Study of TH-302 or Placebo in Combination With Pemetrexed in Patients With Non-squamous Non-small Cell Lung Cancer

A Randomized Phase 2, Double-blind, Placebo-controlled, Multi-center Study Comparing Pemetrexed in Combination With TH-302 vs. Pemetrexed in Combination With Placebo as Second-line Chemotherapy for Advanced Non-Squamous, Non-Small Cell Lung Cancer

The purpose of this study is to determine whether TH-302 in combination with pemetrexed is safe and effective in the treatment of non-squamous non-small cell lung cancer.

Study Overview

• Status: Terminated
• Conditions: Non-small Cell Lung Cancer
• Intervention / Treatment: Drug: TH-302 combination with pemetrexed; Drug: Matched placebo in combination with pemetrexed

Detailed Description

TH-302 is designed to target the hypoxic regions of tumors which are generally located distant from tumor vessels. Pemetrexed has poor tissue penetration and targets the regions of tumors that are located in proximity to the tumor vessels. 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 target the hypoxic microenvironment. There is evidence supporting the presence of hypoxia in NSCLC lesions based on a hypoxia PET study. Combining pemetrexed with TH-302 may enable the targeting of both the normoxic and hypoxic regions of NSCLC lesions.

• Study Type: Interventional
• Enrollment (Actual): 265
• Phase: Phase 2

Contacts and Locations

Study Locations

• Czechia
  • Liben, Czechia, 18081
    • Hospital Na Bulovce, Department of Pneumology and Thoracic Surgery
  • Prague, Czechia, 12800
    • General Univesity Hospital in Prague, Clinic of Oncology
  • Praha 4, Czechia, 140 59
    • Thomayer Hospital, Clinic of Pneumology
  • Zlin, Czechia, 76275
    • Regional Hospital T. Bta, Department of Pneumology
• Germany
  • Berlin, Germany, 12200
    • Charité Universitätsmedizin Berlin;
  • Frankfurt, Germany, 65929
    • Klinikum Frankfurt Höchst GmbH
  • Grosshansdorf, Germany, 22927
    • Lungen Clinic Grosshandsdorf GmbH
  • Lubeck, Germany, 23538
    • Universitätsklinikum Schleswig-Holstein
  • München, Germany, 81925
    • Städtisches Klinikum München - Klinikum Bogenhausen
  • Ulm, Germany, 89081
    • Universitätsklinikum Ulm; Zentrum für Innere Medizin
  • Bavaria
    • Gauting, Bavaria, Germany, 82131
      • Asklepios Fachkliniken Munchen-Gaunting
  • North Rhine-Westphalia
    • Herne, North Rhine-Westphalia, Germany
      • Marien hospital Herne
• Greece
  • Athens, Greece
    • Attikon University General Hospital
  • Athens, Greece, 15562
    • IASO General, Oncology Unit
  • Heraklion, Greece, 71110
    • Department of Medical Oncology
  • Patras, Greece, 26500
    • University General Hospital of Patras, Oncology Unit
• Hungary
  • Budapest, Hungary, 1121
    • Koranyi National Institute of TBC and Pulmonology, 14th Dept of Pulmonology
  • Budapest, Hungary, 1121
    • Koranyi National Institute of TBC and Pulmonology, 6th Department of Pulmonology
  • Budapest, Hungary, 1121
    • Koranyi National Institute of TBC and Pulmonology, 8th Department of Pulmonology
  • Debrecen, Hungary, 4032
    • University of Debrecen, Medical and Health Science Center, Department of Pulmonology
  • Deszk, Hungary, 6772
    • Csongrad County Hospital of Chest Diseases
  • Szolnok, Hungary, 5004
    • Hetenyi Geza Hospital, Department of Oncology
• Italy
  • Bologna, Italy, 40139
    • Hospital Bellaria "Carlo Alberto Pizzardi" - Operative Unit of Oncology
  • Genova, Italy
    • IRCCS Azienda Ospedallera Universitaria San Martino-IST-Istituto Nazionale per la Ricerca sul Cancro
  • Milan, Italy, 20141
    • European Institute of Oncology (IEO) - Medical Care Unit
  • Monza, Italy, 20900
    • S. Gerardo Hospital - Complex Structure of Medical Oncology
  • Napoli, Italy
    • Azienda Ospedaliera Universitaria Policlinico della Seconda Universita di Napoli
  • Pisa, Italy, 56124
    • University Hospital of Pisa, Department of Cardothoracic Surgery, Operative unit of Pneumology
  • Pordenone, Italy, 33170
    • "Santa Maria degli Angeli" - Hospital - Complex Operative Unit of Oncology
  • Rome, Italy, 00152
    • San Camillo-Forlanini Hospital - U.O.C. Pneumologia Oncologica 1
  • Legnago
    • Verona, Legnago, Italy, 37045
      • "Mater Salutis" Hospital - Operative Unit of Oncology
  • Torino
    • Orbassano, Torino, Italy, 10043
      • A.O.U.S. Luigi GonzagaUniversity Hospital
• Poland
  • Poznan, Poland, 60693
    • Med-Polonia Sp. z o.o.
  • Torun, Poland, 87-100
    • L. Rydygier Provencial Hospitals in Torun, Dept. of Tumors Chemotherapy
  • Warsaw, Poland, 02781
