Neoplasms

Digestive System Diseases

All Conditions

Heart and Blood Diseases

Gastrointestinal Neoplasms

Thromboembolism

Digestive System Neoplasms

Gastrointestinal Diseases

Thrombosis

Embolism

Embolism and Thrombosis

Vascular Diseases

Fibrinolytic Agents

Anticoagulants

All Drugs and Chemicals

Enoxaparin

Enoxaparin sodium

Patients under ENOXA® 4000 IU according to randomization:

* Administer ENOXA® 4000 IU (Enoxaparin 4000 IU) per day, regardless of the patient's weight at inclusion
* Start injections 12 hours after the surgical procedure
* Administer ENOXA® subcutaneously
* The administration of ENOXA® should be at the same time on a daily basis for 30 successive days as per the american and french clinical guidelines

Patients under LOVENOX® 4000 IU according to randomization:

* Administer LOVENOX® 4000 IU (Enoxaparin 4000 IU) per day, regardless of the patient's weight at inclusion
* Start injections 12 hours after the surgical procedure
* Administer LOVENOX® subcutaneously
* The administration of LOVENOX® should be at the same time on a daily basis for 30 successive days as per the american and french clinical guidelines

Enoxaparin 4000 IU

Chadli DZIRI, MD

Prospective, monocentric, randomized, parallel group, rater-blinded study using two formulations of Enoxaparin sodium (ENOXA® vs LOVENOX®) to compare the thromboembolic events (symptomatic and asymptomatic) in patients undergoing gastrointestinal cancer surgery and thromboprophylactic treatment with either Enoxaparin formulations.

The study has a secondary focus as to evaluate the immunogenicity of the two formulations of Enoxaparin through a subgroup analysis.

Study followup duration is up to 30 days post surgical procedure.

Comparison of Thromboembolic Events in Patients Undergoing Thromboprophylactic Treatment With ENOXA® vs Lovenox®

Comparison of Thromboembolic Events in Patients Undergoing Gastrointestinal Cancer Surgery and Thromboprophylactic Treatment With Two Enoxaparin Formulations (ENOXA® vs Lovenox®)

To compare the incidence of asymptomatic DVT, assessed by Echo Doppler of the lower limbs, between the two study treatment arms

Compare the incidence of symptomatic DVT and pulmonary embolism (PE) between the two study treatment arms

To compare the safety of both the study of products

To compare the levels of platelet factor 4 (PF4)-Heparin complex antibodies an platelet count between the two study treatment arms

Les Laboratoires des Médicaments Stériles

Heparin, Low-Molecular-Weight

Tinzaparin

Dalteparin

Plasminogen Activator Inhibitor 1

Patients without LMWH treatment.

A thromboembolic event has to be diagnosed according to standard imaging criteria (spiral computed tomography CT, proximal lower limb venous compression ultrasonography US) by clinicians who will not have knowledge of the result of the fibrin structure marker.

The following assays will be performed for these patients :

* Fibrin Structure measured at baseline and every month using prototype assays
* Other markers activity : sFVIII:C and TFPI for coagulation activation, DDimers and PAI-1 for fibrinolysis resistance and fibrin assay, all measured at baseline and every 3 months.

Patients with LMWH treatment at prophylactic dose at enrollment only.

A thromboembolic event has to be diagnosed according to standard imaging criteria (spiral computed tomography CT, proximal lower limb venous compression ultrasonography US) by clinicians who will not have knowledge of the result of the fibrin structure marker.

The following assays will be performed for these patients :

* Fibrin Structure measured at baseline and every month using prototype assays,
* Anti-FXa activity measured at baseline and every month,
* Other markers activity : FVIII:C and TFPI for coagulation activation, DDimers and PAI-1 for fibrinolysis resistance and fibrin assay, all measured at baseline and every 3 months.

Patients with LMWH treatment at therapeutic dose.

A thromboembolic event has to be diagnosed according to standard imaging criteria (spiral computed tomography CT, proximal lower limb venous compression ultrasonography US) by clinicians who will not have knowledge of the result of the fibrin structure marker.

The following assays will be performed for these patients :

* Fibrin Structure measured at baseline and every month using prototype assays,
* Anti-FXa activity measured at baseline and every month,
* Other markers activity : FVIII:C and TFPI for coagulation activation, DDimers and PAI-1 for fibrinolysis resistance and fibrin assay, all measured at baseline and every 3 months.

