A Trial of TH-302 in Combination With Doxorubicin Versus Doxorubicin Alone to Treat Patients 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 sarcoma.

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