    • Maria Sklodowska-Curie Institute of Oncology in Warsaw
• Romania
  • Bucharest, Romania, 022328
    • Pro. Dr. Alex Trestioreanu Institute of Oncology
  • Cluj-Napoca, Romania, 400015
    • Prof. Dr. Ioan Chiricuta Institute of Oncology
  • Dolj County
    • Craiova, Dolj County, Romania
      • Oncology Centre "Sf. Nectarie"
• Russian Federation
  • Moscow, Russian Federation, 115478
    • Russian Oncology Research Center n.a. N.N. Blokhin under the Russian Academy of Medical Sciences
  • Moscow, Russian Federation, 15478
    • Blokhin Russian Oncology Research Center
  • Nizhny Novgorod, Russian Federation, 603081
    • State Healthcare Institution: Nizhny Novgorod Regional Oncology Center
  • St. Petersburg, Russian Federation, 194044
    • St. Petersburg Clinical Center for Applied Special Medical Services (Oncology)
  • St. Petersburg, Russian Federation, 197101
    • St. Petersburg 1st State Medical University n.a.I.P. Pavlov under the Ministry of Healthcare of the Russian Federation
  • St. Petersburg, Russian Federation, 198255
    • City Clinical Oncology Center, Oncology Department (Thoracic Oncology)
  • Republic Of Tatarstan
    • Kazan, Republic Of Tatarstan, Russian Federation, 420029
      • Republican Clinical Oncology Center under the Ministry of Healthcare of Tatarstan Republic
• Spain
  • Madrid, Spain, 28222
    • Hospital Universitario Puerta de Hierro
  • Madrid, Spain, 28007
    • General University Hospital Gregorio Maranon, Dept. of Oncology
  • Madrid, Spain, 28040
    • Jimenez Diaz Foundation
  • Sevilla, Spain, 41014
    • University Hospital Virgen de Valme
  • Valencia, Spain, 46017
    • Dr. Peset University Hospital, Dept. of Oncology
  • Valencia, Spain, 46026
    • Hospital Universitario La Fe, Servicio de Oncologia
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294
      • UAB Cancer Center
  • Arizona
    • Chandler, Arizona, United States, 85224
      • Ironwood Cancer and Research Centers
  • California
    • Encinitas, California, United States, 92024
      • California Cancer Center
    • Fresno, California, United States, 93720
      • California Cancer Center Associates
    • Los Angeles, California, United States, 90095
      • UCLA-Department of Medicine a Division of Hem/Onc
    • Santa Monica, California, United States, 90403
      • Sarcoma Oncology Research Center
  • Colorado
    • Denver, Colorado, United States, 80220
      • VA Eastern Colorado Healthcare System
  • Delaware
    • Newark, Delaware, United States, 19713
      • Christiana Care Health Services
  • Florida
    • Jacksonville Beach, Florida, United States, 32256
      • Cancer Specialists of North Florida - CBO
    • Miami, Florida, United States, 33133
      • AMPM Research
  • Kansas
    • Kansas City, Kansas, United States, 64132
      • Research Medical Center
  • Louisiana
    • New Orleans, Louisiana, United States, 70121
      • Ochsner Clinical Foundation
  • Maryland
    • Bethesda, Maryland, United States, 20889
      • Walter Reed National Military Medical Center
  • Michigan
    • Ann Arbor, Michigan, United States, 48106
      • St. Joseph Mercy Ann Arbor Cancer Center
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic in Rochester
  • New York
    • Bronx, New York, United States, 10461
      • Montefire-Einstein Center for Cancer Care
    • New York, New York, United States, 10021
      • Clinical Research Alliance
  • North Carolina
    • Durham, North Carolina, United States, 27705
      • Durham VA Medical Center
    • Salisbury, North Carolina, United States, 28144
      • W.G. (Bill) Hefner VA Medical Center
  • Ohio
    • Canton, Ohio, United States, 44718
      • Gabrail Cancer Center Research
  • Pennsylvania
    • Hershey, Pennsylvania, United States, 17033
      • Penn State Milton S. Hershey Medical Center
  • South Carolina
    • Columbia, South Carolina, United States, 29209
      • DORN VA Medical Center
  • South Dakota
    • Rapid City, South Dakota, United States, 57701
      • Regional Cancer Care Institute at Regional Health
  • Tennessee
    • Chattanooga, Tennessee, United States, 37421
      • Associates in Oncology & Hematology
  • Texas
    • Fort Sam Houston, Texas, United States, 78234
      • San Antonio Military Medical Center
    • Houston, Texas, United States, 77024
      • Oncology Consultants
    • Houston, Texas, United States, 77090
      • Millennium Oncology
  • Virginia
    • Fort Belvoir, Virginia, United States, 22060
      • Fpr Belvoir Community Hospital
  • Washington
    • Seattle, Washington, United States, 98101
      • Virginia Mason Medical Center

