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

This is an open-label study in patients with advanced solid tumors treated with TH-302 to
assess safety, pharmacokinetics, and potential effects on cardiac repolarization and
antitumor activity in patients with advanced solid tumors.

A dose of 480 mg/m2 of TH 302 will be administered by IV infusion over 30 minutes on Days 1,
8 and 15 of each 28-day cycle. Evaluations of safety, PK, and ECG parameters of cardiac
repolarization will be performed on Study Day 1 and Day 2 of Cycle 1.

Cycles will be repeated every 28 days, until toxicity, progressive disease, patient or
investigator decision to discontinue treatment, or until a maximum of six treatment cycles.
Patients who are clearly benefitting from the treatment based on anti-cancer disease control
and tolerability will be able to continue to receive drug past 6 cycles after discussion with
the Sponsor. Tumor assessments will be performed after every 2 cycles during treatment.

The rationale for conducting this study is based on (a) prior data demonstrating the clinical
benefit in advanced solid tumors as defined by tumor response or stable disease for at least
4 months, (b) tolerability of TH-302 at the proposed dose, and (c) a requirement to perform a
dedicated ECG study to address the clinical evaluation of the potential for QT/QTc interval
prolongation of TH-302.

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