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Tinzaparin And Biomarkers After Neoadjuvant Treatment of Ovarian Cancer

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ClinicalTrials.gov Identifier: NCT05284552
Recruitment Status : Recruiting
First Posted : March 17, 2022
Last Update Posted : September 30, 2022
Sponsor:
Collaborators:
Region Jönköping County
Västervik Hospital
Information provided by (Responsible Party):
Preben Kjolhede, MD, professor, University Hospital, Linkoeping

Brief Summary:

Background:

Previous findings have indicated antineoplastic properties of tinzaparin (Innohep®), a commonly used anti-coagulant. Earlier studies have mainly investigated the antineoplastic effects of tinzaparin in animal models and in human cell-lines. In this pilot study the aim is to examine the potential antitumoral effects of tinzaparin in vivo in women with epithelial ovarian cancer (EOC).

Study objectives:

Primary objective: The primary objective of the study is to evaluate the effects of tinzaparin on changes in levels of CA-125 in EOC patients who receive neoadjuvant chemotherapy (NACT).

Secondary objectives: The secondary objective of the study is to explore the impact of tinzaparin on the dynamic of a spectrum of immunological and coagulation factors in EOC patients who receive NACT. Besides, the compliance of tinzaparin injections and adverse events caused by tinzaparin will be described.


Condition or disease Intervention/treatment Phase
Epithelial Ovarian Cancer Drug: Tinzaparin Injectable Solution Phase 2

Detailed Description:
This is an open randomized controlled clinical pilot trial (Phase II). The study includes women with the International Federation of Obstetrics and Gynecology (FIGO) stage III-IV EOC selected for neoadjuvant chemotherapy (NACT) and without signs of thromboembolic disease or ongoing treatment of thromboembolic disease. The women will be allocated 1:1 to treatment with tinzaparin 4500 IU/8000 IU (dose depending on woman's weight) subcutaneously once daily or no tinzaparin. The treatment group starts tinzaparin when the primary treatment (chemotherapy) starts. The control group will not receive tinzaparin or other low molecular weight heparin preparations. The NACT consists of carboplatin and paclitaxel, given according to the standard regimen with cycle repeats every 21 days. Pre-treatment, before every cycle of chemotherapy, before delayed primary debulking surgery (DPDS) and three weeks after the last cycle of chemotherapy venous blood samples will be taken for measuring the biomarkers hemoglobin, platelets, leucocytes, C-reactive protein (CRP), albumin, cancer antigen-125 (CA-125), Tissue Factor, D-dimer, soluble P-selectin, thrombin-antithrombin complex and thrombin generation potential. Furthermore, a panel of 92 inflammation-associated proteins will be analyzed by a by a high-sensitivity Proximity Extension Assay at baseline, visit 5 and visit 8 or 9. After three cycles of NACT, the patient will be evaluated clinically and with imaging diagnostics in order to determine whether the patient should undergo DPDS. In the investigators´ setting, > 80% of patients receiving NACT for EOC undergo DPDS. After DPDS, all patients will be treated with tinzaparin for 28 days according to clinical practice concerning postoperative thromboembolic prophylaxis and thereafter continue the chemotherapy for additional two-three courses. The participants who were allocated to tinzaparin during the NACT will continue the tinzaparin after ending the postoperative thromboembolic prophylactic tinzaparin treatment for additional 2-3 courses. The biomarkers will be measured preoperatively and four weeks postoperatively after DPDS and then before each course of chemotherapy given during the primary treatment. The women who do not undergo surgery will remain included in the study for the following three cycles of chemotherapy. Thus, the total study period constitutes 22-29 weeks.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 40 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: The Effect of Tinzaparin on Biomarkers in FIGO Stage III-IV Ovarian Cancer Patients Undergoing Neoadjuvant Chemotherapy - A Randomized Pilot Study
Actual Study Start Date : July 12, 2022
Estimated Primary Completion Date : December 31, 2024
Estimated Study Completion Date : December 31, 2024

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Ovarian Cancer

Arm Intervention/treatment
Experimental: Intervention Arm
Drug: Tinzaparin (Innohep®), solution for injection. Administration form: Subcutaneous injection. Dosage: 4500 IU (for subjects weighing below 90 kg) or 8000 IU (for subjects weighing 90 kg and above) daily for 21-28 weeks.
Drug: Tinzaparin Injectable Solution
Subcutaneous injection
Other Name: Innohep®

No Intervention: Control Arm



Primary Outcome Measures :
  1. Changes in serum levels of CA-125 [ Time Frame: 14 weeks ]
    kIU/L


Secondary Outcome Measures :
  1. Changes in serum levels of CA-125 [ Time Frame: 21-28 weeks ]
    kIU/L

