Dose-Escalation Study of TH-302 in Combination With Sunitinib to Treat Patients With Advanced Renal Cell Carcinoma,Gastrointestinal Stromal Tumors and Pancreatic Neuroendocrine Tumors

Inclusion Criteria:

• At least 18 years of age

• Ability to understand the purposes and risks of the study and has signed a writteninformed consent form approved by the investigator's IRB/Ethics Committee

• Pathologically confirmed diagnosis of

• advanced RCC or

• GIST after disease progression on or intolerance to imatinib mesylate (doseescalation only)

• Unresectable locally advanced or metastatic pancreatic neuroendocrine tumors (dose escalation only)

• Recovered from reversible toxicities of prior therapy

• Evaluable disease by RECIST criteria (at least one target or non-target lesion fordose escalation cohorts; at least 1 target lesion for dose expansion cohort)

• ECOG performance status of 0 - 2

• Life expectancy of at least 3 months

• Acceptable liver function:

• Bilirubin less than or equal to 1.5 times upper limit of normal (ULN)

• AST (SGOT) and ALT (SGPT) less than or equal to 3.0 times ULN

• Acceptable renal function:

• Serum creatinine ≤ Upper Limit Normal,

• Acceptable hematologic status (without hematologic support):

• ANC greater than or equal to 1500 cells/μL

• Platelet count greater than or equal to 100,000/μL

• Hemoglobin great than or equal to 9.0 g/dL

• Acceptable cardiac function:

• Normal 12-lead ECG (clinically insignificant abnormalities permitted)

• LVEF normal by MUGA or echocardiogram

• Urinalysis: No clinically significant abnormalities

• Acceptable thyroid function

• All women of childbearing potential must have a negative serum pregnancy test and allsubjects must agree to use effective means of contraception (surgical sterilization orthe use or barrier contraception with either a condom or diaphragm in conjunction withspermicidal gel or an IUD) with their partner from entry into the study through 6months after the last dose

Exclusion Criteria:

• Prior therapy with more than 2 myelosuppressive cytotoxic chemotherapy regimens (doesnot include neoadjuvant and adjuvant therapy)

• Current use of drugs with known cardiotoxicity or known interactions with sunitinib (see product label)

• Anticancer treatment with radiation therapy, chemotherapy, targeted therapies (erlotinib, lapatinib, etc.), immunotherapy, hormones or other antitumor therapieswithin 3 weeks prior to study entry (6 weeks for nitrosoureas or mitomycin C)

• Significant cardiac dysfunction:

• Cardiac events within 12 months prior to treatment including MI andsevere/unstable angina, coronary/peripheral artery bypass graft, symptomatic CHF,cerebrovascular accident or transient ischemic attack or pulmonary embolism

• > Grade 2 QTc prolongation

• Requirement for antiarrhythmics

• Uncontrolled arrhythmias within the past 6 months

• Angina pectoris requiring antianginal medication within the past 6 months

• Clinically significant valvular heart disease

• Poorly controlled hypertension despite adequate blood pressure medication

• Seizure disorders requiring anticonvulsant therapy

• Known brain metastases (unless previously treated and well controlled for a period ofgreater than or equal to 3 months)

• Other active malignancy, except for adequately treated non-melanoma skin cancer, insitu cancer

• Severe chronic obstructive or other pulmonary disease with hypoxemia (requiressupplementary oxygen, symptoms due to hypoxemia or oxygen saturation <90% by pulseoximetry after a 2 minute walk) or in the opinion of the investigator anyphysiological state likely to cause normal tissue hypoxia

• Major surgery, other than diagnostic surgery, within 4 weeks prior to Day 1, withoutcomplete recovery

• Active, uncontrolled bacterial, viral, or fungal infections, requiring systemictherapy

• Prior therapy with an hypoxic cytotoxin

• Subjects who participated in an investigational drug or device study within 21 daysprior to study entry

• Known infection with HIV or active infection with hepatitis B or hepatitis C

• Subjects who have exhibited allergic reactions to a structural compound or biologicalagent similar to TH-302

• Females who are pregnant or breast-feeding

• Concomitant disease or condition that could interfere with the conduct of the study,or that would, in the opinion of the investigator, pose an unacceptable risk to thesubject in this study

• Unwillingness or inability to comply with the study protocol for any reason