Stimulation With Bethanechol in Combination With Gemcitabine and Nab-paclitaxel in Pancreatic Adenocarcinoma

Study Overview
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Brief Summary
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The primary objective of this study is to assess the impact of bethanechol therapy on R0 resection rates. The safety objective will be assessment of the safety and tolerability of bethanechol in combination with gemcitabine and nab-paclitaxel. The exploratory objective will be to evaluate genomic biomarkers associated with parasympathetic stimulation in pancreatic cancer, and the ability to reduce tumor growth rate.

Detailed Description
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The purpose of this study is to determine whether the drug, bethanechol, could potentially be used in combination with chemotherapy regimen gemcitabine and nab-paclitaxel and surgery to decrease the chance of the cancer coming back after it is removed. Animal models have shown that treatment with bethanechol can inhibit cancer growth and spread. The chemotherapy regimen nab-paclitaxel for use in combination with gemcitabine to treat patients with metastatic pancreatic cancer is FDA approved. Although bethanechol is FDA approved, in this study its use is experimental. The aim of the study is to show that the medication is easy to tolerate and that it shows signs of slowing cancer cell growth. The investigators hypothesize that treatment with bethanechol will alter nerve conduction within tumors by stimulating the parasympathetic nervous system and reduce tumor proliferation, decrease CD44+ expression in cancer cells, decrease tumor growth rate resulting in an improved R0 resection rate.

Official Title
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Phase II, Neoadjuvant Study of Parasympathetic Stimulation With Bethanechol in Combination With Gemcitabine and Nab-paclitaxel in Borderline Resectable Pancreatic Adenocarcinoma

Conditions
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Pancreas Cancer

Intervention / Treatment
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* Drug: Bethanechol
* Drug: Gemcitabine
* Drug: nab-paclitaxel


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Pancreatic Ductal Adenocarcinoma Plan for neoadjuvant chemotherapy Available diagnostic tissue adequate for biomarker analysis Ability to tolerate PO meds and comply with study procedures Exclusion Criteria: Metastatic disease Evidence of GI obstruction Baseline bradycardia (HR<55) or hypotension (systolic blood pressure<90) Use of acetylcholinesterase inhibitors Medical conditions including: hyperthyroidism, active/symptomatic coronary artery disease, seizure disorder, peptic ulcer disease.

Ages Eligible for Study
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Minimum Age: 18 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: Other
Intervention Model: Single Group Assignment
Interventional Model Description: This is a Phase IIA study evaluating short term parasympathetic activation with fixed dose bethanechol in subjects with pancreatic cancer who should proceed to surgery after 4 -6 months of chemotherapy.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Bethanechol<br>Patients with borderline resectable pancreatic cancer and no contraindication to bethanechol therapy will receive bethanechol on day 1 and continue until 2 days prior to scheduled surgery for a minimum of 2 months. | Drug: Bethanechol<br>* Study Drug: Bethanechol (generic), supplied as 50mg oral tablets. Subjects will take 2 tablets (100mg) twice daily. Medication should be taken 1 hour before meals in AM and PM. Medication will be purchased commercially and dispensed at our research pharmacy.<br>* Other names: Bethanechol chloride tablet;Drug: Gemcitabine<br>* Non-experimental. Chemotherapy will be administered on a day 1, 8 and 15 schedule with gemcitabine at a dose of 1000 mg/m2<br>Drug: nab-paclitaxel<br>* Non-experimental. Chemotherapy will be administered on a day 1, 8 and 15 schedule with nab-paclitaxel dose at 125 mg/m2<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| R0 resection rate | This rate will be analyzed in patients treated with bethanechol in combination with gemcitabine and nab-paclitaxel compared to historical R0 resection rates. | 36 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Ki-67 expression in tumor cells | This is to measure cell proliferation by Ki-67 expression in tumor cells, to quantify the change in tumor growth and alterations in inflammatory cytokines and immune profiles. | 36 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Pancreas, pancreatic adenocarcinoma, adenocarcinoma, bethanechol, parasympathetic