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Transitional Cell Carcinoma

TRC105

Andrea B Apolo, M.D.

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.

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.

TRC105 in Adults With Advanced/Metastatic Urothelial Carcinoma

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

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).-

Here is the number of participants with adverse events. For a detailed list of adverse events, see the adverse event module.

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.

Date of on-study to the date of death from any cause or last follow up.

Adverse events by grade, (e.g. 1 is mild, 2 is moderate, 3 is severe and 4 is life threatening) related to TRC-105.

National Cancer Institute (NCI)

Principal Investigator

TRC 105 every two weeks

TRC105: 15 mg/kg intravenously

Single Arm-TRC105 in Urothelial Carcinoma

Age, Categorical

Age, Continuous

Gender

Ethnicity (NIH/OMB)

Race (NIH/OMB)

United States

Region of Enrollment

Median Age (Range)

Karnofsky Performance Scale: 60 - requires occasional assistance, but is able to care for most of his/her needs; 70 - cares for self, unable to carry on normal activity or to do active work; 80 - normal activity with effort; some signs or symptoms of disease; 90 - able to carry on normal activity; minor signs or symptoms of disease.

Karnofsky Performance Status

Bladder

Upper urinary tract

Primary Tumor Site

Lung

Liver

Bone

Any visceral metastases

Lymph node only

Metastatic Sites of Disease

Number of Previous Therapies for Metastatic Disease

Dr. Andrea Apolo

Progression Free Survival

Number of Participants With Adverse Events

Complete response

Partial response

Objective Response

Median Overall Survival

Anemia

Anorexia

Cough

Edema (Limbs)

Epistaxis

Fatigue

Gum bleeding

Headache

Hematuria

Hypoalbuminemia

Hypophosphatemia

Increased Alanine Aminotransferase

Infusion-Related Reaction

Maculopapular Rash

Nasal Congestion

Nausea

Proteinuria

Skin Infection

Telangiectasia

Vomiting

Xerostomia

TRC 105 every two weeks

TRC105: 15 mg/kg intravenously

Adverse events grades 1-4 (mild, moderate, severe and life threatening).

TRC105 in Urothelial Carcinoma - Adverse Events - All Grades

TRC 105 every two weeks

TRC105: 15 mg/kg intravenously Grade 1 (mild) adverse events.

TRC105 in Urothelial Carcinoma - Adverse Events - Grade 1

TRC 105 every two weeks

TRC105: 15 mg/kg intravenously Grade 2 (moderate) adverse events.

TRC105 in Urothelial Carcinoma - Adverse Events - Grade 2

TRC 105 every two weeks

TRC105: 15 mg/kg intravenously Grade 3 (severe) adverse events.

TRC105 in Urothelial Carcinoma - Adverse Events - Grade 3

TRC 105 every two weeks

TRC105: 15 mg/kg intravenously Grade 4 (life threatening) adverse events.

TRC105 in Urothelial Carcinoma - Adverse Events - Grade 4

Incidence of TRC-105-Related Adverse Events

Overall Study

Spots Global Cancer Trial Database for neoplasm, ureteral