A Cardiac Safety Study of TH-302 in Patients With Advanced Solid Tumors

Inclusion Criteria:

* Male or Female patients at least 18 years of age
* Advanced solid tumor for which no other higher priority therapies are available
* ECOG performance status of ) to 1
* Measurable or evaluable disease by RECIST 1.1
* Refractory to standard therapy, relapsed after standard therapy, or have no standard therapy that increases survival at least 3 months
* At least 3 weeks from previous cytotoxic chemotherapy or radiation therapy and at least 5 half-lives or 6 weeks, which ever is shorter, after targeted or biologic therapy
* Acceptable renal function defined as serum creatinine ≤ 1.5 times ULN or calculated creatinine clearance ≥ 60mL/min (by Cockcroft Gault formula)
* Acceptable liver function defined as:

  * Bilirubin ≤ 1.5 x upper limit of normal (ULN); does not apply to patients with Gilbert's syndrome
  * AST (SGOT) and ALT (SGPT) ≤ 3.0 x ULN); if liver metastases are present, then ≤ 5 x ULN is allowed
* Adequate bone marrow function (Absolute neutrophil count (ANC) ≥ 1,500 cells/uL; Platelets (PLT) ≥ 100,000 cells/uL)
* Adequate cardiac conduction by ECG without evidence of second- or third-degree atrioventricular block and meeting all of the following ECG criteria:

  * Heart rate 45-100 beats per minute
  * No evidence of second- or third-degree atrioventricular block
  * QRS interval ≤ 110ms
  * QT interval corrected for heart rate by Fridericia's formula (QTcF) ≤ 480ms
  * PR interval ≤ 200ms
  * No arrhythmia interpreted by the study cardiologist to be clinically significant
* Female patients of childbearing age must have a negative serum HCG test unless prior hysterectomy or menopause (defined as age ≥ 55 and twelve consecutive months without menstrual activity). Female patients should not become pregnant or breast-feed while on this study. Sexually active male and female patients should use effective birth control

Exclusion Criteria:

* Receiving QT-prolonging drugs with a risk of causing torsades de pointes (TdP), unless ECG meets inclusion criteria on a stable dose of the drug and with discussion and agreement with the project clinician
* History of risk factors for TdP, including family history of long QT syndrome
* Sustained systolic blood pressure (BP) \>140 mm Hg or \<90 mm Hg, diastolic BP \>100 mm Hg or \<60 mm Hg
* Uncontrolled intercurrent illness, including, but not limited to, myocardial infarction within 6 months, unstable symptomatic ischemic heart disease, active uncontrolled infection requiring systemic therapy, or psychiatric illness/social situations that would limit compliance with study requirements
* Major surgery within the 28 days preceding the first dose of study drug
* Newly diagnosed or uncontrolled cancer-related central nervous system disease
* Receiving medications that are moderate or strong inhibitors or inducers of CYP3A4 or that are sensitive substrate or substrates with a narrow therapeutic index of CYP3A4, CYP2D6, or CYP2C9 (see Appendix D)
* Unwillingness or inability to provide written informed consent and comply with the study protocol for any reason