Modifications of Fibrin Structure in patients who have developed VTE in comparison with patients without VTE.

Fibrin Structure

Isabelle Mahe, MD, PhD

Geneviève Contant, PhD

The purpose of the study is to assess the fibrin structure marker in the plasma of cancer patients, treated or not treated with LMWH at prophylactic or therapeutic doses, in order to determine the venous thromboembolic risk. The occurrence of thromboembolic events in patients without treatment and in patients under LMWH treatment will be recorded, depending on the location and type of cancer, metastases, and treatment of cancer.

Rationale. Venous thromboembolism (VTE) is a major complication often encountered in oncology and onco-hematology, and difficult to handle. It involves the activation of coagulation with the generation of fibrin and plasmin and angiogenesis activation. Low molecular weight heparins (LMWH) are used to treat cancer associated thrombosis. Furthermore, they could have an inhibitory effect on tumor progression.

International recommendations on the treatment and prophylaxis of the disease allow a better management of VTE in patients with cancer. Its prevalence is high, occurring in 15-20% of the patients. It remains the second leading cause of death after cancer. LMWH at therapeutic dosage for at least three months and preferably six months without oral bridging is the reference treatment for VTE, which showed a 50% reduction in the risk of recurrent thromboembolism without increasing the hemorrhagic risk. In case of VTE recurrence under LMWH treatment, the dose can be increased by 10%. Preliminary results suggest that the fibrin structure marker would predict the hemorrhagic or thromboembolic risk, and show that LMWH has a dose-dependent effect on fibrin structure. This marker is evaluated as a tool to guide the treatment of VTE by LMWH in patients with cancer.

Main objective. To assess the fibrin structure marker in the plasma of cancer patients, treated or not treated with LMWH at prophylactic doses at enrollment or therapeutic doses, to determine the venous thromboembolic risk. The occurrence of thromboembolic events in patients without treatment or of recurrent thromboembolic events in patients under LMWH treatment will be studied, depending on the location and type of cancer, metastases, and treatment of cancer.

Patients. At least 300 adult patients over 18 years with all types of malignancies documented before or during therapeutic treatment with LMWH for thromboembolic event. They will be monitored every month in consultation or during hospitalization in the Internal Medicine Department. The patients under prophylaxis with LMWH at enrollment will also be included and classified in the group of prophylactic patients. The patients who receive prophylactic treatment during will be included and classified in the group of untreated patients.

Will not be included: patients with sepsis, severe infections, pneumonia, surgery, suspected thromboembolic event related to catheter implantation, vitamin K antagonists (VKA) in progress, and those with impossible follow-up.

The study is conducted in compliance with French regulation after ethics approval, the authorization for processing personal data (Commission Nationale de l'Informatique et des Libertés, 8, rue Vivienne CS 30223 75083 Paris Cedex 02) receipt number 1867686 v 0, date 18 June 2015.

Reference algorithm. Patients will be supported for the diagnosis and specific treatment of cancer (with or without metastases), according to the daily practice. The baseline risk score is the Khorana score of clinical probability, based on clinical criteria. A thromboembolic event has to be diagnosed according to standard imaging criteria (spiral computed tomography CT, proximal lower limb venous compression ultrasonography US) by clinicians who will not have knowledge of the result of the fibrin structure marker.

Biological parameters to be studied. The following tests will be carried out on frozen citrated plasma or serum, without knowledge of the clinical data and the conclusion of a diagnostic of thromboembolic event:

* Structure of the fibrin using coag-lysis method, measured at baseline and every month for all patients, by one site, using prototype assays
* Anti-FXa activity measured at baseline and every month only for patients treated with LMWH at therapeutic doses,
* FVIII:C and TFPI for coagulation activation, DDimers and PAI-1 for fibrinolysis resistance, Fibrin assay for inflammation and hypercoagulation evaluation, all measured at baseline and every 3 months for all patients.

Evaluation of Fibrin Structure Marker in Cancer Patients Treated and Not Treated With LMWH

Evolution of the optical density delta (ODD) and temporal parameters in patients who have developed VTE in comparison with those without VTE; variations of the Fibrin Structure parameters in comparison with either coagulation activation or fibrinolysis resistance assays, or fibrin assay.

