A Trial of TH-302 in Combination With Doxorubicin Versus Doxorubicin Alone to Treat Patients With Locally Advanced Unresectable or Metastatic Soft Tissue Sarcoma

A Randomized Phase 3, Multicenter, Open-Label Study Comparing TH-302 in Combination With Doxorubicin vs. Doxorubicin Alone in Subjects With Locally Advanced Unresectable or Metastatic Soft Tissue Sarcoma

The purpose of this study is to determine whether TH-302 in combination with Doxorubicin is safe and effective in the treatment of Locally Advanced Unresectable or Metastatic Soft Tissue Sarcoma.

Study Overview

• Status: Completed
• Conditions: Soft Tissue Sarcoma
• Intervention / Treatment: Drug: TH-302 in Combination with Doxorubicin; Drug: Doxorubicin

Detailed Description

TH-302 is designed to target the hypoxic regions of tumors which are generally located distant from tumor vessels. Doxorubicin 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. Soft tissue sarcomas have evidence supporting the presence of hypoxia based on pO2 histography, F-MISO and gene expression profiling. There is an absence of therapeutic options for subjects with soft tissue sarcoma. Combining doxorubicin with TH-302 may enable the targeting of both the normoxic and hypoxic regions of soft tissue sarcoma.

• Study Type: Interventional
• Enrollment (Actual): 640
• Phase: Phase 3

Expanded Access

No longer available outside the clinical trial. See expanded access record.

