Neoplasms

All Conditions

Urinary Tract, Sexual Organs, and Pregnancy Conditions

Carcinoma

Urinary Bladder Neoplasms

Urologic Neoplasms

Urogenital Neoplasms

Urogenital Diseases

Female Urogenital Diseases

Pregnancy Complications

Female Urogenital Diseases and Pregnancy Complications

Urinary Bladder Diseases

Urologic Diseases

Male Urogenital Diseases

Coagulants

All Drugs and Chemicals

Fibrinolytic Agents

Tranexamic Acid

Antifibrinolytic Agents

Hemostatics

Tranexamic acid will be administered as an intravenous infusion of 10 mg/kg over 10 minutes (loading dose) prior to surgical incision, followed by 5 mg/kg/hour continuous maintenance infusion for the length of surgery (typically 4 to 8 hours). For example, an 80 kg patient would receive 800 mg prior to incision and a 400 mg/hr infusion for the duration of surgery. For a 6 hour procedure, the total dose administered would be 3200 mg.

As there is no standard of care concerning administration of anti-fibrinolytic agents in cystectomy procedures, controls will follow the same dosing and schedule as above (loading dose followed by maintenance infusion), but with 0.9% sodium chloride.

Tranexamic acid will be administered as an intravenous infusion of 10 mg/kg over 10 minutes (loading dose) prior to surgical incision, followed by 5 mg/kg/hour continuous maintenance infusion for the length of surgery (typically 4 to 8 hours).

Placebo

Rodney H Breau, MD, FRCSC

A cystectomy is the removal of the bladder and adjacent organs in patients with bladder cancer. This often results in significant blood loss, and about 60% of patients will require a blood transfusion during or up to 30 days after surgery. Significant blood loss may result in cardiovascular morbidity, and the use of blood products are expensive and expose patients to risk.

Tranexamic acid reduces breakdown of hemostatic blood clots and it has therapeutic benefit when used in other surgical procedures to reduce blood loss and the need for transfusion. The current study will be the first to evaluate whether tranexamic acid is effective and safe to use during radical cystectomy. The results of the study will have an immediate impact on patient care.

Removal of the bladder and adjacent organs in patients with bladder cancer (radical cystectomy) often results in significant blood loss, and approximately 60% of patients require peri-operative blood transfusion. Reducing blood loss and the frequency of transfusion offers several benefits, including donor blood conservation, health care cost reduction, and avoidance of blood product exposure. Tranexamic acid is an amino acid lysine derivative with strong antifibrinolytic clotting properties that can be administered systemically. This medication has been used in a variety of operative procedures, notably in high risk cardiac surgery, to decrease peri-operative blood loss, and it is associated with an acceptable risk of adverse events. Systemic anti-hemorrhagics are infrequently used during radical cystectomy, and to the investigators knowledge their effects have not been evaluated in a clinical trial.

Overall objective: To conduct a randomized controlled trial of systemic tranexamic acid compared to placebo in reducing the number of blood transfusions in patients undergoing radical cystectomy for bladder cancer.

Design: A multi-center, randomized, double-blinded, placebo controlled trial.

Study population: Consenting patients 18 years of age and older undergoing a radical cystectomy for bladder cancer, excluding those who: are unwilling to receive blood products due to personal reasons, are pregnant, have active angina, have a known allergy to tranexamic acid, or have a known personal history of deep venous thrombosis, atrial fibrillation, coronary stent, sub-arachnoid hemorrhage, pulmonary embolism, thrombotic stroke and / or acquired disturbance of colour vision. The study will recruit 354 patients from Dalhousie University, McGill University, Université de Montreal, Université Laval, University of Ottawa, University of Western Ontario and University of Alberta.

Intervention:

Tranexamic Acid arm: Tranexamic acid will be administered as an intravenous infusion of 10 mg/kg within 10 minutes (loading dose) and before surgical incision, followed by 5 mg/kg/hour continuous maintenance infusion for the length of surgery (typically 4 to 8 hours). For example, an 80 kg patient would receive 800 mg prior to incision and a 400 mg/hour infusion for the duration of surgery. For a 6 hour procedure, the total dose administered would be 3200 mg.

Placebo arm: As there is no standard of care concerning administration of antifibrinolytic agents in cystectomy procedures, controls will follow the same dosing and schedule described above, but with 0.9% saline infusion.

Outcomes: The primary research objective is whether the use of systemic tranexamic acid compared to placebo reduces the proportion of radical cystectomy patients requiring red blood cell transfusion up to 30 days post-operative (from a 50% transfusion rate with placebo to 35% with tranexamic acid). Secondary questions are: Will use of systemic tranexamic acid compared to placebo result in reductions in: i) intraoperative blood loss, ii) amounts of transfused blood products, and iii) post-operative complications? The safety (thrombotic events) of tranexamic acid will also be evaluated.

