TINzaparin Prophylaxis in Patients With Metastatic Colorectal Cancer

Colorectal Cancer Metastatic Clinical Trial

— PROTINCOL  

Official title:

Prophylaxis of Venous Thromboembolic Disease With Low Molecular Weight (LMWH) (TINzaparin) in Patients With Metastatic Colorectal Cancer Who Start the First Line of Treatment.

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05625932
• Other study ID #: GIT-PRo-2022-02
• Secondary ID: 2022-001534-11
• Status: Recruiting
• Phase: Phase 3
• Start date: March 2, 2023
• Est. completion date: March 2025

Study information

• Verified date: May 2023
• Source: Galician Research Group on Digestive Tumors
• Contact: A responsible person Designated by the Sponsor
• Phone: +34 93 434 44 12
• Email: investigacion[@]mfar.net
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Patients with metastatic colorectal cancer (mCRC) who are scheduled to receive systemic cancer therapy have an increased risk for venous thromboembolic (VTE) events compared with the general population.

PROTINCOL is a randomized, open label, non placebo-controlled, low intervention, and phase III clinical trial that will recruit patients with mCRC. The study hypothesizes that prophylaxis with Tinzaparin could prevent the appearance of symptomatic and incidental VTE.

All patients will receive the first-line anticancer treatment deemed more appropriate according to the physician criteria. Enrolled patients are randomized in a 1:1 ratio (stratifying by BRAF/RAS, resection of primary tumor, and anti-angiogenic first-line treatment) to: control arm (no interventions related to VTE risk and no placebo) or experimental arm (prophylactic Tinzaparin at a fixed dose of 4500 IU/day in patients with up to 80kg, 6000 IU/day for those between 80-100 kg, or 8000 IU/day for those >100kg). Treatment is scheduled for a maximum period of 4 months. Treatment could be stopped earlier in case of unacceptable toxicity, patient consent withdrawal, physician criteria or end of study. Patients will undergo tumor and VTE assessments according to standard clinical practice.

The main objective of the study is to evaluate the efficacy of tinzaparin for the prevention of symptomatic or incidental VTE events. Secondary objectives include the associations between VTE events and tumor characteristics (i.e. laterality, RAS/BRAF mutations) or management (i.e. surgery or treatment with anti-angiogenic or anti-EGFR agents), cancer-specific survival outcomes, safety, the incidence of bleeding events, and patient-reported quality of life. The trial includes also a translational exploratory analysis to assess the predictive value of risk assessment models and genetic risk scores, their evolution through the study and microsatellite instability or other biomarkers.

Description:

This research study is a prospective, randomized, open label (PROBE), non placebo-controlled, and phase III clinical trial; Investigator Initiated Study (IIS). The study has been considered a low-interventional clinical trial.

The trial will compare the efficacy and safety of tinzaparin with a watch and wait strategy for primary prophylaxis of symptomatic or incidental VTE in adult men and women, 18 years of age and older, with metastatic colorectal cancer who are scheduled to initiate systemic cancer therapy as a component of their standard of care anticancer regimen.

The study consists of 3 periods: a 4-week screening period, a 4 months treatment period and post-treatment follow-up period until the end of treatment (EOT) visit, scheduled 2 months after the last dose of tinzaparin or 6 months from the first dose of tinzaparin (whichever occurs latest). The duration of participation in the study for each subject is approximately 6 months. Further long-term phone follow-up to monitor for progression and survival could be carried out at the end of study. Tumor follow-up assessments will adhere to the standard clinical practice within each site.

All patients will receive the first-line anticancer treatment deemed more appropriate according to the physician criteria and current guideline recommendations. Patients in both groups will receive supportive care as per local practice. No formal recommendations will be issued by the study protocol regarding cancer treatment and supportive care, but the drugs used will be recorded in the clinical report form. Constitutive use of anticoagulant drugs will be prohibited during the treatment period.

