Clinical trial NCT01440088: A Trial of TH-302 in Combination With Doxorubicin Versus Doxorubicin Alone to Treat Patients With Locally Advanced Unresectable or Metastatic Soft Tissue Sarcoma
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 type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Soft Tissue Sarcoma
Keywords: TH-302
TH-CR-406
SARC021
Locally Advanced Soft Tissue Sarcoma
Metastatic Soft Tissue Sarcoma
Sarcoma
Doxorubicin
Evofosfamide
Lead sponsor: Threshold Pharmaceuticals
Sponsor class: INDUSTRY
Collaborators: name: Sarcoma Alliance for Research through Collaboration (SARC)
First posted: 2011-09-26
Enrollment: 640
Sex: ALL
Minimum age (years): 15
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Efficacy of TH-302 in combination with doxorubicin
timeFrame: 2 years
Secondary outcomes:
measure: Safety of TH-302 in combination with doxorubicin in subjects with locally advanced unresectable or metastatic soft tissue sarcoma compared with doxorubicin alone
timeFrame: 2 years
Other outcomes:
Locations:
city: Scottsdale
country: United States
facility: Mayo Arizona
state: Arizona
city: Tucson
country: United States
facility: Arizona Cancer Center
state: Arizona
city: Los Angeles
country: United States
facility: USC-Norris Comprehensive Cancer Center
state: California
city: Los Angeles
country: United States
facility: University of California, Los Angeles
state: California
city: Santa Monica
country: United States
facility: Sarcoma Oncology Center
state: California
city: Stanford
country: United States
facility: Stanford Comprehensive Cancer Center
state: California
city: Washington
country: United States
facility: Georgetown University Hospital
state: District of Columbia
city: Washington
country: United States
facility: Washington Cancer Institute
state: District of Columbia
city: Boca Raton
country: United States
facility: South Florida Center for Gynecologic Oncology
state: Florida
city: Jacksonville
country: United States
facility: Mayo Clinic-Florida-Cancer Clinical Studies Unit
state: Florida
city: Orlando
country: United States
facility: MD Anderson Cancer Center Orlando
state: Florida
city: Tampa
country: United States
facility: H.Lee Moffitt Cancer Center and Research Institute
state: Florida
city: Atlanta
country: United States
facility: Winship Cancer Institute of Emory University, Midtown Campus
state: Georgia
city: Coeur d'Alene
country: United States
facility: Kootenai Health - Kootenai Cancer Center
state: Idaho
city: Chicago
country: United States
facility: Northwestern University
state: Illinois
city: Chicago
country: United States
facility: Rush University Medical Center
state: Illinois
city: Park Ridge
country: United States
facility: Oncology Specialists
state: Illinois
city: Indianapolis
country: United States
facility: Indiana University Simon Cancer Center
state: Indiana
city: Iowa City
country: United States
facility: University of Iowa Health Care - University of Iowa Hospital
state: Iowa
city: Baltimore
country: United States
facility: Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins Hospital
state: Maryland
city: Boston
country: United States
facility: Dana Farber Cancer Institute Center for Sarcoma and Bone Oncology
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan Cancer Center
state: Michigan
city: Rochester
country: United States
facility: Mayo Rochester
state: Minnesota
city: St. Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: Bronx
country: United States
facility: Montefiore
state: New York
city: Buffalo
country: United States
facility: Roswell Park Cancer Institute
state: New York
city: New York
country: United States
facility: Memorial Sloan-Kettering Cancer Center
state: New York
city: NY
country: United States
facility: Columbia University Medical Center
state: New York
city: Charlotte
country: United States
facility: Carolinas Hematology-oncology Associates-Blumenthal Cancer Center
state: North Carolina
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
city: Winston Salem
country: United States
facility: Wake Forest University Baptist Medical Center
state: North Carolina
city: Cleveland
country: United States
facility: University Hospitals Seidman Cancer Center
state: Ohio
city: Cleveland
country: United States
facility: Cleveland Clinic Foundation
state: Ohio
city: Columbus
country: United States
facility: The Arthur G. James Cancer Hospital and Richard J Solove Research Institue, The Ohio State University Comprehensive Cancer Center
state: Ohio
city: Portland
country: United States
facility: Oregon Health and Science University
state: Oregon
city: Philadelphia
country: United States
facility: Pennsylvania Oncology Hematology Associates
state: Pennsylvania
city: Philadelphia
country: United States
facility: Fox Chase Cancer Center
state: Pennsylvania
city: Pittsburg
country: United States
facility: University of Pittsburg Medical Center
state: Pennsylvania
city: Charleston
country: United States
facility: MUSC - Hollings Cancer Center
state: South Carolina
city: Nashville
country: United States
facility: Vanderbilt-Ingram Cancer Center
state: Tennessee
city: Burlington