Importance of this study: If tranexamic acid reduces the number of blood transfusions, there will be an immediate impact to cystectomy patients, and surgeons may consider the routine use of systemic tranexamic acid during similar abdomino-pelvic procedures associated with significant blood loss.

Tranexamic Acid During Cystectomy Trial (TACT)

treatment failures noted as the need for anti-hemorrhagic rescue interventions such as topical agents (oxidized cellulose) and recombinant Factor VIIa

intervention noted as reoperation or angioinfarction

Canadian Institutes of Health Research (CIHR)

Dalhousie University

McGill University Health Centre/Research Institute of the McGill University Health Centre

Centre hospitalier de l'Université de Montréal (CHUM)

Laval University

University of Western Ontario, Canada

University Health Network, Toronto

Ottawa Hospital Research Institute

Rare Diseases

Carcinoma, Transitional Cell

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Transitional Cell Carcinoma

Antineoplastic Agents

Docetaxel

Antibodies

Antibodies, Monoclonal

Immunoglobulins

Tubulin Modulators

Antimitotic Agents

IV infusion of docetaxel, 75 mg/m2, followed by IV infusion of vofatamab, 25 mg/kg, on day one of each 21-day cycle. One additional IV infusion of vofatamab (25 mg/kg) given on Day 8 of Cycle 1.

Dosing with vofatamab and docetaxel will continue in each patient until disease progression, unacceptable toxicity, death, or study exit, including withdrawal of patient consent or study termination. Docetaxel treatment beyond 12 cycles of therapy may be considered at the discretion of the treating investigator and Medical Monitor.

IV infusion of docetaxel, 75 mg/m2, followed by IV infusion of placebo on day one of each 21-day cycle.

One additional IV infusion of placebo given on Day 8 of Cycle 1. Dosing of docetaxel and placebo will continue in each patient until disease progression, unacceptable toxicity, death, or study exit, including withdrawal of patient consent or study termination. Docetaxel treatment beyond 12 cycles of therapy may be considered at the discretion of the treating investigator and Medical Monitor

IV infusion vofatamab, 25 mg/kg on day one each 21-day cycle. One additional IV infusion of vofatamab (25 mg/kg) given on Day 8 of Cycle 1.

Dosing of vofatamab will continue in each patient until disease progression, unacceptable toxicity, death, or study exit, including withdrawal of patient consent or study termination.

Vofatamab

Rainier Therapeutics

This is a Phase 1/2(b), sequential, dose escalation, open-label, randomized expansion, multicenter, efficacy and safety study of vofatamab alone or in combination with docetaxel, or versus docetaxel in FGFR3 mutant/fusion subjects with Stage IV, locally advanced or metastatic UCC who have relapsed after, or are refractory to at least one prior line of chemotherapy. This study is divided into 3 phases: Phase 1b (Cohort 1), Phase 2 (Cohorts 2 and 3), and Phase 2b (Monotherapy Expansion Phase and Randomized Phase).

This is a Phase 1/2(b), sequential, dose escalation, open-label, randomized expansion, multicenter, efficacy and safety study of vofatamab alone or in combination with docetaxel, or versus docetaxel in FGFR3 mutant/fusion subjects with Stage IV, locally advanced or metastatic UCC who have relapsed after, or are refractory to at least one prior line of chemotherapy. Vofatamab is a novel monoclonal antibody specific for fibroblast growth factor receptor 3 (FGFR3) that is being developed to target FGFR3-positive tumors.

This study is divided into 3 phases: Phase 1b (Cohort 1), Phase 2 (Cohorts 2 and 3), and Phase 2b (Monotherapy Expansion Phase and Randomized Phase).

Dose Escalation, Expansion Study of Vofatamab (B-701) in Treatment of Locally Advanced or Metastatic Urothelial Cell Carcinoma

A Dose Escalation, Expansion Study of Vofatamab (B-701) Alone, Plus Docetaxel, or Versus Docetaxel in Subjects With Locally Advanced or Metastatic Urothelial Cell Carcinoma Who Have Relapsed After, or Are Refractory to Standard Therapy

Efficacy of vofatamab plus docetaxel, compared with docetaxel plus placebo, and vofatamab alone as measured by PFS; measured from randomization to first occurrence of disease progression (per RECIST v1.1) or death, whichever occurs first. A patient has had to receive at least one vofatamab dose. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.

Safety was assessed through summaries of AEs, changes in key laboratory test results, ECGs and changes in vital signs.

