Dose-Escalation Study of TH-302 in Combination With Doxorubicin to Treat Patients With Advanced Soft Tissue Sarcoma

A broad range of tumors have been shown to contain significant numbers of hypoxic cells and
hypoxia has been shown to be associated with a poor prognosis and an increase in resistance
to chemotherapy and radiotherapy (Brizel 1997, Vaupel 2007, Shannon 2003).

It is likely that an agent that could effectively target hypoxic regions in tumors would
improve efficacy when combined with standard chemotherapy or radiotherapy. TH-302 is
activated at lower oxygen concentrations than other bioreductive prodrugs (Duan 2008) and
tirapazamine, a hypoxic cytotoxin that has been extensively studied in both preclinical and
clinical studies. This should result in an improved therapeutic ratio (tumor vs normal tissue
toxicity) as compared with other bioreductive agents. Because TH-302 is expected to be
minimally toxic to aerobic cancer cells, optimal efficacy would be expected when TH-302 is
combined with treatments that are most effective under aerobic conditions such as
radiotherapy and cytotoxic chemotherapy. Preclinical data have shown at least additive
efficacy when TH-302 is combined with chemotherapy. In order to minimize the risk of additive
toxicity, TH-302 is not being evaluated in combination with alkylating agents. The study will
enroll subjects with advanced soft tissue sarcoma. These tumors have evidence supporting the
presence of hypoxia based on pO2 histography, F-MISO and gene expression profiling (Vaupel
2007, Francis 2007, Rajendran 2003).

Inclusion Criteria

All Subjects:

- At least 18 years of age

- Ability to understand the purposes and risks of the study and 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 subtypes:

- Synovial sarcoma

- High grade fibrosarcoma

- Unclassified, undifferentiated sarcoma

- Liposarcoma

- Leiomyosarcoma (excluding GIST)

- Angiosarcoma (excluding Kaposi's sarcoma)

- Pleomorphic sarcoma/malignant fibrous histiocytoma

- Locally advanced unresectable or metastatic disease with no standard curative therapy
available and for whom treatment with single agent doxorubicin is considered
appropriate; subjects in the dose escalation cohorts must have progressed since their
most recent systemic therapy

- Recovered from reversible toxicities of prior therapy

- Evaluable disease by RECIST criteria (at least one target or non-target lesion for
dose escalation cohorts; at least 1 target lesion for dose expansion cohort)

- ECOG performance status of 0 or 1

- Life expectancy of at least 3 months

- Acceptable liver function:

- Bilirubin ≤ 1.5 times upper limit of normal (ULN)

- AST (SGOT) and ALT (SGPT) ≤ 2.5 times ULN

- Acceptable renal function:

- Serum creatinine within normal limits

- Acceptable hematologic status (without hematologic support):

- ANC ≥ 1500 cells/μL

- Platelet count ≥ 100,000/μL

- Hemoglobin ≥ 9.0 g/dL

- Acceptable cardiac function:

- Normal 12-lead ECG (clinically insignificant abnormalities permitted)

- LVEF normal by MUGA or echocardiogram

- Urinalysis: No clinically significant abnormalities

- All women of childbearing potential must have a negative serum pregnancy test and all
subjects must agree to use effective means of contraception (surgical sterilization or
the use or barrier contraception with either a condom or diaphragm in conjunction with
spermicidal gel or an IUD) with their partner from entry into the study through 6
months after the last dose

Exclusion Criteria

Prior therapy:

- Dose escalation cohort: Prior treatment with more than 2 myelosuppressive cytotoxic
chemotherapy regimens

- Expanded cohort: Prior systemic therapy for advanced disease (neoadjuvant and adjuvant
permitted)

- Low grade tumors according to standard grading systems (eg AJCC Grade 1 and 2)

- Prior therapy with ifosfamide or cyclophosphamide

- Prior therapy with an anthracycline or anthracenedione

- Prior mediastinal/cardiac radiotherapy

- Current use of drugs with known cardiotoxicity or known interactions with doxorubicin
(see product label)

- Anticancer treatment with radiation therapy, chemotherapy, targeted therapies
(erlotinib, lapatinib, etc.), immunotherapy, hormones or other antitumor therapies
within 4 weeks prior to study entry (6 weeks for nitrosoureas or mitomycin C)

- Significant cardiac dysfunction:

- Any history of congestive heart failure

- Any history of transmural myocardial infarction

- Uncontrolled arrhythmias within the past 6 months

- Angina pectoris requiring antianginal medication within the past 6 months

- Clinically significant valvular heart disease

- Poorly controlled hypertension within the last 6 months

- Seizure disorders requiring anticonvulsant therapy

- 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 (requires
supplementary oxygen, symptoms due to hypoxemia or oxygen saturation <90% by pulse
oximetry after a 2 minute walk) 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 an 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, biological
agent, or formulation (containing solutol and/or propylene glycol) similar to TH-302

- 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