TRC105 in Adults With Advanced/Metastatic Urothelial Carcinoma

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )
ClinicalTrials.gov Identifier:
NCT01328574
First received: April 1, 2011
Last updated: March 14, 2014
Last verified: November 2013
  Purpose

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.

Condition Intervention Phase
Urothelial Carcinoma
Ureteral Neoplasms
Ureter Cancer
Neoplasm, Ureteral
Cancer of the Ureter
Drug: TRC105
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase II Study of TRC105 in Adults With Advanced/Mestastic Urothelial Carcinoma

Resource links provided by NLM:


Further study details as provided by National Institutes of Health Clinical Center (CC):

Primary Outcome Measures:
  • To measure PFS of TRC105 as determined by RECIST. [ Time Frame: 4 years ] [ Designated as safety issue: No ]
  • To determine the safety and toxicity of TRC105 in this patient population. [ Time Frame: 2 years ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • To determine the response rate of TRC105 in patients with progressive urothelial cancer who have received prior cytotoxic chemotherapy. [ Time Frame: 2 years ] [ Designated as safety issue: Yes ]
  • To estimate overall survival of patients with metastatic urothelial carcinoma of the bladder treated with TRC105 [ Time Frame: 4 years ] [ Designated as safety issue: No ]

Enrollment: 13
Study Start Date: March 2011
Estimated Study Completion Date: March 2015
Estimated Primary Completion Date: March 2015 (Final data collection date for primary outcome measure)
Intervention Details:
    Drug: TRC105
    N/A
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 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 of TRC105 as determined by RECIST 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 15mg/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.
  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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, NIH.
  • 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 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 grade less than or equal to 1 or baseline
  • Adequate organ function as defined by the following criteria:
  • Serum aspartate transaminase (AST; serum glutamic oxaloacetic transaminase [SGOT]) and serum alanine transaminase (ALT; serum glutamic pyruvic transaminase [SGPT]) 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, aPTT must be within normal range
  • Patients on anticoagulants may be enrolled as long as the INR 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, PTCA or CABG 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.
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT01328574

Locations
United States, Maryland
National Institutes of Health Clinical Center, 9000 Rockville Pike
Bethesda, Maryland, United States, 20892
Sponsors and Collaborators
Investigators
Principal Investigator: Andrea B Apolo, M.D. National Cancer Institute (NCI)
  More Information

Additional Information:
Publications:
Responsible Party: National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )
ClinicalTrials.gov Identifier: NCT01328574     History of Changes
Other Study ID Numbers: 110130, 11-C-0130
Study First Received: April 1, 2011
Last Updated: March 14, 2014
Health Authority: United States: Federal Government

Keywords provided by National Institutes of Health Clinical Center (CC):
Progression-Free Survival
Carcinoma of the Bladder
Cancer of the Renal Pelvis
Ureter Cancer
Survival
Bladder Cancer
Renal Pelvis Cancer
Urothelial Cancer

Additional relevant MeSH terms:
Neoplasms
Carcinoma
Carcinoma, Transitional Cell
Ureteral Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Urologic Neoplasms
Urogenital Neoplasms
Neoplasms by Site
Ureteral Diseases
Urologic Diseases

ClinicalTrials.gov processed this record on April 15, 2014