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

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 infection