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
Intervention: TRC105
Intervention description: 15 mg/kg intravenously
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 13.0
Sex: All
Minimum age: 18 Years
Maximum age: 99 Years
Healthy volunteers: No
Keywords: Progression-Free Survival; Carcinoma of the Bladder; Cancer of the Renal Pelvis; Ureter Cancer; Survival; Bladder Cancer; Renal Pelvis Cancer; Urothelial Cancer

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.
    

Eligibility criteria:

        -  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.