Contacts and Locations

Study Locations

• Austria
  • Graz, Austria, A-8036
    • University Klinikum Graz
  • Innsbruck, Austria, A-6020
    • Univ. Klinik fur Innere Medizin I Internistische Onkologie Medizinische Universitat Innsbruck
  • Wien, Austria, A-1090
    • Allgemeines Krankenhaus Wien
• Belgium
  • Leuven, Belgium, 3000
    • Universitaire Ziekenhuizen (UZ) Leuven - Gasthuisberg
• Canada
  • Calgary, Canada, T2N4N2
    • Tom Baker Cancer Centre
  • Edmonton, Canada, T6G1Z2
    • Cross Cancer Institute
  • Ottawa, Canada, K1H8L6
    • Ottawa Health Research Institue
  • Vancouver, Canada, V5Z4E6
    • BCCA- Vancouver Cancer Centre - Division of Medical Oncology
  • Winnipeg, Canada, R3E0V9
    • Cancer Care Manitoba
  • Ontario
    • Hamilton, Ontario, Canada, L8V5C2
      • Juravinski Cancer Centre at Hamilton Health Sciences - Department of Medicine
  • Quebec
    • Montreal, Quebec, Canada, H3G 1A4
      • McGill University Health Centre
• Denmark
  • Copenhagen
    • Herlev, Copenhagen, Denmark, 2730
      • University Hospital Herlev at Copenhagen
• France
  • Bordeaux, France, 33076
    • Institut Bergonie
  • Dijon, France, 21079
    • Departement d'Oncologie Medicale
  • Lyon, France, 69008
    • Centre Léon Bérard
  • Marseille, France, 13009
    • Département d'Oncologie Moléculaire, Institut Paoli-Calmettes (IPC) and U119 Inserm
  • Nice, France
    • Centre Antoine Lacassagne
  • Strasbourg, France, 67098
    • CHU Strasbourg
  • Toulouse Cedex, France, 31052
    • Institut Claudius Regaud
  • Nantes
    • Saint Herblain Cedex, Nantes, France, 44805
      • Ico Rene Gauducheau
• Germany
  • Berlin, Germany, 13125
    • Helios Klinikum Berlin-Buch
  • Berlin, Germany, 15526
    • Helios Klinikum Bad Saarow, Department of Hematology, Oncology, and Palliative Care, Sarcoma Center Berlin-Brandenburg
  • Essen, Germany, 45122
    • Universitatsklinikum Essen
  • Frankfurt, Germany
    • Krankenhaus Nordwest GmbH
  • Hannover, Germany, 30625
    • Medizinische Hochschule Hannover (MHH) - Klinik fuer Haemonstaseologie, Onkologie und Stammzelltransplantation
  • Mannheim, Germany, D-68165
    • Div. of Surgical Oncology & Thoracic Surgery, Mannheim University Medical Center
  • Munster, Germany, 48149
    • Wilhelm's University, Universitatsklinikum Muenster, Medizinische Klinik und Poliklinik A, Albert-Schweitzer-Campus 1
• Hungary
  • Budapest, Hungary, H-1062
    • Magyar Honvedseg Honvedkorhaz, Onkologiai Osztaly
  • Szolnok, Hungary, H-5004
    • Jasz-Nagykun-Szolnok Megyei Hetenyi Geza Korhaz-Rendelointezet, Megyei Onkologiai Kozpont
• Israel
  • Jerusalem
    • Kiryat Hadassah, Jerusalem, Israel, 91120
      • Sharette Institute of Oncology, Hadassah-Hebrew University Medical Center, Hadassah Medical Org-Ein Karem
• Italy
  • Aviano, Italy, 33081
    • Centro di Riferimento Oncologico (CRO)
  • Catania, Italy, 95122
    • Azienda Ospedaliera Garibaldi
  • Palermo, Italy, 90127
    • Azienda Ospedaliero Universitaria-Policlinico Paolo Giacco
  • Torino, Italy, 10149
    • ASL TO/2 di TORINO_Presidio Sanitario Gradenigo, S.C. di Oncologia
  • Pordenone
    • Aviano, Pordenone, Italy, 33081
      • IRCCS Centro di Riferimento Oncologico-Struttura Operativa
  • Torino
    • Candiolo, Torino, Italy, 10060
      • Fondazione del Piemonte per l'Oncologia, Instituto per la Ricerca e la Cura del cancro (I.R.C.C.), Dipartimento Oncologico, Direzione Operativa Oncologia Medica a Direzione Universitaria
• Poland
  • Gdansk, Poland, 80-219
    • Wojewodzkie Centrum Onkologii
  • Krakow, Poland, 31-115
    • Centrum Onkologii Instytut im M. Sklodowskiej-Curie
  • Warszawa, Poland, 02-781
    • Centrum Onkologii-Instytut im. M. Sklodowskiej-Curie
• Russian Federation
  • Kazan, Russian Federation, 420029
    • GUZ "Regional Oncology Dispensay", Kazan
  • Moscow, Russian Federation, 115478
    • ROTSN RAMS them. Н.Н.Блохина NN Blokhin
  • Moscow, Russian Federation, 125284
    • FGU Moscow Research Institute of Oncology named after P.A. Hertzen of Rosmedtechnology
• Spain
  • Barcelona, Spain, 08041
    • Hospital de la Santa Creu i Sant Pau
  • Barcelona, Spain, 08907
    • Institut Catala d'Oncologia
  • Barcelona, Spain, 08950
    • Hospital Sant Joan de Deu, Department de Oncologia
  • Madrid, Spain, 28034
    • Hospital Universitario Ramón y Cajal.
  • Madrid, Spain, 28034
    • Universidad Complutense Madrid Facultad de Medicina - Hospital Universitario 12 de Octubre, Servicio de Oncologia Medica Hospital Universitario 12 de Octubre
  • Canarias
    • Tenerife, Canarias, Spain, 38320
      • H.U. Canarias, Hospital Universitario de Canarias. Servicio de Oncología Médica
• United States
  • Arizona
    • Scottsdale, Arizona, United States, 85259
      • Mayo Arizona
    • Tucson, Arizona, United States, 85719
      • Arizona Cancer Center
  • California
    • Los Angeles, California, United States, 90033
      • USC-Norris Comprehensive Cancer Center
    • Los Angeles, California, United States, 90095-6901
      • University of California, Los Angeles
    • Santa Monica, California, United States, 90403
      • Sarcoma Oncology Center
    • Stanford, California, United States, 94305
      • Stanford Comprehensive Cancer Center
  • District of Columbia
    • Washington, District of Columbia, United States, 20007
      • Georgetown University Hospital
    • Washington, District of Columbia, United States, 20010
      • Washington Cancer Institute
  • Florida
    • Boca Raton, Florida, United States, 33487
      • South Florida Center for Gynecologic Oncology
    • Jacksonville, Florida, United States, 32224
      • Mayo Clinic-Florida-Cancer Clinical Studies Unit
    • Orlando, Florida, United States, 32806
      • MD Anderson Cancer Center Orlando
    • Tampa, Florida, United States, 33612
      • H.Lee Moffitt Cancer Center and Research Institute
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Winship Cancer Institute of Emory University, Midtown Campus
  • Idaho
    • Coeur d'Alene, Idaho, United States, 83814
      • Kootenai Health - Kootenai Cancer Center
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Northwestern University
    • Chicago, Illinois, United States, 60612
      • Rush University Medical Center
    • Park Ridge, Illinois, United States, 60068
      • Oncology Specialists
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Indiana University Simon Cancer Center
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • University of Iowa Health Care - University of Iowa Hospital
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins Hospital
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Dana Farber Cancer Institute Center for Sarcoma and Bone Oncology
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan Cancer Center
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Rochester
  • Missouri
    • St. Louis, Missouri, United States, 63110
      • Washington University School of Medicine
  • New York
    • Bronx, New York, United States, 10461
      • Montefiore
    • Buffalo, New York, United States, 14263
      • Roswell Park Cancer Institute
    • NY, New York, United States, 10032
      • Columbia University Medical Center
    • New York, New York, United States, 10031
      • Memorial Sloan-Kettering Cancer Center
  • North Carolina
    • Charlotte, North Carolina, United States, 28203
      • Carolinas Hematology-oncology Associates-Blumenthal Cancer Center
    • Durham, North Carolina, United States, 27710
      • Duke University Medical Center
    • Winston Salem, North Carolina, United States, 27157
      • Wake Forest University Baptist Medical Center
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic Foundation
    • Cleveland, Ohio, United States, 44106
      • University Hospitals Seidman Cancer Center
    • Columbus, Ohio, United States, 43202
      • The Arthur G. James Cancer Hospital and Richard J Solove Research Institue, The Ohio State University Comprehensive Cancer Center
  • Oregon
    • Portland, Oregon, United States, 97239
      • Oregon Health and Science University
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19111
      • Fox Chase Cancer Center
    • Philadelphia, Pennsylvania, United States, 19106
      • Pennsylvania Oncology Hematology Associates
    • Pittsburg, Pennsylvania, United States, 15232
      • University of Pittsburg Medical Center
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • MUSC - Hollings Cancer Center
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt-Ingram Cancer Center
  • Vermont
    • Burlington, Vermont, United States, 05405
      • University of Vermont
  • Virginia
    • Richmond, Virginia, United States, 23298
      • Virginia Commonwealth Universtiy-Massey Cancer Center
  • Washington
    • Seattle, Washington, United States, 98109
      • University of Washington Cancer Center
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • Medical College of Wisconsin

