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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

Phase 3
15 Years
Open (Enrolling)
Soft Tissue Sarcoma

Thank you

Trial Information

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

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

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

- 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)

- 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)

- 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

- 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

Type of Study:


Study Design:

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

Outcome Measure:

Efficacy of TH-302 in combination with doxorubicin

Outcome Description:

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

Outcome Time Frame:

2 years

Safety Issue:


Principal Investigator

William Tap, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Memorial Sloan-Kettering Cancer Center


United States: Food and Drug Administration

Study ID:




Start Date:

September 2011

Completion Date:

April 2015

Related Keywords:

  • Soft Tissue Sarcoma
  • TH-302
  • TH-CR-406
  • SARC021
  • Locally Advanced Soft Tissue Sarcoma
  • Metastatic Soft Tissue Sarcoma
  • Sarcoma
  • Doxorubicin
  • Sarcoma



Arizona Cancer CenterTucson, Arizona  85724
Cleveland Clinic FoundationCleveland, Ohio  44195
Roswell Park Cancer InstituteBuffalo, New York  14263
Memorial Sloan-Kettering Cancer CenterNew York, New York  10021
Washington University School of MedicineSaint Louis, Missouri  63110
Fox Chase Cancer CenterPhiladelphia, Pennsylvania  19111
Vanderbilt-Ingram Cancer CenterNashville, Tennessee  37232-6838
Medical College of WisconsinMilwaukee, Wisconsin  53226
Rush University Medical CenterChicago, Illinois  60612-3824
Georgia Cancer SpecialistsDecatur, Georgia  30033
Washington Cancer InstituteWashington, District of Columbia  20010
Pennsylvania Oncology Hematology AssociatesPhiladelphia, Pennsylvania  19107
Duke University Medical CenterDurham, North Carolina  27710
Northwestern UniversityChicago, Illinois  60611
Case Western Reserve UniversityCleveland, Ohio  44106
University of Michigan Cancer CenterAnn Arbor, Michigan  48109
University Of VermontBurlington,, Vermont  05403
University of California, Los AngelesLos Angeles, California  
Oregon Health and Science UniversityPortland, Oregon  97201
Georgetown University HospitalWashington, District of Columbia  20007
Columbia University Medical CenterNew York, New York  10032
Oncology SpecialistsPark Ridge, Illinois  60068
Wake Forest University Baptist Medical CenterWinston-Salem, North Carolina  27157
Stanford Comprehensive Cancer CenterStanford, California  94305
Sarcoma Oncology CenterSanta Monica, California  90403
MUSC - Hollings Cancer CenterCharleston, South Carolina  29425
Indiana University Simon Cancer CenterIndianapolis, Indiana  46202
University of Pittsburg Medical CenterPittsburg, Pennsylvania  15213
South Florida Center for Gynecologic OncologyBoca Raton, Florida  33487
Mayo ArizonaScottsdale, Arizona  85259
USC-Norris Comprehensive Cancer CenterLos Angeles, California  90033
Mayo Clinic-Florida-Cancer Clinical Studies UnitJacksonville, Florida  32224
H.Lee Moffitt Cancer Center and Research InstituteTampa, Florida  33612
Winship Cancer Institute of Emory University, Midtown CampusAtlanta, Georgia  30322
Kootenai Health - Kootenai Cancer CenterCoeur d`Alene, Idaho  83814
University of Iowa Health Care - University of Iowa HospitalIowa City, Iowa  52242
Dana Farber Cancer Institute Center for Sarcoma and Bone OncologyBoston, Massachusetts  02215
Mayo RochesterRochester, Minnesota  55905
MontefioreBronx, New York  10461
Virginia Commonwealth Universtiy-Massey Cancer CenterRichmond, Virginia  23298
University of Washington Cancer CenterSeattle, Washington  98109
Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins HospitalBaltimore, Maryland  21287
Carolinas Hematology-oncology Associates-Blumenthal Cancer CenterCharlotte, North Carolina  28203
The Arthur G. James Cancer Hospital and Richard J Solove Research Institue, The Ohio State University Comprehensive Cancer CenterColumbus, Ohio