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

Soft Tissue Sarcoma Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01440088
• Other study ID #: TH-CR-406/SARC021
• 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
• 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

Related Conditions & MeSH terms

• Sarcoma
• Soft Tissue Sarcoma

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