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

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.

Study Overview

• Status: Completed
• Conditions: Metastatic or Locally Advanced Unresectable Pancreatic Adenocarcinoma
• Intervention / Treatment: Drug: TH-302; Drug: Gemcitabine; Drug: Placebo (5 percent dextrose - D5W)

• Study Type: Interventional
• Enrollment (Actual): 693
• Phase: Phase 3

Contacts and Locations

Study Locations

• Germany
  • Darmstadt, Germany
    • Please Contact Merck Communication Center
• United States
  • Massachusetts
    • Rockland, Massachusetts, United States
      • Please Contact U.S. Medical Information

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Gemcitabine plus TH-302	Drug: TH-302; TH-302 will be administered at a dose of 340 milligrams per square meter (mg/m^2) as intravenous infusion over 30 minutes on Day 1, 8 and 15 of every 28-day cycle. Doses will be administered until evidence of progressive disease, intolerable toxicity or subject withdrawal.; Drug: Gemcitabine; Gemcitabine will be administered at a dose of 1000 (mg/m^2) as intravenous infusion over 30 minutes on Day 1, 8 and 15 of every 28-day cycle. Doses will be administered until evidence of progressive disease, intolerable toxicity or subject withdrawal.
Placebo Comparator: Gemcitabine plus placebo	Drug: Gemcitabine; Gemcitabine will be administered at a dose of 1000 (mg/m^2) as intravenous infusion over 30 minutes on Day 1, 8 and 15 of every 28-day cycle. Doses will be administered until evidence of progressive disease, intolerable toxicity or subject withdrawal.; Drug: Placebo (5 percent dextrose - D5W); TH-302 placebo (5 percent dextrose - D5W) will be administered as intravenous infusion over 30 minutes on Day 1, 8 and 15 of every 28-day cycle. Doses will be administered until evidence of progressive disease, intolerable toxicity or subject withdrawal.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Survival	Overall survival is defined as time from randomization to death or last day known to be alive.	From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 2 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression Free Survival	Progression Free Survival is defined as the time from randomization to either first observation of progressive disease or occurrence of death. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.	From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 2 years

Collaborators and Investigators

• Sponsor: Threshold Pharmaceuticals
• Investigators: Study Director: Antonio Gualberto, MD, PhD, EMD Serono Inc., a subsidiary of Merck KGaA, Darmstadt, Germany

Study record dates

Study Major Dates

• Study Start: December 1, 2012
• Primary Completion (Actual): February 1, 2016
• Study Completion (Actual): May 1, 2016

Study Registration Dates

• First Submitted: December 7, 2012
• First Submitted That Met QC Criteria: December 7, 2012
• First Posted (Estimate): December 11, 2012

Study Record Updates

• Last Update Posted (Actual): December 2, 2017
• Last Update Submitted That Met QC Criteria: October 26, 2017
• Last Verified: October 1, 2017

More Information

Terms related to this study

• Keywords: Pancreatic Cancer; Evofosfamide; TH-302; EMR200592-001
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Carcinoma; Neoplasms, Glandular and Epithelial; Adenocarcinoma; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Gemcitabine
• Other Study ID Numbers: EMR 200592-001; 2012-002957-42 (EudraCT Number)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No