Phase I Dose Escalation of Pazopanib Plus TH-302 in Advanced Solid Tumors

Inclusion Criteria:

- Histologically and/or cytologically confirmed malignant solid tumor that is
refractory to standard therapies, or for which no standard therapies exist, or for
whom pazopanib would be considered a therapeutic option.

- Disease must be measurable by RECIST 1.1 criteria (see Appendix 1).

- Age ≥ 18 years

- Karnofsky Performance status ≥ 80% (see Appendix 2)

- Life expectancy of at least 3 months

- Adequate bone marrow function as shown by:

- ANC ≥ 1.5 x 109

- Platelets ≥ 100 x 109/L

- Hemoglobin ≥ 9 g/dL; Erythropoietin and transfusion support is permitted
provided treatments are not required more than every 8 weeks. Hemoglobin must be
stable above or equal to 9 g/dL for at least 2 weeks prior to day 1of study drug
without blood transfusion to maintain hemoglobin level.

- Adequate liver function as shown by:

- serum bilirubin ≤ 1.5x ULN

- PT/PTT/INR ≤ 1.5x ULN

- ALT and AST ≤ 2.5x ULN

- Adequate renal function: creatinine clearance (estimated) ≥ 50 cc/min by
Cockroft-Gault or 24 hour urine (see Appendix 6).

- Baseline MUGA or ECHO must demonstrate LVEF ≥ 50%

- TSH, T3 and T4 within normal limits; Patients are permitted to receive thyroid
hormone supplements to treat underlying hypothyroidism.

- Women of childbearing potential (WOCBP) must have a negative serum pregnancy test
within 7 days from day 1 of study drug; both men and women must be willing to use two
methods of contraception, one of them being a barrier method during the study and for
6 months after last study drug administration.

- Signed informed consent

Exclusion Criteria:

- Patients currently receiving anticancer therapies or who have received anticancer
therapies within 4 weeks from day 1 of study drug (including investigational agents,
chemotherapy, radiation therapy, antibody based therapy, etc.)

- Patients who:

- have had a major surgery or significant traumatic injury within 4 weeks from day
1 of study drug,

- have not recovered from the side effects of any major surgery (defined as
requiring general anesthesia) or

- are anticipated to require major surgery during the course of the study.

- Patients who have exhibited hypersensitivity reactions to pazopanib and/or a
structural compound, biological agent, or formulation.

- Patients receiving chronic, systemic treatment with corticosteroids or another
immunosuppressive agent with the following exceptions:

- Intermittent steroids (not to exceed 4 mg every day) may be used on an as-needed
basis

- Patients on physiologic replacement doses of steroids due to adrenal insufficiency
for any reason may remain on these medications.

- Topical, inhaled or intra-articular corticosteroids

- Active brain or leptomeningeal metastases, including patients who continue to require
glucocorticoids for brain or leptomeningeal metastases. Treated, asymptomatic
metastases are permitted provided the patient has been off steroids for at least 1
month prior to day 1 of study drug.

- Severe chronic obstructive or other pulmonary disease with hypoxemia (requires
supplementary oxygen, symptoms due to hypoxemia or O2 saturation <90% by pulse
oximetry after a 2 minute walk or in the opinion of the investigator any
physiological state likely to cause systemic or regional hypoxemia.

- Presence of poorly controlled atrial fibrillation (ventricular heart rate >100 bpm)

- Previous history of CVA, TIA, angina pectoris, acute MI or history of recent
re-perfusion procedures (e.g. PTCA), pulmonary embolus or untreated deep vein
thrombosis (DVT) within 6 months from day 1 of study drug.

NOTE: Subjects with recent DVT who have been therapeutically anti-coagulated for at least
6 weeks are eligible.

- Congestive heart failure (New York Heart Association (NYHA classification, see
Appendix 4 functional classification III-IV).

- Proteinuria at screening demonstrated by urine analysis (UA) > 1+ or 24 hour urine
protein ≥ 1 gram/24 hours.

- Patients who have any severe and/or uncontrolled medical conditions or other
conditions that could affect their participation in the study as so judged by the
treating physician. Examples include but are not limited to:

- Severely impaired lung function (e.g. use of home O2, history of Idiopathic Lung
Disease (ILD), any evidence of ILD on scan.

- Active or uncontrolled severe infections requiring treatment with antibiotics.

- Liver disease

- Poorly controlled hypertension [defined as systolic blood pressure (SBP of >140
mmHg or diastolic blood pressure (DBP) of >90 mmHg] NOTE: Initiation or
adjustment of antihypertensive medication(s) is permitted prior to study entry.
Following antihypertensive medication initiation or adjustment, blood pressure
(BP) must be re-assessed three times at approximately 2-minute intervals. At
least 24 hours must have elapsed between anti-hypertensive medication initiation
or adjustment and BP measurement.

- Impairment of gastrointestinal function or gastrointestinal disease that may
significantly alter the absorption of oral medications (e.g., ulcerative
disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome or
small bowel resection).

- Significant vascular disease (e.g., aortic aneurysm requiring surgical repair or
recent peripheral arterial thrombosis) within 6 months prior to day 1 of study drug

- History of hemoptysis within 1 month prior to day 1 of study drug.

- History of abdominal fistula or gastrointestinal perforation at any point within 6
months prior to day 1 of study drug, unless surgically repaired.

- Active peptic ulcer disease inflammatory bowel disease (e.g. ulcerative colitis,
Crohn's disease), or other gastrointestinal conditions with increased risk of
perforation or gastrointestinal bleeding.

- Use or need for full dose anticoagulation other than low molecular weight heparin
(e.g. Lovenox and no other bleeding risk).

- Invasion or encasement of a major artery. Abutment without invasion or encasement is
permitted.

- Serious, non-healing wound, active ulcer, or untreated bone fracture as judged by
treating physician.

- Active, bleeding diathesis.

- Known endobronchial lesions and/or lesions infiltrating major pulmonary vessels that
increase the risk of pulmonary hemorrhage.

- Known history of HIV or Hepatitis B or C seropositivity.

- Female patients who are pregnant or breast feeding, or adults of reproductive
potential who are not using effective birth control methods. Two acceptable forms of
contraceptives must be continued throughout the trial by either sex. Hormonal
contraceptives are not acceptable as a sole method of contraception. (Women of
childbearing potential must have a negative serum pregnancy test within 7 days prior
to day 1 of study drug).

- Concomitant use of CYP3A4 inducers, strong inhibitors or substrates with a narrow
therapeutic window.

- Corrected QTc interval > 480 msec. If QTc interval is > 480 msec, then 2 additional
ECGs should be obtained over a brief period of time (e.g., within 15-20 minutes) to
confirm the abnormality.

- Patients unwilling to or unable to comply with the protocol.