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:

• Men and women ≥ 18 years of age.
• Histologically or cytologically confirmed stage IIIB or IV NSCLC with non-squamous histology
• Recurrent or progressive disease after one prior platinum-based non-pemetrexed chemotherapy treatment for advanced disease with or without maintenance
• Neoadjuvant/adjuvant cytotoxic chemotherapy initiated < 12 months prior to study randomization will be counted as one prior treatment
• Neoadjuvant/adjuvant cytotoxic chemotherapy initiated ≥ 12 months prior to study randomization will not be counted as one prior chemotherapy treatment
• Use of targeted agents (e.g., monoclonal antibodies or kinase inhibitors) will not be counted as a prior chemotherapy treatment
• Patients with known EGFR-activating mutations or ALK rearrangements should have received treatment with a targeted kinase inhibitor (e.g., erlotinib, crizotinib) and no longer be considered as a candidate for such treatment
• Measurable disease according to RECIST 1.1
• ECOG performance status 0-1
• Resolution to Grade ≤ 1 Adverse Events, of all clinically significant toxic effects of prior therapy
• Adequate hematologic, hepatic, cardiac, and renal function
• Female patients of childbearing potential must have a negative serum or urine pregnancy test, whichever is considered standard by the institution

Exclusion Criteria:

• Diagnosis of small cell carcinoma of the lung, squamous cell carcinoma of the lung or NSCLC NOS
• Prior therapy with pemetrexed
• Inability or unwillingness to take folic acid, vitamin B12 supplementation or corticosteroids
• Inability to discontinue non-steroidal anti-inflammatory drugs for 5 days (long half-life) or for 2 days (short half-life, if CrCL <80 mL/min) before pemetrexed dosing and until 2 days after pemetrexed dosing