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 15 years and older (ADULT, OLDER_ADULT, CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Male or female ≥ 15 years of age
• Ability to understand the purposes and risks of the study and has signed or, if appropriate, the subject's parent or legal guardian has signed a written informed consent form approved by the investigator's IRB/Ethics Committee

• Pathologically confirmed diagnosis of soft tissue sarcoma of the following histopathologic types:

  • Synovial sarcoma
  • High grade fibrosarcoma
  • Undifferentiated sarcoma; sarcoma not otherwise specified (NOS)
  • Liposarcoma
  • Leiomyosarcoma (excluding GIST)
  • Angiosarcoma (excluding Kaposi's sarcoma)
  • Malignant peripheral nerve sheath tumor
  • Pleomorphic Rhabdomyosarcoma
  • Myxofibrosarcoma
  • Epithelioid sarcoma
  • Undifferentiated pleomorphic sarcoma/malignant fibrous histiocytoma (MFH) (including pleomorphic, giant cell, myxoid and inflammatory forms)
• Locally advanced unresectable or metastatic disease with no standard curative therapy available and for whom treatment with single agent doxorubicin is considered appropriate.
• Recovered from reversible toxicities of prior therapy
• Measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
• Life expectancy of at least 3 months
• Acceptable liver, renal, hematological and cardiac function
• All women of childbearing potential must have a negative serum pregnancy test and all subjects must agree to use effective means of contraception

Exclusion Criteria:

• Prior systemic therapy for advanced or metastatic disease (neoadjuvant therapy followed by surgical resection and adjuvant therapy permitted). Palliative radiotherapy to non-target lesions is allowed if completed at least two weeks prior to study entry
• Low grade tumors according to standard grading systems
• Prior therapy with ifosfamide or cyclophosphamide or other nitrogen mustards
• Prior therapy with an anthracycline or anthracenedione
• Prior mediastinal/cardiac radiotherapy
• Current use of drugs with known cardiotoxicity or known interactions with doxorubicin
• Anti-cancer treatment with radiation therapy, neoadjuvant or adjuvant chemotherapy, targeted therapies, immunotherapy, hormones or other antitumor therapies within 4 weeks prior to study entry (6 weeks for nitrosoureas or mitomycin C). Palliative radiotherapy to non-target lesions is allowed, is completed at least two weeks prior to study entry.
• Significant cardiac dysfunction precluding treatment with doxorubicin
• Seizure disorders requiring anticonvulsant therapy unless seizure-free for the last year
• Known brain metastases (unless previously treated and well controlled for a period of ≥ 3 months)
• 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
• Severe chronic obstructive or other pulmonary disease with hypoxemia or in the opinion of the investigator any physiological state likely to cause normal tissue hypoxia
• Major surgery, other than diagnostic surgery, within 4 weeks prior to Day 1, without complete recovery
• Active, uncontrolled bacterial, viral, or fungal infections, requiring systemic therapy
• Prior therapy with a hypoxic cytotoxin
• Subjects who participated in an investigational drug or device study within 28 days prior to study entry
• Known infection with HIV, hepatitis B, or hepatitis C
• Subjects who have exhibited allergic reactions to a structural compound similar to TH-302,doxorubicin or their excipients
• Females who are pregnant or breast-feeding
• 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
• 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

