Vanderbilt-Ingram Cancer Center

You are being asked to take part in this research study because you have advanced soft tissue sarcoma. Your doctor plans to treat this with doxorubicin (a chemotherapy drug). Researchers want to find out if an investigational drug called TH-302 can help patients with advanced soft tissue sarcoma when it is combined with doxorubicin. The purpose of this study is to gather information on the safety and effect on your cancer of TH-302 in combination with doxorubicin. The study will also look at how the drug is processed in the body. TH-302 is an investigational drug that is being tested and is not approved for sale in the United States by the U.S. Food and Drug Administration (-FDA) or any other government authority. The safety and effectiveness of an -investigational drug- is still under investigation. Doxorubicin has been approved by the FDA in the United States for treatment of Soft Tissue Sarcoma. TH-302 is a prodrug that, after activation, produces a chemotherapy drug that damages or kills cancer cells and other cells that are nearby. TH-302 is activated in parts of the body that are low in oxygen (hypoxic). Most normal cells are not low in oxygen but cancers often have large areas that are low in oxygen. Cancer cells that are low in oxygen often are not killed effectively by standard chemotherapy or radiation treatment. TH-302 may kill tumor cells that are low in oxygen without causing excessive damage to cells with normal levels of oxygen. However, it is possible that normal cells may also be killed by TH-302. It is hoped that combining TH-302 with standard chemotherapy, the cancer cells that are low in oxygen as well as the cancer cells that have normal levels of oxygen will be killed. A company called Threshold Pharmaceuticals, Inc. is the sponsor of the study. It is planned that up to 450 patients with soft tissue sarcoma who are at least 15 years old will be enrolled in this study. Up to 12 patients will take part at Vanderbilt.

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)

 • 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 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