A Phase 1/2, Multicenter, Dose-Escalation Study to Determine the Safety, Efficacy and Pharmacokinetics of TH-302 in Combination With Doxorubicin in Patients With Advanced Soft Tissue Sarcoma

Inclusion Criteria

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