IV infusion of docetaxel, 75 mg/m2, followed by IV infusion of vofatamab, 25 mg/kg, on day one of each 21-day cycle. One additional IV infusion of vofatamab (25 mg/kg) given on Day 8 of Cycle 1.

Dosing with vofatamab and docetaxel will continue in each patient until disease progression, unacceptable toxicity, death, or study exit, including withdrawal of patient consent or study termination. Docetaxel treatment beyond 12 cycles of therapy may be considered at the discretion of the treating investigator and Medical Monitor.

Vofatamab

Docetaxel

Vofatamab Plus Docetaxel

IV infusion vofatamab, 25 mg/kg on day one each 21-day cycle. One additional IV infusion of vofatamab (25 mg/kg) given on Day 8 of Cycle 1.

Dosing of vofatamab will continue in each patient until disease progression, unacceptable toxicity, death, or study exit, including withdrawal of patient consent or study termination.

Vofatamab

IV infusion of docetaxel, 75 mg/m2, followed by IV infusion of placebo on day one of each 21-day cycle.

One additional IV infusion of placebo given on Day 8 of Cycle 1. Dosing of docetaxel and placebo will continue in each patient until disease progression, unacceptable toxicity, death, or study exit, including withdrawal of patient consent or study termination. Docetaxel treatment beyond 12 cycles of therapy may be considered at the discretion of the treating investigator and Medical Monitor

Docetaxel

Placebo

Placebo Plus Docetaxel

Total

Age, Categorical

Sex: Female, Male

Race (NIH/OMB)

No patients were enrolled in the placebo plus docetaxel group.

Chief Medical Officer

Mut/Fus Phase 1

Wild Type Phase 1

Mut/Fus Phase 2

Mut/Fus Phase 2 Monotherapy

Mut/Fus Phase 2b Monotherapy

Primary Efficacy Outcome: Progression Free Survival (PFS)

Overall Study

Transitional Cell Cancer of the Renal Pelvis and Ureter

A single 1300 nm OCT measurement will be performed during ureterorenoscopy in patients with upper urinary tract tumour(s)

Single Optical Coherence Tomography measurement of upper urinary tract tumour taken during ureterorenoscopy

Optical Coherence Tomography

Jean J. de la Rosette, MD PhD

The purpose of this study is to establish in vivo sensitivity and specificity of OCT in the diagnosis of Upper Urinary Tract Urothelial Carcinoma.

Minimal invasive endoscopic treatment for Upper Urinary Tract Urothelial Carcinoma (UUT-UC) has been accepted as a treatment option instead of radical nephroureterectomy for patients with low grade, low stage disease. For this reason, information on tumour stage and grade is important for a clinical decision. Until now,diagnostic ureterorenoscopy combined with histology/cytology is the gold standard. Unfortunately, histology/cytology is often inconclusive.

Optical Coherence Tomography is a new high resolution imaging technique that has potential to provide the urologist real time per-operative information of grade and stage of the disease.

In this study the investigators aim to establish in vivo sensitivity and specificity of OCT in the diagnosis of Upper Urinary Tract Urothelial Carcinoma. Secondary objectives are inter-observer variability of 1300 nm OCT in the diagnosis of UUT-UC and optical properties of cancerous and healthy ureter and collecting system tissue in vivo in humans.

Diagnostic Accuracy of Optical Coherence Tomography in Upper Urinary Tract Urothelial Carcinoma

a Prospective In-vivo Human Study to Assess the Diagnostic Accuracy of Optical Coherence Tomography for Diagnosis and Staging of Upper Urinary Tract Urothelial Carcinoma

only a single OCT measurement will be done during surgery. This measurement will take a maximum of 10 minutes, including preparation of the OCT device

Only a single OCT measurement will be done during surgery. This measurement will take a maximum of 10 minutes, including preparation of the OCT device

Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)

M.D.

There will be no separate cohorts in this study. All patients will have their specimens processed by conventional means and by the study method. The conventional means will be the control for the study method.

Peter Black, MD

When the bladder is removed for bladder cancer, pelvic lymph nodes (LN) are also removed. While the anatomic extent of this LN dissection is critical, the investigators often use the number of LN removed as a measure of the extent, which in turn is essential for determining the patient's further treatment and prognosis. The LN count, however, is also dependent on the pathologist's processing of the LN tissue, and the standards for this processing are poorly defined. The goal of this study is to establish a standardized method for processing and analyzing lymph node specimens. The investigators hypothesize that if an organic solvent is used to remove excess fat from the lymph nodes that the investigators will discover more clinically significant nodes in a more reproducible fashion when compared to the current method.