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: TH-302 in Combination with Doxorubicin	Drug: TH-302 in Combination with Doxorubicin; 300 mg/m2 of TH-302 will be administered by IV infusion over 30-60 minutes on Days 1 and 8 of a 21-day cycle. Doxorubicin may be delivered as a bolus administration or as a continuous infusion administration; administration schedule must be specified prior to enrollment. Doxorubicin bolus administration: 75 mg/m2 administered by bolus injection starting on Day 1 of a 21-day cycle. Doxorubicin continuous administration: 75 mg/m2 administered by continuous IV infusion over 48-96 hours starting on Day 1 of a 21-day cycle. Doxorubicin administration will start between 2 to 4 hours after completion of the TH-302 infusion when used in combination with TH-302.
ACTIVE_COMPARATOR: Doxorubicin	Drug: Doxorubicin; Doxorubicin may be delivered as a bolus administration or as a continuous infusion administration; administration schedule must be specified prior to enrollment. Doxorubicin bolus administration: 75 mg/m2 administered by bolus injection starting on Day 1 of a 21-day cycle. Doxorubicin continuous administration: 75 mg/m2 administered by continuous IV infusion over 48-96 hours starting on Day 1 of a 21-day cycle.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Efficacy of TH-302 in combination with doxorubicin	Efficacy will be determined by overall survival in subjects with locally advanced unresectable or metastatic soft tissue sarcoma previously untreated with chemotherapy compared with doxorubicin alone	2 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety of TH-302 in combination with doxorubicin in subjects with locally advanced unresectable or metastatic soft tissue sarcoma compared with doxorubicin alone	To investigate the pharmacokinetics of TH-302, Br-IPM, doxorubicin, and doxorubicinol in plasma	2 years

Collaborators and Investigators

• Sponsor: Threshold Pharmaceuticals
• Collaborators: Sarcoma Alliance for Research through Collaboration (SARC)

Publications and helpful links

General Publications

• Tap WD, Papai Z, Van Tine BA, Attia S, Ganjoo KN, Jones RL, Schuetze S, Reed D, Chawla SP, Riedel RF, Krarup-Hansen A, Toulmonde M, Ray-Coquard I, Hohenberger P, Grignani G, Cranmer LD, Okuno S, Agulnik M, Read W, Ryan CW, Alcindor T, Del Muro XFG, Budd GT, Tawbi H, Pearce T, Kroll S, Reinke DK, Schoffski P. Doxorubicin plus evofosfamide versus doxorubicin alone in locally advanced, unresectable or metastatic soft-tissue sarcoma (TH CR-406/SARC021): an international, multicentre, open-label, randomised phase 3 trial. Lancet Oncol. 2017 Aug;18(8):1089-1103. doi: 10.1016/S1470-2045(17)30381-9. Epub 2017 Jun 23. Erratum In: Lancet Oncol. 2018 Feb;19(2):e78.
• Chawla SP, Cranmer LD, Van Tine BA, Reed DR, Okuno SH, Butrynski JE, Adkins DR, Hendifar AE, Kroll S, Ganjoo KN. Phase II study of the safety and antitumor activity of the hypoxia-activated prodrug TH-302 in combination with doxorubicin in patients with advanced soft tissue sarcoma. J Clin Oncol. 2014 Oct 10;32(29):3299-306. doi: 10.1200/JCO.2013.54.3660. Epub 2014 Sep 2.

Study record dates

Study Major Dates

• Study Start: September 1, 2011
• Primary Completion (ACTUAL): December 1, 2015
• Study Completion (ACTUAL): May 1, 2016

Study Registration Dates

• First Submitted: September 20, 2011
• First Submitted That Met QC Criteria: September 23, 2011
• First Posted (ESTIMATE): September 26, 2011

Study Record Updates

• Last Update Posted (ESTIMATE): June 2, 2016
• Last Update Submitted That Met QC Criteria: June 1, 2016
• Last Verified: June 1, 2016

More Information

Terms related to this study

• Keywords: Doxorubicin; Sarcoma; Evofosfamide; TH-302; TH-CR-406; SARC021; Locally Advanced Soft Tissue Sarcoma; Metastatic Soft Tissue Sarcoma
• Additional Relevant MeSH Terms: Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Neoplasms; Sarcoma; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Antibiotics, Antineoplastic; Doxorubicin; Liposomal doxorubicin
• Other Study ID Numbers: TH-CR-406/SARC021