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.

Study Overview

• Status: Completed
• Conditions: Pancreatic Adenocarcinoma
• Intervention / Treatment: Drug: Gemzar (Gemcitabine); Drug: TH-302; Drug: TH-302

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 214
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35223
      • Birmingham Hematology and Oncology Associates, LLC
  • Arizona
    • Scottsdale, Arizona, United States, 85259
      • Mayo Clinic Arizona
    • Tucson, Arizona, United States, 85724
      • University of Arizona
    • Tucson, Arizona, United States, 85704
      • Arizona Oncology Associates, PC - HOPE
  • Arkansas
    • Fort Smith, Arkansas, United States, 72917
      • Saint Edward Mercy Medical Center
  • California
    • Burbank, California, United States, 91505
      • Disney Family Cancer Center
    • La Jolla, California, United States, 92037
      • Scripps Clinical Research Services
    • Los Angeles, California, United States, 90095
      • UCLA Medical Center
    • Mountain View, California, United States, 94040
      • Palo Alto Medical Foundation
    • Salinas, California, United States, 93901
      • Los Palos Oncology and Hematology
    • San Diego, California, United States, 92123
      • Sharp Memorial Hospital
    • San Francisco, California, United States, 94115
      • California Pacific Medical Center
  • Colorado
    • Denver, Colorado, United States, 80218
      • Rocky Mountain Cancer Centers
  • Connecticut
    • Stamford, Connecticut, United States, 06902
      • Hematology Oncology Associates, PC
  • Florida
    • New Port Richey, Florida, United States, 34655
      • Florida Cancer Institute - New Hope
    • Ocala, Florida, United States, 34471
      • Ocala Oncology Center
    • Stuart, Florida, United States, 34994
      • Martin Memorial Cancer Center
  • Georgia
    • Atlanta, Georgia, United States, 30342
      • Atlanta Cancer Care
  • Illinois
    • Maywood, Illinois, United States, 60153
      • Loyola University Medical Center
    • Urbana, Illinois, United States, 61901
      • Carle Cancer Center
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Indiana University Melvin and Bren Simon Cancer
  • Kentucky
    • Paducah, Kentucky, United States, 42002
      • Purchase Cancer Group
  • Louisiana
    • Baton Rouge, Louisiana, United States, 70809
      • Medical Oncology
    • New Orleans, Louisiana, United States, 70121
      • Ochsner Cancer Institute
    • Shreveport, Louisiana, United States, 71130
      • LSU Health Sciences Center - Feist Weiller Cancer Center
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital
    • Worcester, Massachusetts, United States, 01655
      • University of Massachusetts Medical Center
  • Minnesota
    • Minneapolis, Minnesota, United States, 55407
      • Virgina Piper Cancer Institute
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic Rochester
  • Mississippi
    • Tupelo, Mississippi, United States, 38801
      • Hematology and Oncology Associates at Bridgepoint
  • Missouri
    • Columbia, Missouri, United States, 65201
      • Missouri Cancer Associates
  • Montana
    • Missoula, Montana, United States, 59802
      • Montana Cancer Institute Foundation
  • Nevada
    • Las Vegas, Nevada, United States, 89169
      • Comprehensive Cancer Centers of Nevada
  • New York
    • Buffalo, New York, United States, 14263
      • Roswell Park Cancer Institute
    • Hudson, New York, United States, 12534
      • New York Oncology Hematology, P.C.
  • North Carolina
    • Asheville, North Carolina, United States, 28801
      • Cancer Care of Western North Carolina, PA
    • Burlington, North Carolina, United States, 27599
      • Alamance Oncology Hematolgy Associates
    • Durham, North Carolina, United States, 27710
      • Duke University Medical Center
    • Hickory, North Carolina, United States, 28602
      • Carolina Oncology Specialists, PA
    • High Point, North Carolina, United States, 27262
      • Emerywood Hematology and Oncology
  • Ohio
    • Middletown, Ohio, United States, 45042
      • Signal Point Clinical Research Center
  • Oregon
    • Portland, Oregon, United States, 97227
      • Northwest Cancer Specialists, P.C.
    • Portland, Oregon, United States, 97227
      • Kaiser Permanente Northwest Region Oncology Hematology
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19114
      • Greater Philadelphia Cancer and Hematology Specialists, P.C.
    • Pittsburgh, Pennsylvania, United States, 15212
      • Allegheny General Hospital
    • Pittsburgh, Pennsylvania, United States, 15232
      • University of Pittsburgh Medical Center
  • South Carolina
    • Greenville, South Carolina, United States, 29605
      • Institute for Translational Oncology Research (ITOR)
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt University Medical Center, Div. of Medical Oncology
  • Texas
    • Beaumont, Texas, United States, 77702
      • Texas Oncology-Beaumont, Mamie McFaddin Ward Cancer Center
    • Dallas, Texas, United States, 75231
      • Texas Oncology-Dallas Presbyterian Hospital
    • Dallas, Texas, United States, 75390
      • University of Texas Southwestern Medical Center at Dallas
    • Fort Worth, Texas, United States, 76104
      • Texas Oncology- Fort Worth - 12th Avenue
    • Round Rock, Texas, United States, 78665
      • Texas Oncology-Seton Williamson
    • Sherman, Texas, United States, 75090
      • Texas Oncology-Sherman
    • Wichita Falls, Texas, United States, 76310
      • Texas Oncology-Wichita Falls Texoma Cancer Center
  • Virginia
    • Fairfax, Virginia, United States, 22031
      • Fairfax Northern Virginia Hematology Oncology, PC
  • Washington
    • Everett, Washington, United States, 98201
      • Providence Everett Regional Medical Center, Cancer Research Dept.
    • Kennewick, Washington, United States, 99336
      • Columbia Basin Hematology and Oncology0
  • Wisconsin
    • Madison, Wisconsin, United States, 53792
      • University of Wisconsin