• Leptomeningeal disease or any untreated or symptomatic brain metastases, unless the following criteria are met:

  • brain metastases are stable and have been previously treated with either whole-brain radiotherapy or gamma-knife surgery
  • steroids are currently not required and more than 14 days since last steroid treatment
• Symptomatic pleural effusion (> CTCAE Grade 1 dyspnea) that is not amenable to drainage
• Treatment with other systemic anticancer therapy within 4 weeks prior to the first dose of study medication
• Treatment with full field radiation therapy within 4 weeks or limited field radiation therapy within 2 weeks prior to the first dose of study medication
• Major surgery within 4 weeks or minor surgery within 2 weeks prior the first dose of study medication
• Elective or a planned major surgery while on study treatment
• Radiation therapy to greater than 25% of the bone marrow
• Clinically significant active infection (e.g. tuberculosis, viral hepatitis, HIV)
• Any other serious uncontrolled medical disorders or psychological conditions that may interfere with study conduct
• Concurrent active malignancy other than adequately treated basal cell or squamous cell carcinoma of the skin or pre-invasive carcinoma of the cervix.
• Pregnant or breast feeding
• Patients who are taking medications that prolong QT interval and have a risk of Torsades de Pointes (Appendix F) or who have a history of long QT syndrome
• Patients who are taking medications that are strong inducers or inhibitors of CYP3A4

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: TRIPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: TH-302 and pemetrexed; TH-302 in combination with pemetrexed	Drug: TH-302 combination with pemetrexed; 400 mg/m2 of TH-302 will be administered by IV infusion over 30 - 60 minutes on Day 1 and Day 8 of a 21-day cycle. Pemetrexed (500 mg/m2) will be administered as an IV infusion on Day 1 two - four hours after TH-302 administration.
ACTIVE_COMPARATOR: Placebo and pemetrexed; Matching placebo in combination with pemetrexed	Drug: Matched placebo in combination with pemetrexed; Matched placebo will be administered by IV infusion over 30 - 60 minutes on Day 1 and Day 8 of a 21-day cycle. Pemetrexed (500 mg/m2) will be administered as an IV infusion on Day 1 two - four hours after placebo administration.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Survival	To assess the efficacy of pemetrexed in combination with TH-302 as determined by overall survival in patients with advanced non-squamous NSCLC in the second-line chemotherapy setting compared with pemetrexed in combination with placebo	2 years

Collaborators and Investigators

• Sponsor: Threshold Pharmaceuticals
• Collaborators: EMD Serono
• Investigators: Study Chair: Tillman Pearce, MD, Threshold Pharmaceuticals; Principal Investigator: Jonathan Goldman, MD, UCLA-Dept of Medicine a Div of Hem/Onc

Study record dates

Study Major Dates

• Study Start: June 1, 2014
• Primary Completion (ACTUAL): April 1, 2016
• Study Completion (ACTUAL): May 1, 2016

Study Registration Dates

• First Submitted: March 18, 2014
• First Submitted That Met QC Criteria: March 19, 2014
• First Posted (ESTIMATE): March 21, 2014

Study Record Updates

• Last Update Posted (ACTUAL): March 25, 2021
• Last Update Submitted That Met QC Criteria: March 23, 2021
• Last Verified: March 1, 2021

More Information

Terms related to this study

• Keywords: Non-small cell lung cancer; Lung cancer; Pemetrexed; Evofosfamide; TH-302; TH-CR-415
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Neoplasms; Lung Diseases; Neoplasms by Site; Respiratory Tract Neoplasms; Thoracic Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Molecular Mechanisms of Pharmacological Action; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Antineoplastic Agents; Folic Acid Antagonists; Pemetrexed
• Other Study ID Numbers: TH-CR-415