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Clinical Trial Details — Status: Completed

Administrative data

NCT number NCT01440088
Other study ID # TH-CR-406/SARC021
Secondary ID
Status Completed
Phase Phase 3
First received September 20, 2011
Last updated June 1, 2016
Start date September 2011
Est. completion date May 2016

Study information

Verified date June 2016
Source Threshold Pharmaceuticals
Contact n/a
Is FDA regulated No
Health authority
Study type Interventional

Clinical Trial Summary

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.


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.


Recruitment information / eligibility

Status Completed
Enrollment 640
Est. completion date May 2016
Est. primary completion date December 2015
Accepts healthy volunteers No
Gender All
Age group 15 Years and older
Eligibility 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 Design


Related Conditions & MeSH terms


Intervention

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.
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.

Locations

Country Name City State
Austria University Klinikum Graz Graz
Austria Univ. Klinik fur Innere Medizin I Internistische Onkologie Medizinische Universitat Innsbruck Innsbruck
Austria Allgemeines Krankenhaus Wien Wien
Belgium Universitaire Ziekenhuizen (UZ) Leuven - Gasthuisberg Leuven
Canada Tom Baker Cancer Centre Calgary
Canada Cross Cancer Institute Edmonton
Canada Juravinski Cancer Centre at Hamilton Health Sciences - Department of Medicine Hamilton Ontario
Canada McGill University Health Centre Montreal Quebec
Canada Ottawa Health Research Institue Ottawa
Canada BCCA- Vancouver Cancer Centre - Division of Medical Oncology Vancouver
Canada Cancer Care Manitoba Winnipeg
Denmark University Hospital Herlev at Copenhagen Herlev Copenhagen
France Institut Bergonie Bordeaux
France Departement d'Oncologie Medicale Dijon
France Centre Leon Berard Lyon
France Département d'Oncologie Moléculaire, Institut Paoli-Calmettes (IPC) and U119 Inserm Marseille
France Centre Antoine Lacassagne Nice
France ICO Rene Gauducheau Saint Herblain Cedex Nantes
France CHU Strasbourg Strasbourg
France Institut Claudius Regaud Toulouse Cedex
Germany Helios Klinikum Bad Saarow, Department of Hematology, Oncology, and Palliative Care, Sarcoma Center Berlin-Brandenburg Berlin
Germany HELIOS Klinikum Berlin-Buch Berlin
Germany Universitätsklinikum Essen Essen
Germany Krankenhaus Nordwest GmbH Frankfurt
Germany Medizinische Hochschule Hannover (MHH) - Klinik fuer Haemonstaseologie, Onkologie und Stammzelltransplantation Hannover
Germany Div. of Surgical Oncology & Thoracic Surgery, Mannheim University Medical Center Mannheim
Germany Wilhelm's University, Universitatsklinikum Muenster, Medizinische Klinik und Poliklinik A, Albert-Schweitzer-Campus 1 Munster
Hungary Magyar Honvedseg Honvedkorhaz, Onkologiai Osztaly Budapest
Hungary Jasz-Nagykun-Szolnok Megyei Hetenyi Geza Korhaz-Rendelointezet, Megyei Onkologiai Kozpont Szolnok
Israel Sharette Institute of Oncology, Hadassah-Hebrew University Medical Center, Hadassah Medical Org-Ein Karem Kiryat Hadassah Jerusalem
Italy Centro di Riferimento Oncologico (CRO) Aviano
Italy IRCCS Centro di Riferimento Oncologico-Struttura Operativa Aviano Pordenone
Italy 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
Italy Azienda Ospedaliera Garibaldi Catania
Italy Azienda Ospedaliero Universitaria-Policlinico Paolo Giacco Palermo
Italy ASL TO/2 di TORINO_Presidio Sanitario Gradenigo, S.C. di Oncologia Torino
Poland Wojewodzkie Centrum Onkologii Gdansk
Poland Centrum Onkologii Instytut im M. Sklodowskiej-Curie Krakow
Poland Centrum Onkologii-Instytut im. M. Sklodowskiej-Curie Warszawa
Russian Federation GUZ "Regional Oncology Dispensay", Kazan Kazan
Russian Federation FGU Moscow Research Institute of Oncology named after P.A. Hertzen of Rosmedtechnology Moscow
Russian Federation ROTSN RAMS them. ?.?.??????? NN Blokhin Moscow
Spain Hospital de la Santa Creu i Sant Pau Barcelona
Spain Hospital Sant Joan de Deu, Department de Oncologia Barcelona
Spain Institut Catala d'Oncologia Barcelona