country: United States
facility: University of Vermont
state: Vermont
city: Richmond
country: United States
facility: Virginia Commonwealth Universtiy-Massey Cancer Center
state: Virginia
city: Seattle
country: United States
facility: University of Washington Cancer Center
state: Washington
city: Milwaukee
country: United States
facility: Medical College of Wisconsin
state: Wisconsin
city: Graz
country: Austria
facility: University Klinikum Graz
city: Innsbruck
country: Austria
facility: Univ. Klinik fur Innere Medizin I Internistische Onkologie Medizinische Universitat Innsbruck
city: Wien
country: Austria
facility: Allgemeines Krankenhaus Wien
city: Leuven
country: Belgium
facility: Universitaire Ziekenhuizen (UZ) Leuven - Gasthuisberg
city: Hamilton
country: Canada
facility: Juravinski Cancer Centre at Hamilton Health Sciences - Department of Medicine
state: Ontario
city: Montreal
country: Canada
facility: McGill University Health Centre
state: Quebec
city: Calgary
country: Canada
facility: Tom Baker Cancer Centre
city: Edmonton
country: Canada
facility: Cross Cancer Institute
city: Ottawa
country: Canada
facility: Ottawa Health Research Institue
city: Vancouver
country: Canada
facility: BCCA- Vancouver Cancer Centre - Division of Medical Oncology
city: Winnipeg
country: Canada
facility: Cancer Care Manitoba
city: Herlev
country: Denmark
facility: University Hospital Herlev at Copenhagen
state: Copenhagen
city: Saint Herblain Cedex
country: France
facility: ICO Rene Gauducheau
state: Nantes
city: Bordeaux
country: France
facility: Institut Bergonie
city: Dijon
country: France
facility: Departement d'Oncologie Medicale
city: Lyon
country: France
facility: Centre Leon Berard
city: Marseille
country: France
facility: Département d'Oncologie Moléculaire, Institut Paoli-Calmettes (IPC) and U119 Inserm
city: Nice
country: France
facility: Centre Antoine Lacassagne
city: Strasbourg
country: France
facility: CHU Strasbourg
city: Toulouse Cedex
country: France
facility: Institut Claudius Regaud
city: Berlin
country: Germany
facility: HELIOS Klinikum Berlin-Buch
city: Berlin
country: Germany
facility: Helios Klinikum Bad Saarow, Department of Hematology, Oncology, and Palliative Care, Sarcoma Center Berlin-Brandenburg
city: Essen
country: Germany
facility: Universitätsklinikum Essen
city: Frankfurt
country: Germany
facility: Krankenhaus Nordwest GmbH
city: Hannover
country: Germany
facility: Medizinische Hochschule Hannover (MHH) - Klinik fuer Haemonstaseologie, Onkologie und Stammzelltransplantation
city: Mannheim
country: Germany
facility: Div. of Surgical Oncology & Thoracic Surgery, Mannheim University Medical Center
city: Munster
country: Germany
facility: Wilhelm's University, Universitatsklinikum Muenster, Medizinische Klinik und Poliklinik A, Albert-Schweitzer-Campus 1
city: Budapest
country: Hungary
facility: Magyar Honvedseg Honvedkorhaz, Onkologiai Osztaly
city: Szolnok
country: Hungary
facility: Jasz-Nagykun-Szolnok Megyei Hetenyi Geza Korhaz-Rendelointezet, Megyei Onkologiai Kozpont
city: Kiryat Hadassah
country: Israel
facility: Sharette Institute of Oncology, Hadassah-Hebrew University Medical Center, Hadassah Medical Org-Ein Karem
state: Jerusalem
city: Aviano
country: Italy
facility: IRCCS Centro di Riferimento Oncologico-Struttura Operativa
state: Pordenone
city: Candiolo
country: Italy
facility: 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
state: Torino
city: Aviano
country: Italy
facility: Centro di Riferimento Oncologico (CRO)
city: Catania
country: Italy
facility: Azienda Ospedaliera Garibaldi
city: Palermo
country: Italy
facility: Azienda Ospedaliero Universitaria-Policlinico Paolo Giacco
city: Torino
country: Italy
facility: ASL TO/2 di TORINO_Presidio Sanitario Gradenigo, S.C. di Oncologia
city: Gdansk
country: Poland
facility: Wojewodzkie Centrum Onkologii
city: Krakow
country: Poland
facility: Centrum Onkologii Instytut im M. Sklodowskiej-Curie
city: Warszawa
country: Poland
facility: Centrum Onkologii-Instytut im. M. Sklodowskiej-Curie
city: Kazan
country: Russian Federation
facility: GUZ "Regional Oncology Dispensay", Kazan
city: Moscow
country: Russian Federation
facility: ROTSN RAMS them. Н.Н.Блохина NN Blokhin
city: Moscow
country: Russian Federation
facility: FGU Moscow Research Institute of Oncology named after P.A. Hertzen of Rosmedtechnology
city: Tenerife
country: Spain
facility: H.U. Canarias, Hospital Universitario de Canarias. Servicio de Oncología Médica
state: Canarias
city: Barcelona
country: Spain
facility: Hospital de la Santa Creu i Sant Pau
city: Barcelona
country: Spain
facility: Institut Catala d'Oncologia
city: Barcelona
country: Spain
facility: Hospital Sant Joan de Deu, Department de Oncologia
city: Madrid
country: Spain
facility: Hospital Universitario Ramón y Cajal.
city: Madrid
country: Spain
facility: Universidad Complutense Madrid Facultad de Medicina - Hospital Universitario 12 de Octubre, Servicio de Oncologia Medica Hospital Universitario 12 de Octubre
Study officials:
affiliation: Memorial Sloan Kettering Cancer Center
name: William Tap, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.