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:

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: Gemcitabine; Gemcitabine: 1,000 mg/m2 administered IV over 30 minutes on Days 1, 8 and 15 of a 28-day cycle	Drug: Gemzar (Gemcitabine); 1,000 mg/m2 administered IV over 30 minutes on Days 1, 8 and 15 of a 28-day cycle.; Other Names: Gemcitabine
EXPERIMENTAL: 240 mg/m2 TH-302 + Gemcitabine; TH-302: 240 mg/m2 administered IV over 30 minutes Day 1, 8, and 15 of each 28-day cycle Gemcitabine: 1,000 mg/m2 administered IV over 30 minutes on Days 1, 8 and 15 of a 28-day cycle	Drug: Gemzar (Gemcitabine); 1,000 mg/m2 administered IV over 30 minutes on Days 1, 8 and 15 of a 28-day cycle.; Other Names: Gemcitabine; Drug: TH-302; 240 mg/m2 of TH-302 will be administered IV over 30 minutes on Days 1, 8 and 15 of every 28-day cycle.; Other Names: HAP; hypoxia activated prodrug; Drug: TH-302; 340 mg/m2 of TH-302 will be administered IV over 30 minutes on Days 1, 8 and 15 of every 28-day cycle.; Other Names: HAP; hypoxia activated prodrug
EXPERIMENTAL: 340 mg/m2 TH-302 + Gemcitabine; TH-302: 340 mg/m2 of TH-302 be administered IV over 30 minutes on Days 1, 8 and 15 of every 28-day cycle. Gemcitabine: 1,000 mg/m2 administered IV over 30 minutes on Days 1, 8 and 15 of a 28-day cycle	Drug: Gemzar (Gemcitabine); 1,000 mg/m2 administered IV over 30 minutes on Days 1, 8 and 15 of a 28-day cycle.; Other Names: Gemcitabine; Drug: TH-302; 240 mg/m2 of TH-302 will be administered IV over 30 minutes on Days 1, 8 and 15 of every 28-day cycle.; Other Names: HAP; hypoxia activated prodrug; Drug: TH-302; 340 mg/m2 of TH-302 will be administered IV over 30 minutes on Days 1, 8 and 15 of every 28-day cycle.; Other Names: HAP; hypoxia activated prodrug

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-free Survival (PFS)	Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST), 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 1 year

Collaborators and Investigators

• Sponsor: Threshold Pharmaceuticals
• Collaborators: PRA Health Sciences
• Investigators: Principal Investigator: Shantan Reddy, MD, Lousiana Health Sciences Center - Shreveport

Publications and helpful links

General Publications

• Borad MJ, Reddy SG, Bahary N, Uronis HE, Sigal D, Cohn AL, Schelman WR, Stephenson J Jr, Chiorean EG, Rosen PJ, Ulrich B, Dragovich T, Del Prete SA, Rarick M, Eng C, Kroll S, Ryan DP. Randomized Phase II Trial of Gemcitabine Plus TH-302 Versus Gemcitabine in Patients With Advanced Pancreatic Cancer. J Clin Oncol. 2015 May 1;33(13):1475-81. doi: 10.1200/JCO.2014.55.7504. Epub 2014 Dec 15.

Study record dates

Study Major Dates

• Study Start: June 1, 2010
• Primary Completion (ACTUAL): September 1, 2013
• Study Completion (ACTUAL): December 1, 2014

Study Registration Dates

• First Submitted: June 11, 2010
• First Submitted That Met QC Criteria: June 14, 2010
• First Posted (ESTIMATE): June 15, 2010

Study Record Updates

• Last Update Posted (ACTUAL): December 19, 2017
• Last Update Submitted That Met QC Criteria: November 20, 2017
• Last Verified: November 1, 2017

More Information

Terms related to this study

• Keywords: Metastatic Pancreatic Adenocarcinoma; Locally Advanced Unresectable Pancreatic Adenocarcinoma; Locally Advanced Unresectable or Metastatic Pancreatic Adenocarcinoma
• 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; Antineoplastic Agents, Alkylating; Alkylating Agents; Gemcitabine; Phosphoramide Mustards
• Other Study ID Numbers: TH-CR-404