Tinzaparin And Biomarkers After Neoadjuvant Treatment of Ovarian Cancer

Epithelial Ovarian Cancer Clinical Trial

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05284552
• Other study ID #: The TABANETOC-trial
• Secondary ID: 2021-000135-31
• Status: Recruiting
• Phase: Phase 2
• Start date: July 12, 2022
• Est. completion date: December 31, 2026

Study information

• Verified date: January 2024
• Source: University Hospital, Linkoeping
• Contact: Preben Kjölhede, MD, PhD
• Phone: +46101030000
• Email: preben.kjolhede[@]regionostergotland.se
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 40
• Est. completion date: December 31, 2026
• Est. primary completion date: December 31, 2026
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years and older

Eligibility

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)

Related Conditions & MeSH terms

• Carcinoma, Ovarian Epithelial
• Epithelial Ovarian Cancer
• Ovarian Neoplasms

Intervention

Drug:
• Tinzaparin Injectable Solution
Subcutaneous injection

Locations

Country	Name	City	State
Sweden	Department of Obstetrics and Gynecology, Highland Hospital	Eksjö
Sweden	Department of Oncology, Sahlgrenska University Hospital	Gothenburg
Sweden	Department of Obstetrics and Gynecology, Ryhov County Hospital	Jönköping
Sweden	Department of Obstetrics and Gynecology, University Hospital	Linköping	Östergötland
Sweden	Department of Oncology, Linköping University Hospital	Linköping
Sweden	Department of Obstetrics and Gynaecology, Norrland University Hospital	Umeå
Sweden	Department of Obstetrics and Gynecology, Värnamo Hospital	Värnamo
Sweden	Department of Obstetrics and Gynecology, Västervik Hospital	Västervik

Sponsors (5)

Lead Sponsor	Collaborator
University Hospital, Linkoeping	Region Jönköping County, Region Västerbotten, Västervik Hospital, Vastra Gotaland Region

Country where clinical trial is conducted

Sweden, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Plasma levels of tissue factor	µg/L	21-28 weeks
Other	Plasma levels of D-dimer	mg/L	21-28 weeks
Other	Plasma levels of soluble P-selectin	µg/L	21-28 weeks
Other	Plasma levels of thrombin-antithrombin complex	µg/L	21-28 weeks
Other	Thrombin generation potential	lag time (min)	21-28 weeks
Other	Thrombin generation potential	endogenous thrombin generation potential (nmolar*min)	21-28 weeks
Other	Thrombin generation potential	peak nmol/L	21-28 weeks
Other	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
Primary	Changes in serum levels of CA-125	kIU/L	14 weeks
Secondary	Changes in serum levels of CA-125	kIU/L	21-28 weeks
Secondary	Changes in blood levels of hemoglobin	g/L	21-28 weeks
Secondary	Changes in blood levels of platelets	x10^9/L	21-28 weeks
Secondary	Changes in blood levels of leucocytes	x10^9/L	21-28 weeks
Secondary	Changes in plasma levels of CRP	mg/L	21-28 weeks
Secondary	Changes in plasma levels of albumin	g/L	21-28 weeks
Secondary	Changes in plasma levels of interleukin 6	ng/L	21-28 weeks
Secondary	Changes in plasma levels of vascular endothelial growth factor	µg/L	21-28 weeks
Secondary	Self reported compliance to tinzaparin injections	Percent	22-29 weeks
Secondary	Number of participants with treatment-related adverse events as assessed by CTCAE v4.0	Number	22-29 weeks
Secondary	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
Secondary	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
Secondary	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