PURPOSE:

This research aims to compare the clinical significance of the use of a fat emulsifying protocol versus the current standard in the processing of lymph node specimens following radical cystectomy and pelvic lymph node dissection.

HYPOTHESIS:

The investigators hypothesize that the use of a fat-emulsifying protocol in the processing of lymph nodes harvested at the time of radical cystectomy will increase the proportion of patients found to have lymph node metastases when compared to the current standard technique.

JUSTIFICATION:

The mainstay of management of muscle invasive bladder cancer is radical cystectomy with pelvic lymph node dissection (PLND). Despite optimal multimodal therapy, approximately half of patients with invasive bladder cancer die of their disease. Efforts to improve patient outcome have focussed on two principle factors: the delivery of pre-operative chemotherapy and the adequacy of PLND. While a PLND is ultimately defined by its anatomic extent, a popular surrogate measure of extent is the number of lymph nodes removed. Beyond assessing the adequacy of the PLND in the sense of quality of care, the accurate determination of lymph node involvement is essential for the correct staging of the patient, which is used to guide adjuvant therapy and determine patient prognosis. The processing and analysis of the lymph node specimens is therefore critical in multiple ways.

The current convention at Vancouver General Hospital for specimen handling involves the dissection of the nodal specimen by a laboratory technologist in the pathology lab. Only palpable nodes are processed for sectioning and the remaining fat tissue is discarded. The nodal count is determined by the pathologist when reviewing the slides based on a combination of the macroscopic and microscopic examination. This process is highly subjective, depends on the diligence of the technologist's dissection, and limits the final examination to palpable nodes. In the fat emulsifying technique, all fat is dissolved so that the pathologist can visualize and process all nodes. The investigators believe that this may provide for a more standardized and reproducible method in processing lymph nodes.

A standardized and reproducible method for processing lymph nodes is a prerequisite to any use of lymph node counts as a measure of the quality of the PLND. And, it is necessary to allow the comparison of results between centers. Furthermore, standardized methodology is essential to ensure adequate sampling of lymph nodes for clinical staging and prognostication.

OBJECTIVES:

The investigators have designed a prospective trial to compare our current protocol for processing pelvic lymph nodes from radical cystectomy with PLND to a fat-emulsifying protocol. The investigators aim to answer three questions with this trial:

i. While the fat-emulsifying technique will almost certainly identify more nodes than the current technique of manual dissection, and will likely identify more nodal metastases, the aim of this study is to determine whether a more careful analysis will find a greater proportion of patients to have lymph node metastases. This will translate into better staging and prognostication.

ii. The current technique likely misses particularly small lymph nodes that are not easily palpated. The investigators hypothesize that there is no threshold lymph node size below which the risk of metastasis is negligible, and that identification of these smaller nodes is therefore clinically meaningful.

iii. The investigators hypothesize that a fat-emulsifying protocol will remove much of the variability due to human element of manual dissection by the prosector. While the investigators will not test this hypothesis directly, the investigators believe the methodology and photographic documentation of the results will reflect a degree of objectivity in this methodology that is not seen with other techniques.

The ultimate goal of this research proposal is to develop a standardized and reproducible technique that can be used everywhere in order to enhance the care of our patients with invasive bladder cancer.

RESEARCH METHOD:

Patients:

All patients who undergo radical cystectomy with pelvic lymph node dissection at Vancouver General Hospital (VGH) will be invited to participate in this prospective study. Patients with clinical stage T1-4,N0,M0 bladder cancer will be invited to participate in the study and will be enrolled after informed consent is obtained.

Surgical technique:

The extent of lymph node dissection will be defined as either conventional (up to bifurcation of common iliac artery) or extended (at least up to the aortic bifurcation) and will be determined by the surgeon on a case-by-case basis. Dissection of the pre-sacral lymph nodes is also up to the surgeon. Objective documentation of the extent of node dissection will be assured by intra-operative photography in every case.

Pathologic processing of PLND specimen:

Each specimen will be analyzed by both conventional means and by a fat-emulsifying protocol. The current convention at Vancouver General Hospital for specimen handling is described above. In this study the pathologist will count the number of nodes dissected by the prosector according to this current protocol. The tissue remaining after removal of the grossly palpable lymph nodes will be submitted for processing by the fat-emulsifying protocol, which is identical to the LNRS ("lymph node removing solution") protocol defined by Koren et al. This consists of placement of the entire specimen in a specialized solution for 12 hours. The solution is a mixture of 95% ethanol, diethyl ether, glacial acetic acid and buffered formalin in a ratio by volume of 6.5:2:0.5:1 Specimens so treated will be photographed for objective documentation of the nodal count. The additional nodes are then embedded in paraffin, sectioned at 2 mm intervals, and stained with eosin and hematoxylin. The total number of nodes, their size and presence of metastasis will be recorded.