Enrolled patients are randomized in a 1:1 ratio to the control arm, or the experimental arm:

Control arm: A watch and wait strategy will be used. There is no placebo. Since no reference treatment is available for long-term VTE prophylaxis in patients with cancer, patients in the control group will not receive VTE prophylaxis outside the hospital and will receive anticancer treatment and supportive care as per local practice. No formal recommendations will be issued by the study protocol regarding cancer treatment and supportive care, but the drugs used will be recorded in the clinical report form (CRF). Patients in the control group will receive antithrombotic prophylaxis as per local practice during hospitalizations. Any use of LMWH will be recorded in the CRF.

Experimental arm: Patients will receive prophylaxis tinzaparin at a fixed dose daily for 4 months.

The primary objective is to evaluate the efficacy of 4-months prophylaxis with tinzaparin for the prevention of symptomatic or incidental VTE events. Secondary efficacy objectives include the VTE incidence in specific subpopulations (stratification according to the laterality of the primary tumor, first-line treatment with anti-EGFR or antiangiogenics, and mutational status).

Safety of tinzaparin will be evaluated by means of relevant adverse events, incidence of bleedings according to International Society of Thrombosis and Hemostasis (ISTH) criteria, and patient-reported quality of life. Bleeding events will be evaluated locally by the investigator and centrally by a blinded committee.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 526
• Est. completion date: March 2025
• Est. primary completion date: December 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

1. Male or female subjects with age = 18 years.

2. Written informed consent.

3. Patients with a histologically confirmed diagnosis of stage IV colon or rectal adenocarcinoma (mCRC).

4. Locally assessed BRAF and RAS genomic alterations available during screening.

5. Beginning of the first line of treatment for metastatic disease with chemotherapy +/- targeted therapy (i.e. antiangiogenic, anti-EGFR, encorafenib-cetuximab doublet) or immunotherapy.

6. Eastern Cooperative Oncology Group (ECOG) performance status of 0-2.

7. Life expectancy >6 months.

Exclusion Criteria:

1. Contraindication to tinzaparin, or other heparins:

1. Allergy (or hypersensitivity) to heparin, tinzaparin, other LMWHs, or pork products.

2. History or presence of heparin-induced (type II) thrombocytopenia.

3. Have or have had an epidural catheter or a traumatic spinal puncture within the previous 7 days.

2. Prothrombin time (PT) (International normalized ratio [INR] >1.5 for any reason) or aPTT >2 times control value.

3. Active major bleeding or conditions predisposing to major bleeding. a major bleeding is defined as one that meets one of the following three criteria:

1. occurring in a critical area or organ (for example, intracranial, intra-spinal, intraocular, retroperitoneal, intra-articular or pericardial, intrauterine or intramuscular with compartment syndrome),

2. causing a decrease in hemoglobin levels of 2 g/l (1.24 mmol/l) or more, or that requires a transfusion of two or more units of whole blood or packed red blood cells.

4. Lesions or conditions at increased risk of clinically significant bleeding, including:

1. Previously diagnosed/treated VTE = 28 days prior to randomization.

2. Active ulcer disease.

3. Diagnosed cerebral metastases.

4. Stroke within the prior 6 months.

5. History of central nervous system (CNS) or intraocular bleeding.

5. Requirement of other anticoagulant therapy, dual antiplatelet therapy, daily non-steroidal anti-inflammatory drugs, or other medications known to increase the risk of bleeding.

Note: A daily dose of =100 mg of aspirin and single agent clopidogrel are permitted

6. Acute or chronic renal insufficiency with Creatinine clearance < 30 ml / min.

7. Platelet count < 80.000 /ml at the time of inclusion.

8. Severe liver insufficiency as defined by clinical manifestations of ascites, cirrhosis, encephalopathy and/or jaundice and/or biochemical abnormalities in liver function tests including:

1. elevated levels of total bilirubin (> 2 times the upper limit normal [ULN]),

2. elevated liver transaminases (> 2 times the ULN; > 5 in case of hepatic metastasis).

