TRC105 in Adults With Advanced/Metastatic Urothelial Carcinoma
Condition: Urothelial Carcinoma; Ureteral Neoplasms; Ureter Cancer; Neoplasm, Ureteral; Cancer of the Ureter
MeSH terms: Carcinoma; Neoplasms; Carcinoma, Transitional Cell; Ureteral Neoplasms
Study type: Interventional
Phase: Phase 2

Summary: 
      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: 
      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.
    

Intervention name(s): TRC105
Intervention type(s): Drug
Intervention description(s): 15 mg/kg intravenously
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Progression-Free Survival; Carcinoma of the Bladder; Cancer of the Renal Pelvis; Ureter Cancer; Survival; Bladder Cancer; Renal Pelvis Cancer; Urothelial Cancer