Bazedoxifene as a Concomitant Treatment of Patients With Metastatic Pancreatic Adenocarcinoma

Study Overview
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Brief Summary
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Bazedoxifene, a selective estrogen receptor modulator is thought to have effective anti-tumoral properties for pancreatic cancer via IL-6 pathway (GP130/STAT3) inhibition. The objective is to measure IL-6 (GP130/STAT3)-pathway modification on metastasis biopsy of patients with metastatic pancreatic adenocarcinoma before and after treatment with bazedoxifene in addition to chemotherapy. This study is a single-center, prospective, nonrandomized trial.

Detailed Description
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This study is a single-center, prospective, non-randomized trial. The population studied will consist of 10 patients of both sexes, aged 18 to 85 years, with a newly diagnosed metastatic pancreatic adenocarcinoma who will undergo palliative treatment with standard first line chemotherapy (Gemcitabine +/- Nab-paclitaxel). Diagnosis must be confirmed by biopsy and metastasis must be accessible for percutaneous biopsy using imaging guidance. Further, only patients with an IL-6 (GP130/STAT3)-pathway activity of more than 5% on diagnostic biopsy will be included . In addition to chemotherapy, patients will receive 20 mg bazedoxifene (Conbriza®) orally per day, subject to good clinical tolerance and in the absence of a biological contraindication. Patients will receive bazedoxifene once a day at any time, with or without meals. Initiation of treatment will be simultaneous to the initiation of chemotherapy. Bazedoxifene (Conbriza®) will be prescribed and administered for the duration of the study. To minimize the risk of thrombo-embolic events, prophylactic rivaroxaban (Xarelto®) 10 mg orally once per day will be added for the duration of the bazedoxifene (Conbriza®) intake. Pantoprazole 20 mg once per day will be added in selected patients to minimize gastric complications according to the physician's appreciation. Participants will receive bazedoxifene (Conbriza®) and rivaroxaban (Xarelto®) for the entire study duration from a subinvestigator at treatment initiation visit. Physical examination with vital parameters, laboratory testing (blood count, liver enzymes, creatinine) and tumor marker (CA 19-9) will be conducted in order to determine the baseline prior to the initiation of the treatment. The quality of life using the EORTC core quality of life questionnaire (QLQ-C30) will also be assessed at that point. Furthermore, the IL-6 pathway activity (GP130/STAT3) will be assessed immunohistochemically on metastasis biopsy before administration of bazedoxifene (Conbriza®). The tissue will be obtained by percutaneous biopsy using imaging guidance. A biopsy performed before study inclusion can be used as baseline to avoid a second biopsy. Study enrollment and follow-up will be performed by the consultant physician at the HFR Fribourg in the department of oncology. The follow-up will be carried out every 3 to 4 weeks and will consist of a physical examination, vital parameters, laboratory testing (blood count, liver enzymes, creatinine, electrolytes) and tumor marker (CA 19-9). Plasma samples will be collected before and after treatment for storage and samples will be analyzed through next generation sequencing NGS. Quality-of-life will be assessed during the follow-ups and drug adherence will be monitored through patient survey. After 3 months of treatment, the primary endpoint will be assessed. Thoraco-abdominal CT scan or PET-CT will be performed, and a biopsy of metastasis tissue will be repeated (percutaneous under radiological guidance) for immunohistochemical IL-6 pathway activity (GP130/STAT3) analysis. The activity of bazedoxifene (Conbriza®) on inflammatory pathways and tumor progression will be evaluated by comparing the modification in expression of the IL-6 pathway (GP130/STAT3) from baseline. Patients will be instructed by the investigator to report the occurrence of any adverse event. The expected duration of the study for each participant will be 12 to 16 weeks.

Official Title
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Bazedoxifene as a Concomitant Treatment of Patients With Metastatic Pancreatic Adenocarcinoma

Conditions
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Pancreas Cancer

Intervention / Treatment
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* Drug: Bazedoxifene 20 mg


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adults aged from 18 to 85, Newly diagnosed metastatic pancreatic adenocarcinoma (stage IV according to AJCC) Accessible metastasis for percutaneous biopsy using imaging guidance IL-6 (GP130/STAT3)-pathway activity of more than 5% on diagnostic biopsy will be included Palliative chemotherapy planned, Informed Consent as documented by signature (Appendix Informed Consent Form). Exclusion Criteria: No treatment for pancreatic adenocarcinoma, Curative treatment of pancreatic adenocarcinoma, No accessible metastasis for biopsy, Previous thrombo-embolic events, Known hypersensibility or allergy to bazedoxifene or one of the Conbriza excipient, Women who are pregnant or breast feeding, Intention to become pregnant during the course of the study, Lack of safe contraception, defined as: Female participants of childbearing potential, not using and not willing to continue using a medically reliable method of contraception for the entire study duration, such as oral, injectable, or implantable contraceptives, or intrauterine contraceptive devices, or who are not using any other method considered sufficiently reliable by the investigator in individual cases. Female participants who are surgically sterilised / hysterectomised or post-menopausal for longer than 2 years are not considered as being of childbearing potential. Other clinically significant concomitant disease states (e.g., renal failure, hepatic dysfunction, cardiovascular disease, etc.), Known or suspected non-compliance, drug or alcohol abuse, Inability to follow the procedures of the study, e.g. due to language problems, psychological disorders, dementia, etc. of the participant, Inability to give informed consent, Participation in another study with investigational drug within the 30 days preceding and during the present study, Previous enrolment into the current study, Enrolment of the investigator, his/her family members, employees and other dependent persons