9. Participating in another study of an investigational agent at the time of enrollment. Note: Use of an experimental regimen of an approved product is not cause for exclusion.

10. Patients who weigh < 50 Kg.

11. Women of childbearing potential (WOCBP), must provide a negative serum or urine pregnancy test at screening. Women breastfeeding are not eligible.

Note: A pregnancy test is performed on WOCBP as per standard of care for patients undergoing anticancer treatments.

12. Any underlying medical or psychiatric disorder, which, in the opinion of the investigator, makes the administration of tinzaparin unsafe or interferes with the informed consent process or trial procedures.

Related Conditions & MeSH terms

• Colorectal Cancer Metastatic
• Colorectal Neoplasms
• Thromboembolism

Intervention

Drug:
• Tinzaparin
Patients < 80 kg will receive a fixed dose of 4500 IU daily. Patients between 80-100 kg will receive a fixed dose of 6000 IU daily. Patients > 100 kg will receive a fixed dose of 8000 IU daily.

Locations

Country	Name	City	State
Spain	Centro Oncológico de Galicia (A coruña)	A coruña
Spain	Complejo Hospitalario Universitario de A Coruña (CHUAC)	A Coruña
Spain	Complejo Hospitalario Universitario de Ferrol ( Arquitecto Macide)	A Coruña
Spain	Hospital Universitario Príncipe de Asturias (HUPA) de Alcalá de Henares	Alcalá De Henares	Madrid
Spain	Hospital General La Mancha Centro	Alcázar De San Juan	Ciudad Real
Spain	Hospital Público Verge dels Lliris	Alcoy	Alicante
Spain	ICO (Institut Català d'Oncologia) de Badalona	Badalona	Barcelona
Spain	Hospital Clinic Barcelona	Barcelona
Spain	Hospital de la Santa Creu i Sant Pau	Barcelona
Spain	Hospital General Virgen de la Luz de Cuenca	Cuenca
Spain	Hospital Univ. de Jerez de la Frontera	Jerez De La Frontera	Cádiz
Spain	Institut Català d'Oncologia L'Hospitalet	L'Hospitalet De Llobregat	Barcelona
Spain	Hospital Universitario Arnau de Vilanova de Lleida	Lleida
Spain	Hospital Universitario Lucus Augusti	Lugo
Spain	Hospital Clinico San Carlos	Madrid
Spain	Hospital Universitario 12 de Octubre	Madrid
Spain	Hospital Costa del Sol de Marbella	Marbella	Málaga
Spain	Hospital Universitario De Móstoles	Móstoles	Madrid
Spain	Hospital General Universitario Morales Meseguer	Murcia
Spain	Complejo Hospitalario Universitario De Ourense	Ourense
Spain	Hospital Universitario Son Espases	Palma De Mallorca	Baleares
Spain	Hospital Infanta Cristina (Parla)	Parla	Madrid
Spain	Complejo Hospitalario Universitario de Pontevedra	Pontevedra
Spain	Consorcio Corporación Sanitaria Parc Taulí	Sabadell	Barcelona
Spain	Complejo Asistencial Universitario De Salamanca	Salamanca
Spain	Hospital Universitario Marqués de Valdecilla	Santander	Cantabria
Spain	Hospital Clínico Universitario de Santiago CHUS	Santiago De Compostela	A Coruña
Spain	Hospital Universitario Virgen del Rocio	Sevilla
Spain	Hospital Obispo Polanco De Teruel	Teruel	Terul
Spain	Hospital General Universitario de Toledo	Toledo
Spain	Hospital Universitario Infanta Elena	Valdemoro	Madrid
Spain	Hospital General Universitario de Valencia	Valencia
Spain	Complejo Hospitalario Universitario de Vigo (Álvaro Cunqueiro)	Vigo
Spain	Hospital Ribera Povisa	Vigo
Spain	Complejo Asistencial de Zamora	Zamora

Sponsors (2)

