Study of the Safety and Efficacy of TH-302 in Combination With Gemcitabine Compared With Gemcitabine Alone in Previously Untreated Patients With Pancreatic Adenocarcinoma

A Randomized Cross-over Phase 2 Study of the Safety and Efficacy of Two Dose Levels of TH-302 in Combination With Gemcitabine Compared With Gemcitabine Alone in Previously Untreated Patients With Locally Advanced Unresectable or Metastatic Pancreatic Adenocarcinoma

The purpose of this study is to determine whether Gemcitabine versus Gemcitabine and TH-302 are effective in the treatment of subjects with first-line metastatic pancreatic adenocarcinoma.

A hypoxic microenvironment is a characteristic of many solid tumors including pancreatic cancer. The presence of hypoxia in solid tumors is associated with a more malignant phenotype and resistance to chemotherapy. The hypoxia-activated prodrug, TH-302, is designed to selectively physiologically target the hypoxic microenvironment. There is an absence of therapeutic options for subjects with metastatic pancreatic cancer. Gemcitabine provides clinical benefit as a single agent, but median survival is about 6 months. Combining gemcitabine with TH-302 may enable the targeting of both the normoxic and hypoxic regions of pancreatic cancer.

Inclusion Criteria:

1. At least 18 years of age

2. Ability to understand the purposes and risks of the study and has signed a written informed consent form approved by the investigator's IRB/Ethics Committee

3. Locally advanced unresectable or metastatic pancreatic ductal adenocarcinoma proven either by histology or cytology previously untreated with chemotherapy or systemic therapy other than:

   • Radiosensitizing doses of 5-fluorouracil;
   • Radiosensitizing doses of gemcitabine if relapse occurred at least 6 months after completion of gemcitabine;
   • Neoadjuvant chemotherapy if relapse occurred at least 6 months after surgical resection;
   • Adjuvant chemotherapy if relapse occurred at least 6 months after completion of adjuvant chemotherapy.

4. Measurable disease by RECIST 1.1 criteria (at least one target lesion outside of previous radiation fields)

5. Documentation of disease progression since any prior therapy

6. ECOG performance status of 0 or 1

7. Life expectancy of at least 3 months

8. Acceptable liver function:

   1. Bilirubin less than or equal to 1.5 times upper limit of normal
   2. AST (SGOT) and ALT (SGPT) less than or equal to 2.5 times upper limit of normal (ULN); if liver metastases are present, then less than or equal to 5 times ULN is allowed

9. Acceptable renal function:

   a. Serum creatinine less than or equal to ULN

10. Acceptable hematologic status (without hematologic support):

    1. ANC greater than or equal to 1500 cells/μL
    2. Platelet count greater than or equal to 100,000/μL
    3. Hemoglobin greater than or equal to 9.0 g/dL

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

Exclusion Criteria:

1. New York Heart Association (NYHA) Class III or IV, cardiac disease, myocardial infarction within 6 months prior to Day 1, unstable arrhythmia or symptomatic peripheral arterial vascular disease
2. Known brain, leptomeningeal or epidural metastases (unless treated and well controlled for at least 3 months)
3. Previously treated malignancies, except for adequately treated non-melanoma skin cancer, in situ cancer, or other cancer from which the subject has been disease-free for at least 5 years
4. Severe chronic obstructive or other pulmonary disease with hypoxemia (requires supplementary oxygen, symptoms due to hypoxemia or oxygen 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
5. Major surgery, other than diagnostic surgery, within 4 weeks prior to Day 1, without complete recovery
6. Active, uncontrolled bacterial, viral, or fungal infections, requiring systemic therapy
7. Treatment of pancreatic cancer with radiation therapy or surgery within 4 weeks prior to study entry
8. Prior therapy with an hypoxic cytotoxin
9. Subjects who participated in an investigational drug or device study within 28 days prior to study entry
10. Known active infection with HIV, hepatitis B, or hepatitis
11. Subjects who have exhibited allergic reactions to a structural compound, biological agent, or formulation (containing solutol and/or propylene glycol) similar to TH- 302
12. Females who are pregnant or breast-feeding
13. 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 the subject in this study
14. Unwillingness or inability to comply with the study protocol for any reason