Clinical Trial Testing TH-302 in Combination With Gemcitabine in Previously Untreated Subjects With Metastatic or Locally Advanced Unresectable Pancreatic Adenocarcinoma

A Randomized, Double-Blind, Phase III Study of the Efficacy and Safety of Gemcitabine in Combination With TH-302 Compared With Gemcitabine in Combination With Placebo in Previously Untreated Subjects With Metastatic or Locally Advanced Unresectable Pancreatic Adenocarcinoma

This Phase 3 trial is a randomized, double-blind, placebo-controlled trial of gemcitabine in combination with TH-302 compared to gemcitabine in combination with placebo in subjects with locally advanced unresectable or metastatic pancreatic adenocarcinoma. Randomized subjects will receive TH-302 plus gemcitabine or gemcitabine plus placebo in 4-week cycles until there is evidence of progressive disease, intolerable toxicity, or the subject discontinues from the trial for other reasons (for example, withdrawal of consent). The primary efficacy endpoint is overall survival (OS) time. The data cut-off for statistical analyses of the primary and secondary endpoints will be reached when 508 events (deaths) will be reported. No planned interim analyses will be conducted. An Independent Safety Monitoring Board (ISMB) will provide periodic evaluations of the unblinded safety data to ensure subject safety and the validity and scientific merit of the study. A total of 660 subjects will be enrolled.

Inclusion Criteria:

• At least 18 years of age

• Locally advanced unresectable or metastatic pancreatic ductal adenocarcinoma proven by histology or cytology and 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

• Measurable disease (at least one target lesion outside of previous radiation fields) or non-measurable disease by RECIST v.1.1 criteria

• Documentation of disease progression since any prior therapy

• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

• Life expectancy of at least 3 month

• Acceptable liver, renal function and acceptable hematological status

• Other protocol defined inclusion criteria may apply

Exclusion Criteria:

• New York Heart Association (NYHA) Class III or IV congestive heart failure, myocardial infarction within 6 months prior to the date of randomization, unstable arrhythmia or symptomatic peripheral arterial vascular disease
• Symptomatic ischemic heart disease
• Known brain, leptomeningeal or epidural metastases (unless treated and well controlled for at least 3 months)
• Previous malignancy other than pancreatic cancer in the last 5 years, except for adequately treated non-melanoma skin cancer or pre-invasive cancer of the cervix
• Severe chronic obstructive or other pulmonary disease with hypoxemia
• Major surgery, other than diagnostic surgery, less than or equal to 28 days prior to the date of randomization. Subject must have completely recovered from surgery
• Active, uncontrolled bacterial, viral, or fungal infections, requiring systemic therapy
• Treatment of pancreatic cancer with radiation therapy or surgery less than or equal to 28 days prior to the date of randomization
• Prior therapy with a hypoxic cytotoxin
• Subjects who participated in an investigational drug or device trial less than or equal to 28 days prior to Day 1 of the first cycle
• Known infection with Human Immunodeficiency Virus (HIV), or an active infection with Hepatitis B or Hepatitis C
• Subjects who have exhibited allergic reactions to a structural compound similar to TH-302 or the drug product excipients or to gemcitabine or its excipients
• Other protocol defined exclusion criteria may apply