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

NCT ID: NCT01440088

Last Updated: 2016-06-02

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 640 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2011-09-30
• Study Completion Date: 2016-05-31

Brief 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.

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.

Conditions

Soft Tissue Sarcoma

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

TH-302 in Combination with Doxorubicin

Group Type: EXPERIMENTAL

TH-302 in Combination with Doxorubicin

Intervention Type: DRUG

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

Group Type: ACTIVE_COMPARATOR

Doxorubicin

Intervention Type: DRUG

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.

Interventions

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.

Intervention Type: 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.

Intervention Type: DRUG

Eligibility Criteria

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

• Minimum Eligible Age: 15 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Sarcoma Alliance for Research through Collaboration (SARC)

UNKNOWN

Sponsor Role: collaborator

Threshold Pharmaceuticals

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

William Tap, MD

Role: PRINCIPAL_INVESTIGATOR

Memorial Sloan Kettering Cancer Center

Locations

Mayo Arizona

Scottsdale, Arizona, United States

Arizona Cancer Center

Tucson, Arizona, United States

USC-Norris Comprehensive Cancer Center

Los Angeles, California, United States

University of California, Los Angeles

Los Angeles, California, United States

Sarcoma Oncology Center

Santa Monica, California, United States

Stanford Comprehensive Cancer Center

Stanford, California, United States

Georgetown University Hospital

Washington D.C., District of Columbia, United States

Washington Cancer Institute

Washington D.C., District of Columbia, United States

South Florida Center for Gynecologic Oncology

Boca Raton, Florida, United States

Mayo Clinic-Florida-Cancer Clinical Studies Unit

Jacksonville, Florida, United States

MD Anderson Cancer Center Orlando

Orlando, Florida, United States

H.Lee Moffitt Cancer Center and Research Institute

Tampa, Florida, United States

Winship Cancer Institute of Emory University, Midtown Campus

Atlanta, Georgia, United States

Kootenai Health - Kootenai Cancer Center

Coeur d'Alene, Idaho, United States

Northwestern University

Chicago, Illinois, United States

Rush University Medical Center

Chicago, Illinois, United States

Oncology Specialists

Park Ridge, Illinois, 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

Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins Hospital

Baltimore, Maryland, United States

Dana Farber Cancer Institute Center for Sarcoma and Bone Oncology

Boston, Massachusetts, United States

University of Michigan Cancer Center

Ann Arbor, Michigan, United States

Mayo Rochester

Rochester, Minnesota, United States

Washington University School of Medicine

St Louis, Missouri, United States

Roswell Park Cancer Institute

Buffalo, New York, United States

Memorial Sloan-Kettering Cancer Center

New York, New York, United States

Columbia University Medical Center

New York, New York, United States

Montefiore

The Bronx, New York, United States

Carolinas Hematology-oncology Associates-Blumenthal Cancer Center

Charlotte, North Carolina, United States

Duke University Medical Center

Durham, North Carolina, United States

Wake Forest University Baptist Medical Center

Winston-Salem, North Carolina, United States

University Hospitals Seidman Cancer Center

Cleveland, Ohio, United States

Cleveland Clinic Foundation

Cleveland, Ohio, 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

Oregon Health and Science University

Portland, Oregon, United States

Pennsylvania Oncology Hematology Associates

Philadelphia, Pennsylvania, United States

Fox Chase Cancer Center

Philadelphia, Pennsylvania, United States

University of Pittsburg Medical Center

Pittsburgh, Pennsylvania, United States

MUSC - Hollings Cancer Center

Charleston, South Carolina, United States

Vanderbilt-Ingram Cancer Center

Nashville, Tennessee, United States

University of Vermont

Burlington, Vermont, United States

Virginia Commonwealth Universtiy-Massey Cancer Center

Richmond, Virginia, United States

University of Washington Cancer Center

Seattle, Washington, United States

Medical College of Wisconsin

Milwaukee, Wisconsin, United States

University Klinikum Graz

Graz, , Austria

Univ. Klinik fur Innere Medizin I Internistische Onkologie Medizinische Universitat Innsbruck

Innsbruck, , Austria

Allgemeines Krankenhaus Wien

Vienna, , Austria

Universitaire Ziekenhuizen (UZ) Leuven - Gasthuisberg

Leuven, , Belgium

Juravinski Cancer Centre at Hamilton Health Sciences - Department of Medicine

Hamilton, Ontario, Canada

McGill University Health Centre

Montreal, Quebec, Canada

Tom Baker Cancer Centre

Calgary, , Canada

Cross Cancer Institute

Edmonton, , Canada

Ottawa Health Research Institue

Ottawa, , Canada

BCCA- Vancouver Cancer Centre - Division of Medical Oncology

Vancouver, , Canada

Cancer Care Manitoba

Winnipeg, , Canada

University Hospital Herlev at Copenhagen

Herlev, Copenhagen, Denmark

ICO Rene Gauducheau

Saint-Herblain, Nantes, 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

CHU Strasbourg

Strasbourg, , France

Institut Claudius Regaud

Toulouse, , France

HELIOS Klinikum Berlin-Buch

Berlin, , Germany

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

Berlin, , Germany

Universitätsklinikum Essen

Essen, , Germany

Krankenhaus Nordwest GmbH

Frankfurt, , Germany

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

Hanover, , 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

Münster, , Germany

Magyar Honvedseg Honvedkorhaz, Onkologiai Osztaly

Budapest, , Hungary

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

Szolnok, , Hungary

Sharette Institute of Oncology, Hadassah-Hebrew University Medical Center, Hadassah Medical Org-Ein Karem

Kiryat Hadassah, Jerusalem, Israel

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

Centro di Riferimento Oncologico (CRO)

Aviano, , 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, , Italy

Wojewodzkie Centrum Onkologii

Gdansk, , Poland

Centrum Onkologii Instytut im M. Sklodowskiej-Curie

Krakow, , Poland

Centrum Onkologii-Instytut im. M. Sklodowskiej-Curie

Warsaw, , Poland

GUZ "Regional Oncology Dispensay", Kazan

Kazan', , Russia

ROTSN RAMS them. Н.Н.Блохина NN Blokhin

Moscow, , Russia

FGU Moscow Research Institute of Oncology named after P.A. Hertzen of Rosmedtechnology

Moscow, , Russia

H.U. Canarias, Hospital Universitario de Canarias. Servicio de Oncología Médica

Santa Cruz de Tenerife, Canary Islands, Spain

Hospital de la Santa Creu i Sant Pau

Barcelona, , Spain

Institut Catala d'Oncologia

Barcelona, , Spain

Hospital Sant Joan de Deu, Department de 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

Countries

United States; Austria; Belgium; Canada; Denmark; France; Germany; Hungary; Israel; Italy; Poland; Russia; Spain

References

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.

Reference Type: DERIVED

PMID: 28651927 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 25185097 (View on PubMed)

Other Identifiers

TH-CR-406/SARC021

Identifier Type: -

Identifier Source: org_study_id