  2. Changes in blood levels of hemoglobin [ Time Frame: 21-28 weeks ]
    g/L

  3. Changes in blood levels of platelets [ Time Frame: 21-28 weeks ]
    x10^9/L

  4. Changes in blood levels of leucocytes [ Time Frame: 21-28 weeks ]
    x10^9/L

  5. Changes in plasma levels of CRP [ Time Frame: 21-28 weeks ]
    mg/L

  6. Changes in plasma levels of albumin [ Time Frame: 21-28 weeks ]
    g/L

  7. Changes in plasma levels of interleukin 6 [ Time Frame: 21-28 weeks ]
    ng/L

  8. Changes in plasma levels of vascular endothelial growth factor [ Time Frame: 21-28 weeks ]
    µg/L

  9. Self reported compliance to tinzaparin injections [ Time Frame: 22-29 weeks ]
    Percent

  10. Number of participants with treatment-related adverse events as assessed by CTCAE v4.0 [ Time Frame: 22-29 weeks ]
    Number

  11. Proportion of participants with treatment-related adverse events as assessed by CTCAE v4.0 [ Time Frame: 22-29 weeks ]
    Proportion constitutes the relative number in the group in percent

  12. Objectively confirmed venous thromboembolism (VTE), i.e. pulmonary embolism, lower-limb deep vein thrombosis or upper extremity deep vein thrombosis. Death due to VTE. [ Time Frame: 22-29 weeks ]
    Number

  13. Objectively confirmed venous thromboembolism (VTE), i.e. pulmonary embolism, lower-limb deep vein thrombosis or upper extremity deep vein thrombosis. Death due to VTE. [ Time Frame: 22-29 weeks ]
    Percent


Other Outcome Measures:
  1. Plasma levels of tissue factor [ Time Frame: 21-28 weeks ]
    µg/L

  2. Plasma levels of D-dimer [ Time Frame: 21-28 weeks ]
    mg/L

  3. Plasma levels of soluble P-selectin [ Time Frame: 21-28 weeks ]
    µg/L

  4. Plasma levels of thrombin-antithrombin complex [ Time Frame: 21-28 weeks ]
    µg/L

  5. Thrombin generation potential [ Time Frame: 21-28 weeks ]
    lag time (min)

  6. Thrombin generation potential [ Time Frame: 21-28 weeks ]
    endogenous thrombin generation potential (nmolar*min)

  7. Thrombin generation potential [ Time Frame: 21-28 weeks ]
    peak nmol/L

  8. Olink Target 96 Inflammation - plasma levels a panel of 92 inflammation associated proteins [ Time Frame: 21-28 weeks ]
    All 92 inflammation associated proteins are measured in pg/mL



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • The subject has given written consent to participate in the study.
  • Age 18 and above
  • Epithelial ovarian, fallopian tube or peritoneal cancer, or abdominal cancer where a biopsy indicates an origin from the ovary, fallopian tube or peritoneum.
  • Histology diagnosis of either high grade serous carcinoma, endometrioid carcinoma or clear cell carcinoma.
  • FIGO stage III-IV disease.
  • Selected for NACT with platinum double regimen at a multidisciplinary conference at Department of Oncology at Linköping University Hospital
  • Receive treatment at either of the University Hospital in Linköping, or the hospitals in Jönköping (Ryhov Hospital), Eksjö (Highland Hospital, Eksjö), Västervik (Västervik hospital), Kalmar (County Hospital, Kalmar), Värnamo (Värnamo hospital).
  • Planned for platinum doublet regimen.
  • Prior to start of NACT pregnancy should be ruled out by menstrual history or in unclear cases by a urine human chorionic gonadotropin (hCG) test.
  • Women of childbearing potential should use a safe birth control method (combined hormonal contraception, progesterone only hormonal contraception, intra uterine device, bilateral tubal occlusion, vasectomized partner, sexual abstinence, male or female condom, diaphragm with spermicide).
  • World Health Organization (WHO) Performance Status 0-1
  • Weight 50-150 kg
  • CA-125-level ≥250 kIU/L at diagnosis

Exclusion Criteria:

  • Concomitant treatment with heparins, low molecular weight heparins, warfarin or nonvitamin K antagonist oral anticoagulants. Platelet inhibitors are allowed.
  • Treatment with heparins, low molecular weight heparins or non-vitamin K antagonist oral anticoagulants within the last year.
  • Known or suspected allergies against any product included in the study
  • Ongoing pregnancy, independent of gestational age. Breastfeeding or planned pregnancy
  • EOC disclosed at Cesarean section
  • Abdominal surgery or other major surgery within the last year
  • Mental inability, reluctance or language difficulties that result in difficulty understanding the meaning of study participation
  • Treatment or disease which, according to the investigator, can affect treatment or study results
  • Known brain metastasis
  • Participation or recent participation (within the last 30 days) in a clinical study with an investigational product
  • Ongoing treatment of thromboembolic disease.
  • Thromboembolic disease within the last year.
  • Hypersensitivity to the active substance (tinzaparin) or any of the excipients.
  • Serious hemorrhage or conditions predisposing to serious hemorrhage. Serious hemorrhage is defined as fulfilling any one of these three criteria:

