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Trial record 1 of 1 for:    GIT-PRo-2022-02 PROTINCOL
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TINzaparin Prophylaxis in Patients With Metastatic Colorectal Cancer (PROTINCOL)

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ClinicalTrials.gov Identifier: NCT05625932
Recruitment Status : Recruiting
First Posted : November 23, 2022
Last Update Posted : May 1, 2024
Sponsor:
Collaborator:
LEO Pharma
Information provided by (Responsible Party):
Galician Research Group on Digestive Tumors

Study Description
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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.


Condition or disease Intervention/treatment Phase
Colorectal Cancer Metastatic Thromboembolism Drug: Tinzaparin Phase 3

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.

Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 526 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Two-arm, randomized, non-placebo controlled, open-label
Masking: None (Open Label)
Primary Purpose: Prevention
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.
Actual Study Start Date : March 2, 2023
Estimated Primary Completion Date : December 2024
Estimated Study Completion Date : March 2025
Arms and Interventions
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Arm Intervention/treatment
No Intervention: 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.
Experimental: 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.

 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.
Other Name: Innohep


Outcome Measures
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Primary Outcome Measures :
  1. Incidence of any VTE [ Time Frame: Throughout the study period, approximately 6 months per patient ]

    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



Secondary Outcome Measures :
  1. Incidence of symptomatic non-fatal PE [ Time Frame: Throughout the study period, approximately 6 months per patient ]
    Percentage of patients experiencing the event during the observation period (6 months)

  2. Incidence of sllDVT [ Time Frame: Throughout the study period, approximately 6 months per patient ]
    Percentage of patients experiencing the event during the observation period (6 months)

  3. Incidence of sueDVT [ Time Frame: Throughout the study period, approximately 6 months per patient ]
    Percentage of patients experiencing the event during the observation period (6 months)

  4. Incidence of incidentally diagnosed PE or proximal DVT [ Time Frame: Throughout the study period, approximately 6 months per patient ]
    Percentage of patients experiencing the event during the observation period (6 months)

  5. Incidence of symptomatic central venous catheter thromboembolism [ Time Frame: Throughout the study period, approximately 6 months per patient ]
    Percentage of patients experiencing the event during the observation period (6 months)

  6. Incidence of iVVT [ Time Frame: Throughout the study period, approximately 6 months per patient ]
    Percentage of patients experiencing the event during the observation period (6 months)

  7. Incidence of sVVT [ Time Frame: Throughout the study period, approximately 6 months per patient ]
    Percentage of patients experiencing the event during the observation period (6 months)

  8. Incidence of VTE-related deaths [ Time Frame: Throughout the study period, approximately 6 months per patient ]
    Percentage of patients experiencing the event during the observation period (6 months)

  9. Incidence of confirmed VTE events in BRAF/RAS mutated patients [ Time Frame: Throughout the study period, approximately 6 months per patient ]
    Percentage of patients experiencing confirmed VTE events in patients with BRAF / RAS tumor genomic mutations vs native BRAF / RAS tumors.

  10. Incidence of confirmed VTE events in resected or not resected patients [ Time Frame: Throughout the study period, approximately 6 months per patient ]
    Percentage of patients experiencing confirmed VTE events in patients with primary tumor resection vs not resection.

  11. Incidence of confirmed VTE events in patients with antiangiogenic therapy [ Time Frame: Throughout the study period, approximately 6 months per patient ]
    Percentage of patients experiencing confirmed VTE events in patients on antiangiogenic treatment

  12. Incidence of confirmed VTE events in patients with anti-EGFR therapy [ Time Frame: Throughout the study period, approximately 6 months per patient ]
    Percentage of patients experiencing confirmed VTE events in patients on anti-EGFR treatment

  13. Incidence of confirmed VTE events in patients according to tumor laterality [ Time Frame: Throughout the study period, approximately 6 months per patient ]
    Percentage of patients experiencing confirmed VTE events in patients with right-side / transverse primary tumor vs left-side primary tumor.

