TRC105 in Adults With Advanced/Metastatic Urothelial Carcinoma

Study Overview
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Brief Summary
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Background: - Urothelial cancer (tumors of the bladder, urethra, ureter, or renal pelvis) often responds initially to standard chemotherapy treatments, but frequently recurs and can often spread to other parts of the body. TRC105, an experimental drug that blocks the development of the new blood vessels needed for tumor growth, may be able to shrink or stabilize urothelial cancer tumors. TRC105 has been given previously to individuals with other types of cancer, and researchers are interested in determining its safety and effectiveness in treating urothelial cancer. Objectives: - To determine the safety and effectiveness of TRC105 as a treatment for metastatic urothelial cancer that has not responded to standard treatments. Eligibility: - Individuals at least 18 years of age who have been diagnosed with urothelial cancer that has spread to other parts of the body and has not responded to standard chemotherapy. Design: Participants will be screened with a physical examination, medical history, blood tests, and tumor imaging studies. Participants will receive TRC105 intravenously once every 2 weeks on days 1 and 15 of a 28-day treatment cycle. The first dose of TRC105 will be given over a 4-hour period; participants who do not have side effects may receive the next dose over 2 hours. If the second dose is tolerated, subsequent doses can be given over at least 1 hour. To help prevent known side effects of TRC105, participants will take two doses (one in the morning and one in the evening) of the steroid dexamethasone on the day before each infusion is scheduled. Participants may have additional dexamethasone 30 minutes before infusion, and may have the infusion slowed or stopped to adjust for side effects. Participants will be monitored with blood samples, physical examinations, and tumor imaging studies through the cycles of treatment. Participants will continue to take TRC105 for as long as the treatment is effective against the cancer and as long as the side effects are not severe enough to stop treatment.

Detailed Description
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BACKGROUND: In the United States, urothelial carcinoma (UC) of the bladder is the 4th most common malignancy in men and the 9th most common in women with an estimated 70,980 new cases and 14,330 deaths in the year 2009. Although it is chemosensitive with response proportions of over 50% with conventional cytotoxic regimens, the response durations are short and the median survival of patients with metastatic disease is approximately 14 months. TRC105 is a genetically engineered human/murine chimeric monoclonal antibody that inhibits angiogenesis and tumor growth via endothelial cell growth inhibition and apoptosis. TRC105 is directed against human CD105 (endoglin), an angiogenic membrane protein that is highly expressed on proliferating vasculature in solid tumors and up-regulated following anti-VEGF (vascular endothelial growth factor) therapy. Clinical studies in bladder cancer with anti-angiogenic agents have shown anti-tumor activity. TRC105 targets a unique mechanism for tumor angiogenesis, through modification of CD105 signaling. In patients with advanced bladder cancer that have progressed through standard chemotherapy and have no further life prolonging therapeutic options, use of this novel angiogenesis inhibitor may improve outcomes. OBJECTIVES: To measure PFS (progression free survival) of TRC105 as determined by RECIST (Response Evaluation Criteria in Solid Tumors) v1.1 To determine the safety and toxicity of TRC105 in this patient population. In addition, in a preliminary fashion, response rate and overall survival of patients with metastatic urothelial carcinoma of the bladder treated with TRC105 will be estimated. ELIGIBILITY: Adults with progressive advanced/metastatic urothelial carcinoma that have progressed despite treatment with prior cytotoxic chemotherapy. Subjects must have received at least one prior cytotoxic agent (which must have included at least one of the following: cisplatin, carboplatin, paclitaxel, docetaxel, or gemcitabine). DESIGN: TRC105 will be administered at a dose of 15 mg/kg intravenously every two weeks, on days 1 and 15 of each 28 day cycle. Patients may continue on study as long as they are tolerating therapy and are free of disease progression. The study will be conducted as a two-stage optimal design (Simon 1989). With alpha=0.10 and beta=0.10 as acceptable error probabilities, the trial will target 30% as the desirable proportion of patients who are still without progression by radiographic criteria at approximately 6 months (p1=0.30), and will be considered inadequate if only a fraction consistent with 10% are without progression by the same evaluation time (p0=0.10). Initially 12 patients will be enrolled and followed for progression. If 2 or more of the first 12 patients reach 6 months without progression, then enrollment will continue until a total of 35 evaluable patients (37 total patients to allow for a small number of inevaluable patients) have been entered.

Official Title
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A Phase II Study of TRC105 in Adults With Advanced/Metastatic Urothelial Carcinoma

Conditions
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Urothelial Carcinoma, Ureteral Neoplasms, Ureter Cancer, Neoplasm, Ureteral, Cancer of the Ureter

Intervention / Treatment
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* Drug: TRC105


Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA: Patients must have a diagnosis of urothelial carcinoma of the bladder, urethra, ureter, or renal pelvis, with histological confirmation at the Laboratory of Pathology of the NCI (National Cancer Institute), NIH (National Institutes of Health). Patients must have progressive metastatic disease. Progressive disease will be defined as new or progressive lesions on cross-sectional imaging. Patients must have at least: One measurable site of disease (according to RECIST criteria) that has not been previously irradiated. If the patient has had previous radiation to the marker lesion(s), there must be evidence of progression since the radiation. Or, appearance of one new bone lesion. Patients must have been previously treated, as defined by the following: Treatment with at least one prior cytotoxic agent (which must have included at least one of the following: cisplatin, carboplatin, paclitaxel, docetaxel, or gemcitabine), administered in the perioperative or metastatic setting and may have been administered sequentially (e.g., first-line treatment followed by second-line treatment at time of progression) or as part of a single regimen. 18 years of age or older ECOG (Eastern Cooperative Oncology Group) performance status of < 2 or Karnofsky Performance Status greater than or equal to 60% Resolution of all acute toxic effects of prior chemotherapy, radiotherapy, or surgical procedure to NCI CTCAE (Common Terminology Criteria in Adverse Events) grade less than or equal to 1 or baseline Adequate organ function as defined by the following criteria: Serum aspartate transaminase (AST (Aspartate transaminase); serum glutamic oxaloacetic transaminase [SGOT (serum glutamic oxaloacetic)]) and serum alanine transaminase (ALT (alanine transaminase); serum glutamic pyruvic transaminase [SGPT (serum glutamic pyruvic transaminase)]) less than or equal to 2.5 times the upper limit of normal (ULN); 5.0 times the ULN in cases of liver metastases Total serum bilirubin less than or equal to 1.5 mg/dL (unless elevation from Gilbert's disease or similar syndrome due to slow conjugation of bilirubin) Absolute neutrophil count (ANC) greater than or equal to 1000/microL Platelets greater than or equal to 100,000/microL Serum creatinine less than or equal to 2.0 mg/dl or calculated creatinine clearance (CrCl) greater than or equal to 30 mL/min Hemoglobin > 9gm/dL PT (prothrombin time), aPTT (activated partial thromboplastin time) must be within normal range Patients on anticoagulants may be enrolled as long as the INR (International normalized ratio) does not exceed 3. EXCLUSION CRITERIA: Receipt of an investigational agent within 4 weeks prior to first dose with TRC105 Major surgery including open biopsy or systemic therapy < 4 weeks prior to first dose with TRC105 Radiation therapy (except small field) < 3 weeks prior to first dose with TRC105 Small field radiation therapy < 2 weeks prior to first dose with TRC105 Minor surgical procedures within 2 weeks Uncontrolled chronic hypertension (systolic > 140 or diastolic > 90mm Hg despite optimal therapy) Brain metastasis, or leptomeningeal disease because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events. Unstable angina, MI, symptomatic congestive heart failure, cerebrovascular accident, transient ischemic attack, arterial embolism, pulmonary embolism, DVT (deep vein thrombosis), PTCA (percutaneous transluminal coronary angioplasty) or CABG (coronary artery bypass graft) within the past 6 months Cardiac arrhythmias of NCI CTCAE grade greater than or equal to 2 within the last month Serious, non-healing wound, ulcer, or bone fracture Known active hepatitis Hemorrhage within 30 days of dosing or history of persistent gross hematuria Known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS) related illness History of hypersensitivity reaction to human or mouse antibody products Pregnancy or breastfeeding. Female patients must be surgically sterile (i.e.: hysterectomy) or be postmenopausal, or must agree to use effective contraception during the study and for 3 months following last dose of TRC105. All female patients of reproductive potential must have a negative pregnancy test (serum) within 7 days prior to first dose. Male patients must be surgically sterile or must agree to use effective contraception during the study and for 3 months following last dose of TRC105. The definition of effective contraception will be based on the judgment of the Principal Investigator or a designated associate. Other severe acute or chronic medical or psychiatric condition, or laboratory abnormality that may increase the risk associated with study participation or study drug administration, or may interfere with the interpretation of study results, and in the judgment of the Investigator would make the patient inappropriate for entry into this study History of peptic ulcer disease, unless a subsequent endoscopy has confirmed complete resolution of the ulcer History of acquired or inherited hypocoagulopathies (bleeding risk), including but not limited to hereditary hemorrhagic telangiectasis.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 99 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Single Arm - TRC105 in Urothelial Carcinoma<br>TRC105 15 mg/kg/dose every two weeks | Drug: TRC105<br>* 15 mg/kg intravenously<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival | Time interval from start of treatment to documented evidence of disease progression. Progressive disease is at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm (Note: the appearance of one or more new lesions is also considered progression).- | after 6 months on study | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Adverse Events | Here is the number of participants with adverse events. For a detailed list of adverse events, see the adverse event module. | 24 months | 
| Objective Response | Objective response is defined as the number of participants who meet the criteria for a complete response (CR) or a partial response (PR) per the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. CR is disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. PR is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. | up to 25 months | 
| Median Overall Survival | Date of on-study to the date of death from any cause or last follow up. | up to 25 months | 
| Incidence of TRC-105-Related Adverse Events | Adverse events by grade, (e.g. 1 is mild, 2 is moderate, 3 is severe and 4 is life threatening) related to TRC-105. | 24 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Progression-Free Survival, Carcinoma of the Bladder, Cancer of the Renal Pelvis, Ureter Cancer, Survival, Bladder Cancer, Renal Pelvis Cancer, Urothelial Cancer