- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT00742963
Dose-Escalation Study of TH-302 in Combination With Doxorubicin to Treat Patients With Advanced Soft Tissue Sarcoma
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
Study Overview
Detailed Description
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).
Study Type
Enrollment (Actual)
Phase
- Phase 2
- Phase 1
Contacts and Locations
Study Locations
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Arizona
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Tucson, Arizona, United States, 85719
- Arizona Cancer Center
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California
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Santa Monica, California, United States, 90403
- Sarcoma Oncology Center
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Stanford, California, United States, 94305
- Stanford University
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Florida
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Tampa, Florida, United States, 33612
- H. Lee Moffitt Cancer Center and Research Institute
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Indiana
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Indianapolis, Indiana, United States, 46204
- Indiana University Cancer Center
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Massachusetts
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Boston, Massachusetts, United States, 02115
- Dana Farber Cancer Institute
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Minnesota
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Rochester, Minnesota, United States, 55905
- Mayo Clinic Rochester
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Missouri
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Saint Louis, Missouri, United States, 63110
- Washingon University Siteman Cancer Center
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Texas
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Dallas, Texas, United States, 75201
- Mary Crowley Cancer Research Centers
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
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
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: N/A
- Interventional Model: Single Group Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
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Experimental: 1
75 mg/m2 of Doxorubicin administered by bolus injection starting on Day 1 of a 21-day cycle.
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TH-302 will be administered by IV infusion over 30-60 minutes on Days 1 and 8 of a 21-day cycle. Dose escalation dose levels: Dose level -1 (if needed): 180 mg/m2 Starting dose: 240 mg/m2 |
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Time Frame |
---|---|
Maximum Tolerated Dose (MTD) Measured of TH-302 When Used in Combination With Doxorubicin and Prophylactic Growth Factor Support in Subjects With Advanced Soft Tissue Sarcoma
Time Frame: Two years
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Two years
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Collaborators and Investigators
Sponsor
Study record dates
Study Major Dates
Study Start
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimate)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
Other Study ID Numbers
- TH-CR-403
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
Clinical Trials on Soft Tissue Sarcoma
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OHSU Knight Cancer InstituteNational Cancer Institute (NCI)WithdrawnStage III Adult Soft Tissue Sarcoma | Stage IV Adult Soft Tissue Sarcoma | Stage II Adult Soft Tissue Sarcoma | Stage IIA Adult Soft Tissue Sarcoma | Stage IIB Adult Soft Tissue Sarcoma | Stage IIC Adult Soft Tissue Sarcoma
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CytRxUnknownUnresectable Soft Tissue Sarcoma | Metastatic Soft Tissue Sarcoma | Locally Advanced Soft Tissue SarcomaUnited States, Australia, Russian Federation, Hungary, India, Romania, Ukraine
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University of WashingtonAadi Bioscience, Inc.Active, not recruitingAdvanced Soft Tissue Sarcoma | Metastatic Soft Tissue Sarcoma | Locally Advanced Soft Tissue SarcomaUnited States
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National Institutes of Health Clinical Center (CC)CompletedRecurrent Adult Soft Tissue Sarcoma | Stage III Adult Soft Tissue Sarcoma | Stage IVA Adult Soft Tissue Sarcoma | Stage IIB Adult Soft Tissue Sarcoma | Stage IIC Adult Soft Tissue Sarcoma | Stage IVB Adult Soft Tissue Sarcoma
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National Cancer Institute (NCI)TerminatedRecurrent Adult Soft Tissue Sarcoma | Stage III Adult Soft Tissue Sarcoma | Stage IV Adult Soft Tissue Sarcoma | Stage I Adult Soft Tissue Sarcoma | Stage II Adult Soft Tissue SarcomaUnited States
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National Cancer Institute (NCI)RecruitingMetastatic Alveolar Soft Part Sarcoma | Unresectable Alveolar Soft Part Sarcoma | Advanced Soft Tissue Sarcoma | Advanced Alveolar Soft Part SarcomaUnited States
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Centre Leon BerardNovartis; National Cancer Institute, FranceRecruitingAdvanced Soft-tissue Sarcoma | Metastatic Soft-tissue SarcomaFrance
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UNICANCERRecruitingAdvanced Soft-tissue Sarcoma | Metastatic Soft-tissue SarcomaFrance
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University of Colorado, DenverAgenus Inc.RecruitingAdvanced Soft Tissue Sarcoma | Metastatic Soft Tissue SarcomaUnited States
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Wake Forest University Health SciencesMerck Sharp & Dohme LLCCompletedSoft Tissue Sarcoma, Adult | Soft Tissue Sarcoma, ChildUnited States
Clinical Trials on TH-302
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Threshold PharmaceuticalsCompletedAcute Lymphoblastic Leukemia | Chronic Lymphocytic Leukemia | Acute Myelogenous Leukemia | Chronic Myelogenous Leukemia | High-risk Myelodysplastic Syndrome | Advanced MyelofibrosisUnited States
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Threshold PharmaceuticalsTerminatedMetastatic MelanomaUnited States, Canada
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Sarcoma Alliance for Research through CollaborationThreshold PharmaceuticalsNo longer availableSoft Tissue Sarcoma
-
Threshold PharmaceuticalsUnknown
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Threshold PharmaceuticalsCompletedHypoxia | TumorsUnited States
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Seoul National University HospitalThreshold PharmaceuticalsCompletedBiliary Tract CancerKorea, Republic of
-
Herbert Hurwitz, MDGlaxoSmithKline; National Comprehensive Cancer Network; Threshold PharmaceuticalsCompleted
-
Merck KGaA, Darmstadt, GermanyThreshold PharmaceuticalsCompleted
-
Threshold PharmaceuticalsUnknownGastrointestinal Stromal Tumors | Advanced Renal Cell Carcinoma | Pancreatic Neuroendocrine TumorsUnited States
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Threshold PharmaceuticalsCompletedPancreatic Cancer | Non-Small Cell Lung Cancer | Prostate CancerUnited States