Lead Sponsor	Collaborator
Galician Research Group on Digestive Tumors	LEO Pharma

Country where clinical trial is conducted

Spain, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Incidence of any VTE	The primary efficacy endpoint is the cumulative incidence (percentage of patients) of any VTE event including: Symptomatic non-fatal pulmonary thromboembolism (PE). Symptomatic lower-limb deep vein thromboembolism (sllDVT). Symptomatic upper extremity deep vein thromboembolism (sueDVT). Incidentally diagnosed PE or proximal DVT. Symptomatic central venous catheter thromboembolism. Incidentally visceral vein thrombosis (iVVT). Symptomatic visceral vein thrombosis (sVVT). VTE-related deaths	Throughout the study period, approximately 6 months per patient
Secondary	Incidence of symptomatic non-fatal PE	Percentage of patients experiencing the event during the observation period (6 months)	Throughout the study period, approximately 6 months per patient
Secondary	Incidence of sllDVT	Percentage of patients experiencing the event during the observation period (6 months)	Throughout the study period, approximately 6 months per patient
Secondary	Incidence of sueDVT	Percentage of patients experiencing the event during the observation period (6 months)	Throughout the study period, approximately 6 months per patient
Secondary	Incidence of incidentally diagnosed PE or proximal DVT	Percentage of patients experiencing the event during the observation period (6 months)	Throughout the study period, approximately 6 months per patient
Secondary	Incidence of symptomatic central venous catheter thromboembolism	Percentage of patients experiencing the event during the observation period (6 months)	Throughout the study period, approximately 6 months per patient
Secondary	Incidence of iVVT	Percentage of patients experiencing the event during the observation period (6 months)	Throughout the study period, approximately 6 months per patient
Secondary	Incidence of sVVT	Percentage of patients experiencing the event during the observation period (6 months)	Throughout the study period, approximately 6 months per patient
Secondary	Incidence of VTE-related deaths	Percentage of patients experiencing the event during the observation period (6 months)	Throughout the study period, approximately 6 months per patient
Secondary	Incidence of confirmed VTE events in BRAF/RAS mutated patients	Percentage of patients experiencing confirmed VTE events in patients with BRAF / RAS tumor genomic mutations vs native BRAF / RAS tumors.	Throughout the study period, approximately 6 months per patient
Secondary	Incidence of confirmed VTE events in resected or not resected patients	Percentage of patients experiencing confirmed VTE events in patients with primary tumor resection vs not resection.	Throughout the study period, approximately 6 months per patient
Secondary	Incidence of confirmed VTE events in patients with antiangiogenic therapy	Percentage of patients experiencing confirmed VTE events in patients on antiangiogenic treatment	Throughout the study period, approximately 6 months per patient
Secondary	Incidence of confirmed VTE events in patients with anti-EGFR therapy	Percentage of patients experiencing confirmed VTE events in patients on anti-EGFR treatment	Throughout the study period, approximately 6 months per patient
Secondary	Incidence of confirmed VTE events in patients according to tumor laterality	Percentage of patients experiencing confirmed VTE events in patients with right-side / transverse primary tumor vs left-side primary tumor.	Throughout the study period, approximately 6 months per patient
Secondary	Incidence of confirmed VTE events in patients according to progression (PD)	Percentage of patients experiencing confirmed VTE events in patients with PD according to usual clinical practice determined by the treating physician during treatment with tinzaparin	Throughout the study period, approximately 6 months per patient
Secondary	Incidence of confirmed VTE events in patients according genetic risk scores	Percentage of patients experiencing confirmed VTE events in patients according to their genetic risk score	Throughout the study period, approximately 6 months per patient
Secondary	Incidence of confirmed VTE events in patients according to blood type	Percentage of patients experiencing confirmed VTE events in patients according to their blood type	Throughout the study period, approximately 6 months per patient
Secondary	Incidence of arterial thromboembolic events (ATE)	Percentage of patients experiencing ATE	Throughout the study period, approximately 6 months per patient