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Bazedoxifene administered in addition to standard chemotherapy protocol<br> | Drug: Bazedoxifene 20 mg<br>* Bazedoxifene will be administered during the duration of the study in the experimental arm together with chemotherapy. Prophylactic rivaroxaban (Xarelto®) 10 mg per day orally will be added to avoid thromboembolic events.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in IL-6/GP-130/STAT3 pathway expression (%) | Assessment of IL-6 (GP130/STAT3) activity by immunohistochemistry on metastasis biopsy before and after treatment with bazedoxifene in addition to chemotherapy. | 3 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Carbohydrate-Antigen 19-9 (CA 19-9) in U/ml | The change in tumor marker CA 19-9 as a reflection of tumor progression. CA 19-9 will be measured on blood samples collected every 3 to 4 weeks throughout the trial and compared with the baseline prior to treatment initiation. | every 3 weeks for 3 months | 
| Change in Quality of life measured by EORTC QLQ-C30 | Quality of life using the quality-of-life questionnaire EORTC QLQ-C30. This variable will be measured every 3 to 4 weeks throughout the trial and compared with the baseline prior to treatment initiation. Score ranging from 0 to 100. High scale score represents a higher response level. | every 3 weeks for 3 months | 
| Heart rate (bpm) | Assess toxicity of bazedoxifene in combination with chemotherapy. Physical examination will be performed and blood samples, including renal and hepatic parameters, will be analyzed every 3 to 4 weeks. | every 3 weeks for 3 months | 
| Blood pressure (mmHg) | Assess toxicity of bazedoxifene in combination with chemotherapy. Physical examination will be performed and blood samples, including renal and hepatic parameters, will be analyzed every 3 to 4 weeks. | every 3 weeks for 3 months | 
| Oxygen saturation (%) | Assess toxicity of bazedoxifene in combination with chemotherapy. Physical examination will be performed and blood samples, including renal and hepatic parameters, will be analyzed every 3 to 4 weeks. | every 3 weeks for 3 months | 
| weight (kg) | Assess toxicity of bazedoxifene in combination with chemotherapy. Physical examination will be performed and blood samples, including renal and hepatic parameters, will be analyzed every 3 to 4 weeks. | every 3 weeks for 3 months | 
| body temperature (°Celcius) | Assess toxicity of bazedoxifene in combination with chemotherapy. Physical examination will be performed and blood samples, including renal and hepatic parameters, will be analyzed every 3 to 4 weeks. | every 3 weeks for 3 months | 
| liver enzymes (GOT/ASAT in U/l) | Assess toxicity of bazedoxifene in combination with chemotherapy. Physical examination will be performed and blood samples, including renal and hepatic parameters, will be analyzed every 3 to 4 weeks. | every 3 weeks for 3 months | 
| liver enzymes (GPT/ALAT in U/l) | Assess toxicity of bazedoxifene in combination with chemotherapy. Physical examination will be performed and blood samples, including renal and hepatic parameters, will be analyzed every 3 to 4 weeks. | every 3 weeks for 3 months | 
| liver enzymes (GGT in U/l) | Assess toxicity of bazedoxifene in combination with chemotherapy. Physical examination will be performed and blood samples, including renal and hepatic parameters, will be analyzed every 3 to 4 weeks. | every 3 weeks for 3 months | 
| liver enzymes (alkaline phosphatase in U/l) | Assess toxicity of bazedoxifene in combination with chemotherapy. Physical examination will be performed and blood samples, including renal and hepatic parameters, will be analyzed every 3 to 4 weeks. | every 3 weeks for 3 months | 
| liver enzymes (bilirubine in umol/l) | Assess toxicity of bazedoxifene in combination with chemotherapy. Physical examination will be performed and blood samples, including renal and hepatic parameters, will be analyzed every 3 to 4 weeks. | every 3 weeks for 3 months | 
| renal parameters (creatinine in umol/l) | Assess toxicity of bazedoxifene in combination with chemotherapy. Physical examination will be performed and blood samples, including renal and hepatic parameters, will be analyzed every 3 to 4 weeks. | every 3 weeks for 3 months | 
| electrolytes (sodium in mmol/l) | Assess toxicity of bazedoxifene in combination with chemotherapy. Physical examination will be performed and blood samples, including renal and hepatic parameters, will be analyzed every 3 to 4 weeks. | every 3 weeks for 3 months | 
| electrolytes (potassium in mmol/l) | Assess toxicity of bazedoxifene in combination with chemotherapy. Physical examination will be performed and blood samples, including renal and hepatic parameters, will be analyzed every 3 to 4 weeks. | every 3 weeks for 3 months | 
| electrolytes (phosphate in mmol/l) | Assess toxicity of bazedoxifene in combination with chemotherapy. Physical examination will be performed and blood samples, including renal and hepatic parameters, will be analyzed every 3 to 4 weeks. | every 3 weeks for 3 months | 
| electrolytes (calcium in mmol/l) | Assess toxicity of bazedoxifene in combination with chemotherapy. Physical examination will be performed and blood samples, including renal and hepatic parameters, will be analyzed every 3 to 4 weeks. | every 3 weeks for 3 months | 
| Number of patients with adverse events | Assess the number of patients with adverse events (according to CTCAE v5.0) | every 3 weeks for 3 months |