TINzaparin Prophylaxis in Patients With Metastatic Colorectal Cancer

NCT ID: NCT05625932

Last Updated: 2025-08-22

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 232 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2023-03-02
• Study Completion Date: 2025-06-04

Brief 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.

Detailed 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.

Conditions

Colorectal Cancer Metastatic; Thromboembolism

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: PREVENTION
• Blinding Strategy: NONE

Study Groups

Control Arm

Those patients allocated in the control arm will receive no interventions related to VTE risk. No placebo will be administered to avoid discomfort of these patients who are already under treatment for their cancer.

Group Type: NO_INTERVENTION

No interventions assigned to this group

Experimental arm

Those patients allocated to the experimental arm will receive prophylactic Tinzaparin at a fixed dose according to their weight:

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.

Accordingly, the effective dose of tinzaparin is estimated to be in the range of 56-90 IU/kg. Tinzaparin dose will be adjusted according to the dose levels specified above in patients who experience changes in body weight greater than 10% during treatment period.

Group Type: EXPERIMENTAL

Tinzaparin

Intervention Type: DRUG

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.

Interventions

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.

Intervention Type: DRUG

Other Intervention Names

Innohep

Eligibility Criteria

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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

LEO Pharma

INDUSTRY

Sponsor Role: collaborator

Galician Research Group on Digestive Tumors

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Mercedes Salgado, M.D. Ph.D.

Role: STUDY_CHAIR

Complexo Hospitalario Universitario de Ourense (Galicia)

Andrés Muñoz, M.D. Ph.D.

Role: STUDY_CHAIR

Hospital Universitario Gregorio Marañón (Madrid)

Locations

Hospital Clínico Universitario de Santiago CHUS

Santiago de Compostela, A Coruña, Spain

Hospital Público Verge dels Lliris

Alcoy, Alicante, Spain

Hospital Universitario Son Espases

Palma de Mallorca, Balearic Islands, Spain

ICO (Institut Català d'Oncologia) de Badalona

Badalona, Barcelona, Spain

Institut Català d'Oncologia L'Hospitalet

L'Hospitalet de Llobregat, Barcelona, Spain

Consorcio Corporación Sanitaria Parc Taulí

Sabadell, Barcelona, Spain

Hospital Universitario Marqués de Valdecilla

Santander, Cantabria, Spain

Hospital General La Mancha Centro

Alcázar de San Juan, Ciudad Real, Spain

Hospital Univ. de Jerez de la Frontera

Jerez de la Frontera, Cádiz, Spain

Hospital Universitario Príncipe de Asturias (HUPA) de Alcalá de Henares

Alcalá de Henares, Madrid, Spain

Hospital Universitario De Móstoles

Móstoles, Madrid, Spain

Hospital Infanta Cristina (Parla)

Parla, Madrid, Spain

Hospital Universitario Infanta Elena

Valdemoro, Madrid, Spain

Hospital Costa del Sol de Marbella

Marbella, Málaga, Spain

Hospital Obispo Polanco De Teruel

Teruel, Terul, Spain

Complejo Hospitalario Universitario de A Coruña (CHUAC)

A Coruña, , Spain

Centro Oncológico de Galicia (A coruña)

A Coruña, , Spain

Complejo Hospitalario Universitario de Ferrol ( Arquitecto Macide)

A Coruña, , Spain

Hospital de la Santa Creu i Sant Pau

Barcelona, , Spain

Hospital Clinic Barcelona

Barcelona, , Spain

Hospital General Virgen de la Luz de Cuenca

Cuenca, , 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 General Universitario Morales Meseguer

Murcia, , Spain

Complejo Hospitalario Universitario De Ourense

Ourense, , Spain

Complejo Hospitalario Universitario de Pontevedra

Pontevedra, , Spain

Complejo Asistencial Universitario De Salamanca

Salamanca, , Spain

Hospital Universitario Virgen del Rocio

Seville, , Spain

Hospital General Universitario de Toledo

Toledo, , Spain

Hospital General Universitario de Valencia

Valencia, , Spain

Hospital Ribera Povisa

Vigo, , Spain

Complejo Hospitalario Universitario de Vigo (Álvaro Cunqueiro)

Vigo, , Spain

Complejo Asistencial de Zamora

Zamora, , Spain

Countries

Spain

Other Identifiers

2022-001534-11

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

GIT-PRo-2022-02

Identifier Type: -

Identifier Source: org_study_id