Data collection:

Demographic, clinical and pathological information will be recorded prospectively. Demographic variables analyzed will include: age, sex, weight, height and race. Clinical variables will include: date of cancer diagnosis, clinical and pathologic stage at diagnosis and at time of surgery (TNM staging), date of radical cystectomy, history of intravesical chemotherapy, other medical co-morbidities and prior abdominal surgeries, extent of lymph node dissection, and complications during the procedure. Pathological variables will be recorded for the findings on both the conventional and fat-emulsifying protocols. The number, size and presence of metastasis for each node found will be recorded.

STATISTICAL ANALYSIS:

Outcome measure:

The primary outcome will be the proportion of patients found to have lymph nodes metastases on pathologic examination. Specifically, the difference in proportion of specimens found to contain nodal metastases using the fat-emulsifying protocol compared to the conventional lymph node processing will be analyzed. Secondary outcome measures will be: the total number of lymph nodes and the total number of lymph node metastases counted by both techniques and the relationship between the size of lymph node and the presence of metastatic carcinoma.

Sample size calculation:

An increase in the identification of nodal metastases by 15% (fat-emulsifying compared to conventional processing) will be considered clinically significant. The current rate of node positivity at the time of radical cystectomy with PLND at VGH is 28%, so that an increase to 43% would be deemed clinically relevant. To detect this difference with a power (1-β) of 80% and an α error of 10%, 125 patients will need be enrolled in each arm of the study.

Analysis of Data:

Data will be analyzed using SPSS software. The independent samples t-test will be used to compare the results from the lymph node analysis when processed by conventional means versus the same nodes processed using the fat-emulsifying protocol (p\<0.5). The relationship of size to presence of metastatic disease will be done by linear regression model (p\<0.5). A significant difference between the groups will be defined as p\<0.05. A biostatistician (Robert Bell) at the Vancouver Prostate Centre will assist with data analysis.

SUMMARY

The investigators have the opportunity with simple and inexpensive technical processing measures to enhance an integral component of our clinical risk stratification in patients with invasive bladder cancer. The investigators can establish a solid foundation in pelvic lymph node counting upon which clinical concepts of lymph node yield and density can be validated. The investigators expect to demonstrate that the fat-emulsifying protocol is easy to adopt, reproducible and suitable for widespread use. It has the potential to impact every patient undergoing radical cystectomy with PLND.

Lymph Node Processing Protocol for Radical Cystectomy and Pelvic Lymph Node Dissection in Bladder Cancer

Standardising an Approach for Analysis of Lymph Node Specimens From Radical Cystectomy With Pelvic Lymph Node Dissection Through the Use of an Organic Fat-emulsifying Agent

The primary outcome will be the proportion of patients found to have lymph nodes metastases on pathologic examination. Specifically, the difference in proportion of specimens found to contain nodal metastases using the fat-emulsifying protocol compared to the conventional lymph node processing will be analyzed.

Secondary outcome measures will be: the total number of lymph nodes and the total number of lymph node metastases counted by both techniques and the relationship between the size of lymph node and the presence of metastatic carcinoma.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Tranexamic Acid During Cystectomy Trial (TACT)	NCT01869413	Bladder Cancer	Tranexamic Acid Placebo	18 Years -	Ottawa Hospital Research Institute
Dose Escalation, Expansion Study of Vofatamab (B-701) in Treatment of Locally Advanced or Metastatic Urothelial Cell Carcinoma	NCT02401542	Locally Advance... Urinary Bladder... Urological Dise...	Vofatamab Docetaxel Placebo	18 Years -	Rainier Therapeutics
Diagnostic Accuracy of Optical Coherence Tomography in Upper Urinary Tract Urothelial Carcinoma	NCT02326909	Transitional Ce...	Optical Coheren... Optical Coheren...	18 Years -	Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
Tranexamic Acid During Cystectomy Trial (TACT)	NCT01869413	Bladder Cancer	Tranexamic Acid Placebo	18 Years -	Ottawa Hospital Research Institute
Lymph Node Processing Protocol for Radical Cystectomy and Pelvic Lymph Node Dissection in Bladder Cancer	NCT01395225	Bladder Cancer Transitional Ce...		18 Years -	University of British Columbia
Lymph Node Processing Protocol for Radical Cystectomy and Pelvic Lymph Node Dissection in Bladder Cancer	NCT01395225	Bladder Cancer Transitional Ce...		18 Years -	University of British Columbia

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