A Trial of TH-302 in Combination With Doxorubicin Versus Doxorubicin Alone to Treat Patients With Locally Advanced Unresectable or Metastatic Soft Tissue Sarcoma

Threshold Pharmaceuticals

Status and phase

Completed

Phase 3

Conditions

Soft Tissue Sarcoma

Treatments

Drug: Doxorubicin

Drug: TH-302 in Combination with Doxorubicin

Study type

Interventional

Funder types

Industry

Other

Identifiers

NCT01440088

TH-CR-406/SARC021

Details and patient eligibility

About

The purpose of this study is to determine whether TH-302 in combination with Doxorubicin is safe and effective in the treatment of Locally Advanced Unresectable or Metastatic Soft Tissue Sarcoma.

Full description

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.

Enrollment

640 patients

Sex

All

Ages

15+ years old

Volunteers

No Healthy Volunteers

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