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Female Urogenital Diseases and Pregnancy Complications

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Urethral Cancer

Subjects with confirmed metastatic urothelial cancer willing to participate in biospecimen collection (tissue and blood) for genetic studies.

Subjects consent to provide access to archival tumor tissue and whole blood samples for genetic analysis. Subjects also consent to the indefinite use of their specimens and linked clinical information for ongoing or future research related to metastatic urothelial cancer.

Biospecimen Collection

Matthew Milowsky, M.D.

This comprehensive genomic analysis and biospecimen repository study incorporates Next Generation Sequencing (NGS) of archival tumor tissue from 200 subjects with metastatic urothelial cancer in support of several parallel goals. The immediate goal involves generation of a comprehensive report identifying subject specific genetic mutations and/or alterations based on NGS. Additionally, DNA and RNA extracted from tumor specimens and any remaining blocks/slides from the NGS will be stored for future research. Long-term, the goal of this endeavor is to support collaborative translational research projects in metastatic urothelial cancer by allowing investigators to interrogate abstracted coded clinical data linked to data from any biospecimen studies.

OUTLINE: This is a multi-center study.

STUDY PLAN:

SUBJECT IDENTIFICATION AND CONSENT:

Sites may approach all subjects who attend an appointment for evaluation of metastatic urothelial cancer for inclusion. Study staff review consent documents with potential subjects and answer any and all questions. If a subject desires additional time or wishes to delay enrollment in the study, he/she is given a copy of the consent document and informed about how to ask questions or enroll at a later date. If the subject chooses to participate in the study, he or she signs the consent, and is given a copy for his or her own records.

BIOSPECIMEN COLLECTION AND PROCESSING:

When subjects are consented for entry into this study, they consent to access of any archival tumor tissue (whether from the primary or any metastatic site) for genetic analysis. This tissue is not de-identified at the time of testing so that a subject specific report may be generated and sent to the treating physician. Further, subjects consent to the indefinite use of their specimens and linked clinical information for ongoing or future biomedical research. Additionally, sites inform subjects during the consent process that researchers may use their information for genetic research including research on somatic or germline mutations. The specimens and report provided to HCRN are de-identified and future analyses will be performed on coded (de-identified) data/specimens.

Collection of Archived Tumor Samples:

* After the subject is consented, sites will request primary and/or metastatic archived tumor tissue. The tissue specimen sent may come in the form of a block or slides. Needle biopsy is also acceptable.
* Each institution can use its own standard operating procedure for the preparation of the FFPE material. Each participating site will ship specimens accessed under GU15-217 directly to the lab performing the NGS analysis. Sites will also request corresponding pathology report(s). A de-identified pathology report will then be sent to HCRN with the tissue.

Collection of Blood for Research Purposes Only:

* Each subject will have 47 mL of blood collected and banked for future testing. 10mL of the sample will be used for plasma for banking. 17 mL of the sample will be used for PBMC isolation and cryopreservation. 20mL of the sample will be used for plasma for cfDNA. Any DNA analysis of blood (including possible germline analysis) is for research purposes only and will be performed on coded (de-identified) samples.

Report Generation:

* The subject specific report generated includes a summary of genomic alterations highlighting those variations considered potentially actionable, a concise discussion of the molecular analyses, a list of potential clinical trials incorporating relevant targeted agents, and potential therapeutic options based on the specific alterations discovered along with associated levels of evidence for each. The selection of clinical trials and levels of evidence provided are based on extensive review and analysis of the literature as well as a BCGC convened panel of experts in bladder cancer. This BCGC expert panel will work with the NGS lab to ensure that all potential clinical trials are represented in the individual subject reports.

Storage for Future Research:

* The BCAN Biobank at Hoosier Cancer Research Network (HCRN) will store DNA and RNA isolated for the study, additional FFPE and any biospecimens remaining after the NGS. If at any point a subject wishes to withdraw from the study, the subject will contact their study physician. HCRN will destroy any specimens that it may link to the subject. Once specimens have been stripped of all identifying information or links to identifying information they cannot be recalled to be destroyed.

