VTE Prevention With Rivaroxaban in Genitourinary Cancer Patients Receiving Systemic Therapy (PREVENT-GU)

Prevention of Thromboembolism With Rivaroxaban in Genitourinary Cancer Patients Receiving Systemic Therapy: A Randomized Placebo-Controlled, Double-Blind Clinical Trial

Patients with genitourinary cancers (ex: bladder, testicular, kidney) are at high risk of developing blood clots if they receive systemic therapy (ex: chemotherapy, immunotherapy). Blood clots cause pain, may require hospitalization and invasive testing, and in some cases cause death. In fact, blood clots are one of the leading causes of death in patients with cancer. Furthermore, patients who develop a blood clot require medication to thin the blood for a prolonged (sometimes indefinite) period of time, and this can disrupt other important cancer treatments. Studies have shown that using low dose blood thinners to prevent blood clots during systemic therapy is effective in some patients with cancer. However very few patients in these studies had genitourinary cancers, therefore physicians in Canada are not sure if recommending blood thinners to patients with genitourinary cancers is useful or safe. Safety is a primary concern because blood thinners may cause bleeding, and patients with genitourinary cancers may have higher risk of bleeding than patients with other types of cancer. The investigators hypothesize that blood thinners are effective and safe for reducing blood clots in patients with genitourinary cancers. The objective of this study is to determine if a large clinical trial testing the effectiveness and safety of low dose blood thinners for preventing blood clots in patients with genitourinary cancers receiving systemic therapy is feasible.

Study Overview

• Status: Not yet recruiting
• Conditions: Venous Thromboembolism; Urologic Cancer
• Intervention / Treatment: Drug: Rivaroxaban 10 MG; Other: Placebo control

Detailed Description

Background and Importance: Patients with cancer receiving systemic therapy are at high risk of venous thromboembolism (VTE). Thromboprophylaxis with antiocoagulants reduces VTEs during chemotherapy by 60%. Despite this, thromboprophylaxis is not routinely used in Canada for patients with genitourinary (GU) malignancies (bladder, testis, kidney). Reasons prophylaxis is not used are that very few GU patients were included in landmark trials evaluating DOACs, and because GU patients may be at higher risk of bleeding compared to non-GU cancer patients. The omission of GU patients from prior trials has created an important gap in knowledge because these patients have among the highest risk of VTE of all cancer patients. Prior studies have reported VTE rates during chemotherapy for bladder and testis cancer in the range of 10-15%, well above thresholds at which guidelines usually recommend thromboprophylaxis.

Hypotheses: The investigators hypothesize that thromboprophylaxis with a direct oral anticoagulant (DOAC) during systemic therapy for GU malignancies will reduce the risk of VTE with acceptable risk of major bleeding. Secondly, the investigators hypothesize that a randomized trial of thromboprophylaxis versus placebo in GU patients is feasible and needed to change care in Canada.

Research goals: The goal of this pilot study is to determine if a randomized control trial of thromboprophylaxis with rivaroxaban versus placebo in GU patients receiving systemic therapy is feasible.

Methods: This internal pilot feasibility study will randomize patients with GU malignancies receiving systemic therapy (patients) to rivaroxaban 10mg daily (intervention) versus placebo (control). The primary outcome of this internal pilot study will be feasibility of patient accrual. Feasibility will be reported as the average number of patients enrolled per month. Secondary outcomes will be time to trial initiation, number of patients enrolled per site, and proportion of patients who complete the intervention. If feasibility is confirmed, patients enrolled in the pilot will be included in the full trial using a vanguard design.

The primary outcome(s) of the full trial will be VTE (efficacy outcome) and major bleeding (safety outcome) during the intervention. Patient reported outcomes including quality of life will also be recorded.

Expected outcomes: While thromboprophylaxis is effective in cancer patients, medical guidelines only recommend prophylaxis for some patients due to limited evidence in disease-specific subgroups. Importantly, safety concerns in GU patients are a particular concern necessitating further study of this population. The investigators expect the results of this internal pilot study to prove feasibility of a full trial. The full trial will determine the net benefits/harms of prophylaxis in GU patients and change practice worldwide, regardless of the results.

• Study Type: Interventional
• Enrollment (Estimated): 120
• Phase: Phase 2; Phase 3

Contacts and Locations

• Study Contact: Name: Luke T Lavallee, MDCM MSc FRCSC; Phone Number: 71393 613-737-8899; Email: lulavallee@toh.ca
• Study Contact Backup: Name: David J Yachnin, MSc; Phone Number: 74639 613-798-5555; Email: dyachnin@toh.ca

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Patients who are starting systemic therapy for active GU cancer (bladder, testis, ureter/renal pelvis, kidney, urethral, penile) except for prostate cancer.
• Age ≥ 18
• Eligible systemic therapies include chemotherapy, targeted therapies (tyrosine kinase inhibitors and antiangiogenic therapy), and immunotherapies.
• Patients must be initiating systemic therapy with a minimum planned treatment duration of 8 weeks.