Changes of the Fibrin structure parameters in patients of group III in comparison with group I and/or group II.

Hôpital Louis Mourier

Hopital Lariboisière

Diagnostica Stago R&D

Symptoms and General Pathology

Body Weight

Colorectal Neoplasms

Intestinal Neoplasms

Colonic Diseases

Intestinal Diseases

Rectal Diseases

Heparin

Calcium heparin

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.

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.

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.

A responsible person Designated by the Sponsor

Responsible person Designated by the Sponsor

Principal Investigator Designated by the sponsor, M.D.

Principal Investigator Designated by the Sponsor, M.D.

Responsible person Designated by the sponsor

A responsible person Designated by the sponsor

Mercedes Salgado, M.D.

Mercedes Salgado, M.D. Ph.D.

Andrés Muñoz, M.D. Ph.D.

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.

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.

Two-arm, randomized, non-placebo controlled, open-label

TINzaparin Prophylaxis in Patients With Metastatic Colorectal Cancer

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

Anonymized individual participant data (IPD) may be available upon request if it is within the same scope approved by the participants when they gave their written informed consent to participate

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

Percentage of patients experiencing the event during the observation period (6 months)

Percentage of patients experiencing confirmed VTE events in patients with BRAF / RAS tumor genomic mutations vs native BRAF / RAS tumors.

Percentage of patients experiencing confirmed VTE events in patients with primary tumor resection vs not resection.

Percentage of patients experiencing confirmed VTE events in patients on antiangiogenic treatment

Percentage of patients experiencing confirmed VTE events in patients on anti-EGFR treatment

Percentage of patients experiencing confirmed VTE events in patients with right-side / transverse primary tumor vs left-side primary tumor.

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

Percentage of patients experiencing confirmed VTE events in patients according to their genetic risk score

Percentage of patients experiencing confirmed VTE events in patients according to their blood type

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

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

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

Defined as the time elapsed from the first dose of study treatment until death from any cause

Percentage of patients who died through the study

Percentage of patients who experience grade 3-5 according to CTCAE version 5.0

Percentage of patients who experience TRAEs

Percentage of patients who experience MB according to ISTH criteria throughout the study period and up to month 2 of end of tinzaparin treatment

Percentage of patients who experience CRNMB according to ISTH criteria throughout the study period and up to month 2 of end of tinzaparin treatment

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.

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

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

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

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

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

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

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Comparison of Thromboembolic Events in Patients Undergoing Thromboprophylactic Treatment With ENOXA® vs Lovenox®	NCT02444572	Gastrointestina... Thromboembolic ...	Enoxaparin 4000...	19 Years - 90 Years	Les Laboratoires des Médicaments Stériles
Evaluation of Fibrin Structure Marker in Cancer Patients Treated and Not Treated With LMWH	NCT02552381	Malignant Tumor	Fibrin Structur...	18 Years -	Diagnostica Stago R&D
Comparison of Thromboembolic Events in Patients Undergoing Thromboprophylactic Treatment With ENOXA® vs Lovenox®	NCT02444572	Gastrointestina... Thromboembolic ...	Enoxaparin 4000...	19 Years - 90 Years	Les Laboratoires des Médicaments Stériles
Evaluation of Fibrin Structure Marker in Cancer Patients Treated and Not Treated With LMWH	NCT02552381	Malignant Tumor	Fibrin Structur...	18 Years -	Diagnostica Stago R&D
Comparison of Thromboembolic Events in Patients Undergoing Thromboprophylactic Treatment With ENOXA® vs Lovenox®	NCT02444572	Gastrointestina... Thromboembolic ...	Enoxaparin 4000...	19 Years - 90 Years	Les Laboratoires des Médicaments Stériles
Evaluation of Fibrin Structure Marker in Cancer Patients Treated and Not Treated With LMWH	NCT02552381	Malignant Tumor	Fibrin Structur...	18 Years -	Diagnostica Stago R&D
TINzaparin Prophylaxis in Patients With Metastatic Colorectal Cancer	NCT05625932	Colorectal Canc... Thromboembolism	Tinzaparin	18 Years -	Galician Research Group on Digestive Tumors

Spots Global Cancer Trial Database for thromboembolic event