    1. occurs in a critical area or organ (e.g. intracranial, intraspinal, intraocular, retroperitoneal, intra-articular or pericardial, intra-uterine or intramuscular with compartment syndrome),
    2. causes a fall in hemoglobin level of 20 g/L (1.24 mmol/L) or more, or
    3. leads to transfusion of two or more units of whole blood or red blood cells.
  • Severe coagulation disorder.
  • Acute gastro duodenal ulcer.
  • Septic endocarditis.
  • Previous heparin-induced thrombocytopenia.
  • WHO Performance Status >1.
  • Platinum single regimen
  • Estimated glomerular filtration rate (E-GFR) <30ml/min (analyzed no more than 14 days before start of treatment with investigational product)
  • Platelets <100 x10^9/L (analyzed no more than 14 days before start of treatment with investigational product)
  • Treatment for other known malignancy within the last year (except basal cell carcinoma)

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): NCT05284552


Contacts
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Contact: Preben Kjölhede, MD, PhD +46101030000 ext 3187 preben.kjolhede@regionostergotland.se
Contact: Anna Karlsson, MD +46101030000 ext 3117 anna.br.karlsson@regionostergotland.se

Locations
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Sweden
Department of Obstetrics and Gynecology, Highland Hospital Recruiting
Eksjö, Sweden, 575 81
Contact: Malena Tiefenthal Thrane, MD    +46102410000    malena.tiefenthal.thrane@rjl.se   
Principal Investigator: Malena Tiefenthal Thrane, MD         
Department of Obstetrics and Gynecology, Ryhov County Hospital Recruiting
Jönköping, Sweden, 55305
Contact: Laila Falknäs, MD    +46102410000    laila.falknas@rjl.se   
Principal Investigator: Laila Falknäs, MD         
Department of Oncology, Linköping University Hospital Not yet recruiting
Linköping, Sweden, 58185
Contact: Gabriel Lindahl, MD, PhD    +46101030000    gabriel.lindahl@regionostergotland.se   
Principal Investigator: Gabriel Lindahl, MD, PhD         
Sub-Investigator: Annika Holmquist, MD, PhD         
Sub-Investigator: Oscar Derke, MD         
Sub-Investigator: Ulrica Beiron, MD         
Department of Obstetrics and Gynecology, Värnamo Hospital Recruiting
Värnamo, Sweden, 33152
Contact: Shefqet Halili, MD    +46102410000    shefqet.halili@rjl.se   
Principal Investigator: Shefqet Halili, MD         
Department of Obstetrics and Gynecology, Västervik Hospital Recruiting
Västervik, Sweden, 593 81
Contact: Anders Rosenmüller, MD    +4649086000    anders.rosenmuller@regionkalmar.se   
Principal Investigator: Anders Rosenmüller, MD         
Department of Obstetrics and Gynecology, University Hospital Active, not recruiting
Linköping, Östergötland, Sweden, 58185
Sponsors and Collaborators
University Hospital, Linkoeping
Region Jönköping County
Västervik Hospital
Investigators
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Study Chair: Preben Kjölhede, MD, PhD University Hospital, Linkoeping
Study Chair: Gabriel Lindahl, MD, PhD University Hospital, Linkoeping
Study Chair: Anna-Clara Spetz Holm, MD, PhD University Hospital, Linkoeping
Study Chair: Anna Karlsson, MD University Hospital, Linkoeping
  Study Documents (Full-Text)

Documents provided by Preben Kjolhede, MD, professor, University Hospital, Linkoeping:
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Responsible Party: Preben Kjolhede, MD, professor, Professor, senior consultant, University Hospital, Linkoeping
ClinicalTrials.gov Identifier: NCT05284552    
Other Study ID Numbers: The TABANETOC-trial
2021-000135-31 ( EudraCT Number )
First Posted: March 17, 2022    Key Record Dates
Last Update Posted: September 30, 2022
Last Verified: September 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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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 Preben Kjolhede, MD, professor, University Hospital, Linkoeping:
Tinzaparin
Neoadjuvant chemotherapy
FIGO stage III-IV
Additional relevant MeSH terms:
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Ovarian Neoplasms
Carcinoma, Ovarian Epithelial
Endocrine Gland Neoplasms
Neoplasms by Site
Neoplasms
Ovarian Diseases
Adnexal Diseases
Genital Neoplasms, Female
Urogenital Neoplasms
Endocrine System Diseases
Gonadal Disorders
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Tinzaparin
Heparin, Low-Molecular-Weight
Dalteparin
Anticoagulants
Fibrinolytic Agents
Fibrin Modulating Agents
Molecular Mechanisms of Pharmacological Action