Secondary	Thrombosis-free survival (TFS)	Defined as the time elapsed from the first dose of study treatment to the diagnosis of thrombotic event, or death from any cause, whichever occurs first	Throughout the study period, approximately 6 months per patient
Secondary	Event-free survival (EFS)	Events are defined as the endpoint of mortality, major bleeding and VTE. EFS is defined as the time elapsed from the first dose of study treatment to the diagnosis of VTE event, major bleeding event, or death by any cause, whichever occurs first	Throughout the study period, approximately 6 months per patient
Secondary	Progression-free survival (PFS)	Defined as the time elapsed from the first dose of study treatment to progression determined by the treating physician according to local standard clinical practice, or death from any cause, whichever occurs first	Throughout the study period, approximately 6 months per patient
Secondary	Overall survival (OS)	Defined as the time elapsed from the first dose of study treatment until death from any cause	Throughout the study period, approximately 6 months per patient
Secondary	Mortality rate	Percentage of patients who died through the study	Throughout the study period, approximately 2 years
Secondary	Incidence of relevant adverse events (AE)	Percentage of patients who experience grade 3-5 according to CTCAE version 5.0	Throughout the study period, approximately 2 years
Secondary	Incidence of treatment-related AEs (TRAEs)	Percentage of patients who experience TRAEs	Throughout the study period, approximately 2 years
Secondary	Incidence of major bleeding (MB) events	Percentage of patients who experience MB according to ISTH criteria throughout the study period and up to month 2 of end of tinzaparin treatment	Throughout the study period, approximately 6 months per patient
Secondary	Incidence of Clinically relevant non-major bleeding (CRNMB)	Percentage of patients who experience CRNMB according to ISTH criteria throughout the study period and up to month 2 of end of tinzaparin treatment	Throughout the study period, approximately 6 months per patient
Secondary	Quality of life score	Patients reported outcomes through the EORTC quality of life questionnaire (QLQ)-C30 questionnaire. QLQ-C30 scale is a 28 items that are scored on a 4-point response scale. All scale scores are linearly converted to range from 0 to 100. For the functioning scales and global QOL higher scores indicate better functioning.	Throughout the study period, approximately 6 months per patient
Secondary	Incidence of bleeding events in BRAF/RAS mutated patients	Percentage of patients who experienced a MB or CRNMB according to ISTH criteria throughout the study period and up to month 2 of end of tinzaparin treatment. Results will be reported according to BRAF/RAS mutational statu	Throughout the study period, approximately 6 months per patient
Secondary	Incidence of bleeding events according to surgery	Percentage of patients who experienced a MB or CRNMB according to ISTH criteria throughout the study period and up to month 2 of end of tinzaparin treatment. Results will be reported according to previous surgery of the primary tumor	Throughout the study period, approximately 6 months per patient
Secondary	Incidence of bleeding events according to antiangiogenic therapy	Percentage of patients who experienced a MB or CRNMB according to ISTH criteria throughout the study period and up to month 2 of end of tinzaparin treatment. Results will be reported according to first-line antiangiogenic agents treatment	Throughout the study period, approximately 6 months per patient
Secondary	Incidence of bleeding events according to anti-EGFR therapy	Percentage of patients who experienced a MB or CRNMB according to ISTH criteria throughout the study period and up to month 2 of end of tinzaparin treatment. Results will be reported according to first-line anti-EGFR treatment	Throughout the study period, approximately 6 months per patient
Secondary	Incidence of bleeding events according to tumor laterality	Percentage of patients who experienced a MB or CRNMB according to ISTH criteria throughout the study period and up to month 2 of end of tinzaparin treatment. Results will be reported in patients with right-sided or transversal vs. left-sided primary tumor	Throughout the study period, approximately 6 months per patient
Secondary	Incidence of bleeding events according to genetic risk	Percentage of patients who experienced a MB or CRNMB according to ISTH criteria throughout the study period and up to month 2 of end of tinzaparin treatment. Results will be reported in patients according to their genetic risk score	Throughout the study period, approximately 6 months per patient