Spain Hospital Universitario Ramón y Cajal. Madrid
Spain Universidad Complutense Madrid Facultad de Medicina - Hospital Universitario 12 de Octubre, Servicio de Oncologia Medica Hospital Universitario 12 de Octubre Madrid
Spain H.U. Canarias, Hospital Universitario de Canarias. Servicio de Oncología Médica Tenerife Canarias
United States University of Michigan Cancer Center Ann Arbor Michigan
United States Winship Cancer Institute of Emory University, Midtown Campus Atlanta Georgia
United States Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins Hospital Baltimore Maryland
United States South Florida Center for Gynecologic Oncology Boca Raton Florida
United States Dana Farber Cancer Institute Center for Sarcoma and Bone Oncology Boston Massachusetts
United States Montefiore Bronx New York
United States Roswell Park Cancer Institute Buffalo New York
United States University of Vermont Burlington Vermont
United States MUSC - Hollings Cancer Center Charleston South Carolina
United States Carolinas Hematology-oncology Associates-Blumenthal Cancer Center Charlotte North Carolina
United States Northwestern University Chicago Illinois
United States Rush University Medical Center Chicago Illinois
United States Cleveland Clinic Foundation Cleveland Ohio
United States University Hospitals Seidman Cancer Center Cleveland Ohio
United States Kootenai Health - Kootenai Cancer Center Coeur d`Alene Idaho
United States The Arthur G. James Cancer Hospital and Richard J Solove Research Institue, The Ohio State University Comprehensive Cancer Center Columbus Ohio
United States Duke University Medical Center Durham North Carolina
United States Indiana University Simon Cancer Center Indianapolis Indiana
United States University of Iowa Health Care - University of Iowa Hospital Iowa City Iowa
United States Mayo Clinic-Florida-Cancer Clinical Studies Unit Jacksonville Florida
United States University of California, Los Angeles Los Angeles California
United States USC-Norris Comprehensive Cancer Center Los Angeles California
United States Medical College of Wisconsin Milwaukee Wisconsin
United States Vanderbilt-Ingram Cancer Center Nashville Tennessee
United States Memorial Sloan-Kettering Cancer Center New York New York
United States Columbia University Medical Center NY New York
United States MD Anderson Cancer Center Orlando Orlando Florida
United States Oncology Specialists Park Ridge Illinois
United States Fox Chase Cancer Center Philadelphia Pennsylvania
United States Pennsylvania Oncology Hematology Associates Philadelphia Pennsylvania
United States University of Pittsburg Medical Center Pittsburg Pennsylvania
United States Oregon Health and Science University Portland Oregon
United States Virginia Commonwealth Universtiy-Massey Cancer Center Richmond Virginia
United States Mayo Rochester Rochester Minnesota
United States Sarcoma Oncology Center Santa Monica California
United States Mayo Arizona Scottsdale Arizona
United States University of Washington Cancer Center Seattle Washington
United States Washington University School of Medicine St. Louis Missouri
United States Stanford Comprehensive Cancer Center Stanford California
United States H.Lee Moffitt Cancer Center and Research Institute Tampa Florida
United States Arizona Cancer Center Tucson Arizona
United States Georgetown University Hospital Washington District of Columbia
United States Washington Cancer Institute Washington District of Columbia
United States Wake Forest University Baptist Medical Center Winston Salem North Carolina

Sponsors (2)

Lead Sponsor Collaborator
Threshold Pharmaceuticals Sarcoma Alliance for Research through Collaboration (SARC)

Countries where clinical trial is conducted

United States,  Austria,  Belgium,  Canada,  Denmark,  France,  Germany,  Hungary,  Israel,  Italy,  Poland,  Russian Federation,  Spain, 

Outcome

Type Measure Description Time frame Safety issue
Primary 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 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
See also
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