Exclusion Criteria:

• Anticoagulation (prophylactic or therapeutic dosing) required for another indication for entire duration of study
• Known allergies to rivaroxaban
• Concomitant use of dual antiplatelet therapy (two antiplatelet medications oncomitantly)
• Ongoing refractory bleeding that may be exacerbated by rivaroxaban.
• Concomitant use of strong inducers or inhibitors of CYP3A4 or glycoprotein-P (known interaction with rivaroxaban).
• Severe renal insufficiency (Creatinine clearance <30 mL/min (defined by Cockcroft-Gault))
• Severe liver disease (e.g. acute clinical hepatitis, chronic active hepatitis, cirrhosis)
• Thrombocytopenia < 50 x 109/L
• Life expectancy under 6 months.
• Pregnancy (if child bearing age under 50 and sexually active, documentation of use of effective contraception or negative B- HCG is required)
• Patient is breastfeeding or lactating
• History of condition at increased bleeding risk including, but not limited to:

cerebral infarction (hemorrhagic or ischemic), active peptic ulcer disease with recent bleeding, spontaneous or acquired impairment of hemostasis in the previous 4 weeks.

• Chronic hemorrhagic disorder
• Inability to adhere to protocol or obtain consent.
• Patients may be excluded from the study for other reasons, at the investigator's discretion.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Rivaroxaban; Participants receiving study drug (Rivaroxaban)	Drug: Rivaroxaban 10 MG; The intervention in the experimental arm will be rivaroxaban, 10 mg PO once daily (prophylactic dosing) for 180 days after the start of systemic therapy or until one of the primary study outcomes occurs (VTE or major bleeding).; Other Names: Xarelto
Placebo Comparator: Control; Participants receiving matched placebo	Other: Placebo control; Identical to Rivaroxaban intervention except participants will receive a matched placebo instead of the study drug

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Feasibility of enrollment, assesed by the number of patients accrued per month	The primary outcome of this Pilot Trial is feasibility of enrollment. Feasibility will be measured by the average number of patients accrued per month.	Enrollment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Recruitment rate	Number of participants recruited per month at each study site	Enrollment
VTE incidence	VTE will be recorded and adjudicated similarly to the full trial. Outcomes will be examined in aggregate to ascertain an estimate of baseline risk for patients in the trial. VTE outcomes will NOT be examined or reported by allocation group in the Pilot so all patients can be included in Full Trial analyses (internal pilot design).	During 180 days of study intervention
Bleeding incidence	Bleeding outcomes (major and minor) will be recorded and adjudicated similarly to the full trial. Outcomes will be examined in aggregate to ascertain an estimate of baseline risk for patients in the trial. Bleeding outcomes will NOT be examined or reported by allocation group in the Pilot so all patients can be included in Full Trial analyses (internal pilot design).	During 180 days of study intervention
Adherence to the study intervention, assessed as the proportion of patients taking the study medication >80% of days taken during the study period,	This outcome will measure patient adherence to the study intervention (defined as >80% of medication taken during the study intervention period). This will be assessed using pill counts during study follow-ups.	During 180 days of study intervention

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
VTE-related death	VTE-related death will be collected during the pilot but will not be analyzed until the full trial. VTE-related death will assess the frequency of deaths among participants directly related to a VTE event.	During 180 days of study intervention
Overall survival	Overall survival will be collected during the pilot but will not be analyzed until the full trial. Overall survival will assess the frequency with which participants die by any cause during the intervention.	During 180 days of study intervention
Incremental cost-effectiveness ratio	Incremental cost-effectiveness ratio will be collected during the pilot but will not be analyzed until the full trial. Incremental cost-effectiveness ratio will take the form of a cost utility analysis with outcome expressed as incremental cost per quality adjusted life year (QALY) gained.	During 180 days of study intervention
Health-related Quality of Life assessed using the EQ-5D-5L Score	Health-related Quality of Life will be collected during the pilot but will not be analyzed until the full trial. Health-related Quality of Life will be assessed using the EQ-5D-5L questionnaire. EQ-5D-5L contains two scores: The VAS ranges from 0-100 and represents a patient's sense of their overall health. Higher VAS scores represent a better outcome. The second measure is the EQ-5D-5L index which ranges from 0-1 (scores are reported with three decimal points) and shows quality of life along 5 dimensions which are weighted based on regional values in the final index score. Higher index scores represent a better outcome	During 180 days of study intervention

Collaborators and Investigators

• Sponsor: Ottawa Hospital Research Institute
• Collaborators: Canadian Institutes of Health Research (CIHR); Canadian Venous Thromboembolism Clinical Trials and Outcomes Research (CanVECTOR) Network; Kidney Cancer Research Network of Canada
• Investigators: Principal Investigator: Luke T Lavallee, MDCM MSc FRCSC, Ottawa Hospital Research Institute

Study record dates

Study Major Dates

• Study Start (Estimated): February 1, 2024
• Primary Completion (Estimated): February 1, 2026
• Study Completion (Estimated): February 1, 2026

Study Registration Dates

• First Submitted: June 8, 2023
• First Submitted That Met QC Criteria: June 16, 2023
• First Posted (Actual): June 27, 2023

Study Record Updates

• Last Update Posted (Actual): November 1, 2023
• Last Update Submitted That Met QC Criteria: October 30, 2023
• Last Verified: October 1, 2023

More Information

Terms related to this study

• Keywords: Venous Thromboembolism; Systemic Therapy; Thromboprophylaxis; Genitourinary Cancer
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Neoplasms; Neoplasms by Site; Urologic Diseases; Embolism and Thrombosis; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Thromboembolism; Venous Thromboembolism; Urologic Neoplasms; Urogenital Neoplasms; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Protease Inhibitors; Factor Xa Inhibitors; Antithrombins; Serine Proteinase Inhibitors; Anticoagulants; Rivaroxaban
• Other Study ID Numbers: PGU2023

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: No plan to share individual participant data with other researchers.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No