Tinzaparin And Biomarkers After Neoadjuvant Treatment of Ovarian Cancer

The Effect of Tinzaparin on Biomarkers in FIGO Stage III-IV Ovarian Cancer Patients Undergoing Neoadjuvant Chemotherapy - A Randomized Pilot Study

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.

Study Overview

• Status: Recruiting
• Conditions: Epithelial Ovarian Cancer
• Intervention / Treatment: Drug: Tinzaparin Injectable Solution

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.

• Study Type: Interventional
• Enrollment (Estimated): 40
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Preben Kjölhede, MD, PhD; Phone Number: 3187 +46101030000; Email: preben.kjolhede@regionostergotland.se
• Study Contact Backup: Name: Anna Karlsson, MD; Phone Number: 3117 +46101030000; Email: anna.br.karlsson@regionostergotland.se

Study Locations

• Sweden
  • Eksjö, Sweden, 575 81
    • Recruiting
    • Department of Obstetrics and Gynecology, Highland Hospital
    • Contact: Malena Tiefenthal Thrane, MD; Phone Number: +46102410000; Email: malena.tiefenthal.thrane@rjl.se
    • Principal Investigator: Malena Tiefenthal Thrane, MD
    • Sub-Investigator: Catarina Notelid Claus, MD
    • Sub-Investigator: Hanna Reimerson, MD
  • Gothenburg, Sweden, 41345
    • Recruiting
    • Department of Oncology, Sahlgrenska University Hospital
    • Contact: Karin Bergmark, MD, PhD; Phone Number: +46313421000; Email: Karin.Bergmark@vgregion.se
    • Principal Investigator: Karin Bergmark, MD, PhD
    • Sub-Investigator: Pernilla Dahm-Kähler, MD, PhD
    • Sub-Investigator: Boglarka Fekete, MD
  • Jönköping, Sweden, 55305
    • Recruiting
    • Department of Obstetrics and Gynecology, Ryhov County Hospital
    • Contact: Laila Falknäs, MD; Phone Number: +46102410000; Email: laila.falknas@rjl.se
    • Principal Investigator: Laila Falknäs, MD
    • Sub-Investigator: Christiane Sackbrook, MD
    • Sub-Investigator: Anke Zbikowski, MD
    • Sub-Investigator: Narmin Rasul, MD
  • Linköping, Sweden, 58185
    • Recruiting
    • Department of Oncology, Linköping University Hospital
    • Contact: Gabriel Lindahl, MD, PhD; Phone Number: +46101030000; Email: 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
    • Sub-Investigator: Tommy Leijon, MD
  • Umeå, Sweden, 90719
    • Recruiting
    • Department of Obstetrics and Gynaecology, Norrland University Hospital
    • Contact: Ulrika Ottander, MD, PhD; Phone Number: +46907850000; Email: Ulrika.Ottander@umu.se
    • Principal Investigator: Ulrika Ottander, MD, PhD
    • Sub-Investigator: Charlotte Öfverman, MD, PhD
    • Sub-Investigator: Pernilla Israelsson, MD, PhD
  • Värnamo, Sweden, 33152
    • Recruiting
    • Department of Obstetrics and Gynecology, Värnamo Hospital
    • Contact: Shefqet Halili, MD; Phone Number: +46102410000; Email: shefqet.halili@rjl.se
    • Principal Investigator: Shefqet Halili, MD
  • Västervik, Sweden, 593 81
    • Recruiting
    • Department of Obstetrics and Gynecology, Västervik Hospital
    • Contact: Anders Rosenmüller, MD; Phone Number: +4649086000; Email: anders.rosenmuller@regionkalmar.se
    • Principal Investigator: Anders Rosenmüller, MD
    • Sub-Investigator: Helena Avenström, MD
  • Östergötland
    • Linköping, Östergötland, Sweden, 58185
      • Active, not recruiting
      • Department of Obstetrics and Gynecology, University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
No Intervention: Control Arm
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 Names: Innohep®

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes in serum levels of CA-125	kIU/L	14 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes in serum levels of CA-125	kIU/L	21-28 weeks
Changes in blood levels of hemoglobin	g/L	21-28 weeks
Changes in blood levels of platelets	x10^9/L	21-28 weeks
Changes in blood levels of leucocytes	x10^9/L	21-28 weeks
Changes in plasma levels of CRP	mg/L	21-28 weeks
Changes in plasma levels of albumin	g/L	21-28 weeks
Changes in plasma levels of interleukin 6	ng/L	21-28 weeks
Changes in plasma levels of vascular endothelial growth factor	µg/L	21-28 weeks
Self reported compliance to tinzaparin injections	Percent	22-29 weeks
Number of participants with treatment-related adverse events as assessed by CTCAE v4.0	Number	22-29 weeks
Proportion of participants with treatment-related adverse events as assessed by CTCAE v4.0	Proportion constitutes the relative number in the group in percent	22-29 weeks
Objectively confirmed venous thromboembolism (VTE), i.e. pulmonary embolism, lower-limb deep vein thrombosis or upper extremity deep vein thrombosis. Death due to VTE.	Number	22-29 weeks
Objectively confirmed venous thromboembolism (VTE), i.e. pulmonary embolism, lower-limb deep vein thrombosis or upper extremity deep vein thrombosis. Death due to VTE.	Percent	22-29 weeks

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Plasma levels of tissue factor	µg/L	21-28 weeks
Plasma levels of D-dimer	mg/L	21-28 weeks
Plasma levels of soluble P-selectin	µg/L	21-28 weeks
Plasma levels of thrombin-antithrombin complex	µg/L	21-28 weeks
Thrombin generation potential	lag time (min)	21-28 weeks
Thrombin generation potential	endogenous thrombin generation potential (nmolar*min)	21-28 weeks
Thrombin generation potential	peak nmol/L	21-28 weeks
Olink Target 96 Inflammation - plasma levels a panel of 92 inflammation associated proteins	All 92 inflammation associated proteins are measured in pg/mL	21-28 weeks

Collaborators and Investigators

• Sponsor: University Hospital, Linkoeping
• Collaborators: Vastra Gotaland Region; Region Jönköping County; Region Västerbotten; Västervik Hospital
• Investigators: 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 record dates

Study Major Dates

• Study Start (Actual): July 12, 2022
• Primary Completion (Estimated): December 31, 2026
• Study Completion (Estimated): December 31, 2026

Study Registration Dates

• First Submitted: February 6, 2022
• First Submitted That Met QC Criteria: March 8, 2022
• First Posted (Actual): March 17, 2022

Study Record Updates

• Last Update Posted (Estimated): January 25, 2024
• Last Update Submitted That Met QC Criteria: January 23, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Keywords: Neoadjuvant chemotherapy; Tinzaparin; FIGO stage III-IV
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Carcinoma; Neoplasms, Glandular and Epithelial; Genital Neoplasms, Female; Endocrine System Diseases; Ovarian Diseases; Adnexal Diseases; Gonadal Disorders; Endocrine Gland Neoplasms; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Diseases; Genital Diseases, Female; Ovarian Neoplasms; Carcinoma, Ovarian Epithelial; Molecular Mechanisms of Pharmacological Action; Fibrinolytic Agents; Fibrin Modulating Agents; Anticoagulants; Heparin, Low-Molecular-Weight; Tinzaparin; Dalteparin
• Other Study ID Numbers: The TABANETOC-trial; 2021-000135-31 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No