  14. Incidence of confirmed VTE events in patients according to progression (PD) [ Time Frame: Throughout the study period, approximately 6 months per patient ]
    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

  15. Incidence of confirmed VTE events in patients according genetic risk scores [ Time Frame: Throughout the study period, approximately 6 months per patient ]
    Percentage of patients experiencing confirmed VTE events in patients according to their genetic risk score

  16. Incidence of confirmed VTE events in patients according to blood type [ Time Frame: Throughout the study period, approximately 6 months per patient ]
    Percentage of patients experiencing confirmed VTE events in patients according to their blood type

  17. Incidence of arterial thromboembolic events (ATE) [ Time Frame: Throughout the study period, approximately 6 months per patient ]
    Percentage of patients experiencing ATE

  18. Thrombosis-free survival (TFS) [ Time Frame: Throughout the study period, approximately 6 months per patient ]
    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

  19. Event-free survival (EFS) [ Time Frame: Throughout the study period, approximately 6 months per patient ]
    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

  20. Progression-free survival (PFS) [ Time Frame: Throughout the study period, approximately 6 months per patient ]
    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

  21. Overall survival (OS) [ Time Frame: Throughout the study period, approximately 6 months per patient ]
    Defined as the time elapsed from the first dose of study treatment until death from any cause

  22. Mortality rate [ Time Frame: Throughout the study period, approximately 2 years ]
    Percentage of patients who died through the study

  23. Incidence of relevant adverse events (AE) [ Time Frame: Throughout the study period, approximately 2 years ]
    Percentage of patients who experience grade 3-5 according to CTCAE version 5.0

  24. Incidence of treatment-related AEs (TRAEs) [ Time Frame: Throughout the study period, approximately 2 years ]
    Percentage of patients who experience TRAEs

  25. Incidence of major bleeding (MB) events [ Time Frame: Throughout the study period, approximately 6 months per patient ]
    Percentage of patients who experience MB according to ISTH criteria throughout the study period and up to month 2 of end of tinzaparin treatment

  26. Incidence of Clinically relevant non-major bleeding (CRNMB) [ Time Frame: Throughout the study period, approximately 6 months per patient ]
    Percentage of patients who experience CRNMB according to ISTH criteria throughout the study period and up to month 2 of end of tinzaparin treatment

  27. Quality of life score [ Time Frame: Throughout the study period, approximately 6 months per patient ]
    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.

  28. Incidence of bleeding events in BRAF/RAS mutated patients [ Time Frame: Throughout the study period, approximately 6 months per patient ]
    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

  29. Incidence of bleeding events according to surgery [ Time Frame: Throughout the study period, approximately 6 months per patient ]
    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

  30. Incidence of bleeding events according to antiangiogenic therapy [ Time Frame: Throughout the study period, approximately 6 months per patient ]
    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

  31. Incidence of bleeding events according to anti-EGFR therapy [ Time Frame: Throughout the study period, approximately 6 months per patient ]
    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

  32. Incidence of bleeding events according to tumor laterality [ Time Frame: Throughout the study period, approximately 6 months per patient ]
    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

  33. Incidence of bleeding events according to genetic risk [ Time Frame: Throughout the study period, approximately 6 months per patient ]
    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


Eligibility Criteria
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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT05625932


Contacts
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Contact: A responsible person Designated by the Sponsor +34 93 434 44 12 investigacion@mfar.net

Locations
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Sponsors and Collaborators
Galician Research Group on Digestive Tumors
LEO Pharma
Investigators
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Study Chair: Mercedes Salgado, M.D. Ph.D. Complexo Hospitalario Universitario de Ourense (Galicia)
Study Chair: Andrés Muñoz, M.D. Ph.D. Hospital Universitario Gregorio Marañón (Madrid)
More Information
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Responsible Party: Galician Research Group on Digestive Tumors
ClinicalTrials.gov Identifier: NCT05625932    
Other Study ID Numbers: GIT-PRo-2022-02
2022-001534-11 ( EudraCT Number )
First Posted: November 23, 2022    Key Record Dates
Last Update Posted: May 1, 2024
Last Verified: May 2023
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Plan Description: 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

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Galician Research Group on Digestive Tumors:
LMWH
Prophylaxis
Thromboembolic event
Colorectal cancer
Additional relevant MeSH terms:
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Colorectal Neoplasms
Thromboembolism
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Neoplasms
Digestive System Diseases
Gastrointestinal Diseases
Colonic Diseases
Intestinal Diseases
 Rectal Diseases
Embolism and Thrombosis
Vascular Diseases
Cardiovascular Diseases
Tinzaparin
Heparin, Low-Molecular-Weight
Dalteparin
Anticoagulants
Fibrinolytic Agents
Fibrin Modulating Agents
Molecular Mechanisms of Pharmacological Action