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

Information source: Threshold Pharmaceuticals
ClinicalTrials.gov processed this data on August 20, 2015
Link to the current ClinicalTrials.gov record.

Condition(s) targeted: Soft Tissue Sarcoma

Intervention: TH-302 in Combination with Doxorubicin (Drug); Doxorubicin (Drug)

Phase: Phase 3

Status: Active, not recruiting

Sponsored by: Threshold Pharmaceuticals

Official(s) and/or principal investigator(s):
William Tap, MD, Principal Investigator, Affiliation: Memorial Sloan Kettering Cancer Center


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.

Clinical Details

Official title: 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

Study design: Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Primary outcome: Efficacy of TH-302 in combination with doxorubicin

Secondary outcome: Safety of TH-302 in combination with doxorubicin in subjects with locally advanced unresectable or metastatic soft tissue sarcoma compared with doxorubicin alone

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.


Minimum age: 15 Years. Maximum age: N/A. Gender(s): Both.


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


- 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


- 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

Locations and Contacts

University Klinikum Graz, Graz A-8036, Austria

Univ. Klinik fur Innere Medizin I Internistische Onkologie Medizinische Universitat Innsbruck, Innsbruck A-6020, Austria

Allgemeines Krankenhaus Wien, Wien A-1090, Austria

Universitaire Ziekenhuizen (UZ) Leuven - Gasthuisberg, Leuven 3000, Belgium

Tom Baker Cancer Centre, Calgary T2N4N2, Canada

Cross Cancer Institute, Edmonton T6G1Z2, Canada

Ottawa Health Research Institue, Ottawa K1H8L6, Canada

BCCA- Vancouver Cancer Centre - Division of Medical Oncology, Vancouver V5Z4E6, Canada

Cancer Care Manitoba, Winnipeg R3E0V9, Canada

Institut Bergonie, Bordeaux 33076, France

Departement d'Oncologie Medicale, Dijon 21079, France

Centre Leon Berard, Lyon 69008, France

Département d'Oncologie Moléculaire, Institut Paoli-Calmettes (IPC) and U119 Inserm, Marseille 13009, France

Centre Antoine Lacassagne, Nice, France

CHU Strasbourg, Strasbourg 67098, France

Institut Claudius Regaud, Toulouse Cedex 31052, France

Helios Klinikum Bad Saarow, Department of Hematology, Oncology, and Palliative Care, Sarcoma Center Berlin-Brandenburg, Berlin 15526, Germany

HELIOS Klinikum Berlin-Buch, Berlin 13125, Germany

Universitätsklinikum Essen, Essen 45122, Germany

Krankenhaus Nordwest GmbH, Frankfurt, Germany

Medizinische Hochschule Hannover (MHH) - Klinik fuer Haemonstaseologie, Onkologie und Stammzelltransplantation, Hannover 30625, Germany

Div. of Surgical Oncology & Thoracic Surgery, Mannheim University Medical Center, Mannheim D-68165, Germany

Wilhelm's University, Universitatsklinikum Muenster, Medizinische Klinik und Poliklinik A, Albert-Schweitzer-Campus 1, Munster 48149, Germany

Magyar Honvedseg Honvedkorhaz, Onkologiai Osztaly, Budapest H-1062, Hungary

Jasz-Nagykun-Szolnok Megyei Hetenyi Geza Korhaz-Rendelointezet, Megyei Onkologiai Kozpont, Szolnok H-5004, Hungary

Centro di Riferimento Oncologico (CRO), Aviano 33081, Italy

Azienda Ospedaliera Garibaldi, Catania 95122, Italy

Azienda Ospedaliero Universitaria-Policlinico Paolo Giacco, Palermo 90127, Italy

ASL TO/2 di TORINO_Presidio Sanitario Gradenigo, S.C. di Oncologia, Torino 10149, Italy

Wojewodzkie Centrum Onkologii, Gdansk 80-219, Poland

Centrum Onkologii Instytut im M. Sklodowskiej-Curie, Krakow 31-115, Poland

Centrum Onkologii-Instytut im. M. Sklodowskiej-Curie, Warszawa 02-781, Poland

GUZ "Regional Oncology Dispensay", Kazan, Kazan 420029, Russian Federation

FGU Moscow Research Institute of Oncology named after P.A. Hertzen of Rosmedtechnology, Moscow 125284, Russian Federation

ROTSN RAMS them. Н.Н.Блохина NN Blokhin, Moscow 115478, Russian Federation

Hospital de la Santa Creu i Sant Pau, Barcelona 08041, Spain

Hospital Sant Joan de Deu, Department de Oncologia, Barcelona 08950, Spain

Institut Catala d'Oncologia, Barcelona 08907, Spain

Hospital Universitario Ramón y Cajal., Madrid 28034, Spain

Universidad Complutense Madrid Facultad de Medicina - Hospital Universitario 12 de Octubre, Servicio de Oncologia Medica Hospital Universitario 12 de Octubre, Madrid 28034, Spain