COMMUNICATION OF NGS RESULTS TO PROVIDER AND SUBJECT:

After NGS testing is complete, a subject specific report will be provided to the subject's treating physician either in hard copy and/or via on-line portal (typically within 14 business days from receipt of tumor tissue) and a de-identified report to HCRN. If an addendum is made to a report, an updated report will be provided to the treating physician and HCRN in the manner described above. During the informed consent process, sites inform each subject that his or her physician will communicate results of the genetic testing on their tumor specimens. Along with the results that are communicated, the subjects' treating physician will explain the implications of their testing results, including whether their genetic profiles render them potentially eligible for a specific therapy or clinical trial.

Sites also inform subjects that researchers will store any specimens remaining after genetic profiling of their tumor is complete. Storage continues indefinitely for future biomedical research. This may include development of commercial products from their specimens.

Sites must explain to subjects that although a blood sample is being obtained, this study is not aimed at discovering germline mutations. Sites must emphasize that genetic analyses performed within this study should not be construed as genetic testing for genetic mutations associated with hereditary cancer susceptibility. Nevertheless, because NGS may be performed on blood, it is possible that a germline mutation that predisposes a subject to cancer will incidentally be discovered. Subjects will not receive any information about such mutations, however, as this analysis will be performed on de-identified samples.

ABSTRACTION OF MEDICAL RECORDS:

Research staff at each site abstracts clinical information from each subject and enters the information into the web based clinical research platform (EDC system). Data abstracted includes details on the following: demographics, cancer diagnosis, cancer stage, surgical and medical management, any treatment decisions made in response to the NGS results communicated to the physician and any response/longer term outcome data as a result of these treatment decisions.

ACCESS TO DATA/SPECIMENS FOR FUTURE RESEARCH:

The database links coded clinical and genetic data, creating a biospecimen and data repository. These data, along with biospecimens stored at HCRN, will ultimately be available for researchers with BCGC-approved and IRB-approved studies allowing access to these data/specimens, and with HCRN managing the data, protecting the confidentiality of study subjects.

UC-GENOME: Urothelial Cancer-GENOmic Analysis to iMprove Patient Outcomes and rEsearch

UC-GENOME: Urothelial Cancer-GENOmic Analysis to iMprove Patient Outcomes and rEsearch: Hoosier Cancer Research Network GU15-217

Subject-specific report that includes a summary of genomic alterations and potential therapeutic options based on the specific alterations and evidence discovered.

Tissue and blood samples will be preserved and stored in a biorepository that cancer investigators can access for future IRB approved translational studies

Subjects whose treatment options include targeted therapy, of either approved or investigational drugs

Subjects who enroll in a clinical trial based on NGS results.

Subjects who receive targeted therapy, outside of a clinical trial, based on NGS results

Subject demographic characteristics compiled and recorded in a data repository, maintained in a secure platform, that will provide an archive for future research.

Subject treatment histories compiled and recorded in a data repository, maintained in a secure platform, that will provide an archive for future research.

Subject clinical outcomes data compiled and recorded in a data repository, maintained in a secure platform, that will provide an archive for future research.

Number and type of clinical trials and basic/translational science or other research projects initiated, based on the biospecimen and data repository

Compare the overall survival for patients with metastatic urothelial cancer who received a treatment based on the NGS results (on or off of a clinical trial) to those patients who did not

Bladder Cancer Advocacy Network (BCAN®)

Hoosier Cancer Research Network

Matthew Milowsky, MD

Sponsor-Investigator

Symptoms and General Pathology

Disease Progression

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

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.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
UC-GENOME: Urothelial Cancer-GENOmic Analysis to iMprove Patient Outcomes and rEsearch	NCT02643043	Urothelial Carc... Bladder Cancer Urethral Cancer Cancer of the U...	Biospecimen Col...	18 Years -	Hoosier Cancer Research Network
UC-GENOME: Urothelial Cancer-GENOmic Analysis to iMprove Patient Outcomes and rEsearch	NCT02643043	Urothelial Carc... Bladder Cancer Urethral Cancer Cancer of the U...	Biospecimen Col...	18 Years -	Hoosier Cancer Research Network
TRC105 in Adults With Advanced/Metastatic Urothelial Carcinoma	NCT01328574	Urothelial Carc... Ureteral Neopla... Ureter Cancer Neoplasm, Urete... Cancer of the U...	TRC105	18 Years - 99 Years	National Institutes of Health Clinical Center (CC)

Spots Global Cancer Trial Database for cancer of the ureter