous severe (CTCAE grade 3) immune mediated adverse reaction that required treatment with corticosteroids (more than 10 mg/day prednisone or equivalent dose) for longer than 12 weeks, c) Has a transplanted organ, d) Has interstitial lung disease or active, non-infectious pneumonitis, e) Has received a live vaccine within 30 days prior to first dose, f) Previous severe hypersensitivity reaction to another monoclonal antibody (mAb), g) Has been treated with another monoclonal antibody ≤ 4 weeks before first dose.