Mayo Arizona, Scottsdale, Arizona 85259, United States

Arizona Cancer Center, Tucson, Arizona 85719, United States

University of California, Los Angeles, Los Angeles, California 90095-6901, United States

USC-Norris Comprehensive Cancer Center, Los Angeles, California 90033, United States

Sarcoma Oncology Center, Santa Monica, California 90403, United States

Stanford Comprehensive Cancer Center, Stanford, California 94305, United States

H.U. Canarias, Hospital Universitario de Canarias. Servicio de Oncología Médica, Tenerife, Canarias 38320, Spain

University Hospital Herlev at Copenhagen, Herlev, Copenhagen 2730, Denmark

Georgetown University Hospital, Washington, District of Columbia 20007, United States

Washington Cancer Institute, Washington, District of Columbia 20010, United States

South Florida Center for Gynecologic Oncology, Boca Raton, Florida 33487, United States

Mayo Clinic-Florida-Cancer Clinical Studies Unit, Jacksonville, Florida 32224, United States

MD Anderson Cancer Center Orlando, Orlando, Florida 32806, United States

H.Lee Moffitt Cancer Center and Research Institute, Tampa, Florida 33612, United States

Winship Cancer Institute of Emory University, Midtown Campus, Atlanta, Georgia 30322, United States

Kootenai Health - Kootenai Cancer Center, Coeur d`Alene, Idaho 83814, United States

Northwestern University, Chicago, Illinois 60611, United States

Rush University Medical Center, Chicago, Illinois 60612, United States

Oncology Specialists, Park Ridge, Illinois 60068, United States

Indiana University Simon Cancer Center, Indianapolis, Indiana 46202, United States

University of Iowa Health Care - University of Iowa Hospital, Iowa City, Iowa 52242, United States

Sharette Institute of Oncology, Hadassah-Hebrew University Medical Center, Hadassah Medical Org-Ein Karem, Kiryat Hadassah, Jerusalem 91120, Israel

Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins Hospital, Baltimore, Maryland 21287, United States

Dana Farber Cancer Institute Center for Sarcoma and Bone Oncology, Boston, Massachusetts 02215, United States

University of Michigan Cancer Center, Ann Arbor, Michigan 48109, United States

Mayo Rochester, Rochester, Minnesota 55905, United States

Washington University School of Medicine, St. Louis, Missouri 63110, United States

ICO Rene Gauducheau, Saint Herblain Cedex, Nantes 44805, France

Montefiore, Bronx, New York 10461, United States

Roswell Park Cancer Institute, Buffalo, New York 14263, United States

Memorial Sloan-Kettering Cancer Center, New York, New York 10031, United States

Columbia University Medical Center, NY, New York 10032, United States

Carolinas Hematology-oncology Associates-Blumenthal Cancer Center, Charlotte, North Carolina 28203, United States

Duke University Medical Center, Durham, North Carolina 27710, United States

Wake Forest University Baptist Medical Center, Winston Salem, North Carolina 27157, United States

Cleveland Clinic Foundation, Cleveland, Ohio 44195, United States

University Hospitals Seidman Cancer Center, Cleveland, Ohio 44106, United States

The Arthur G. James Cancer Hospital and Richard J Solove Research Institue, The Ohio State University Comprehensive Cancer Center, Columbus, Ohio 43202, United States

Juravinski Cancer Centre at Hamilton Health Sciences - Department of Medicine, Hamilton, Ontario L8V5C2, Canada

Oregon Health and Science University, Portland, Oregon 97239, United States

Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, United States

Pennsylvania Oncology Hematology Associates, Philadelphia, Pennsylvania 19106, United States

University of Pittsburg Medical Center, Pittsburg, Pennsylvania 15232, United States

IRCCS Centro di Riferimento Oncologico-Struttura Operativa, Aviano, Pordenone 33081, Italy

McGill University Health Centre, Montreal, Quebec H3G 1A4, Canada

MUSC - Hollings Cancer Center, Charleston, South Carolina 29425, United States

Vanderbilt-Ingram Cancer Center, Nashville, Tennessee 37232, United States

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, Candiolo, Torino 10060, Italy

University of Vermont, Burlington, Vermont 05405, United States

Virginia Commonwealth Universtiy-Massey Cancer Center, Richmond, Virginia 23298, United States

University of Washington Cancer Center, Seattle, Washington 98109, United States

Medical College of Wisconsin, Milwaukee, Wisconsin 53226, United States

Additional Information

Starting date: September 2011
Last updated: March 6, 2014

Page last updated: August 20, 2015

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