Bethanechol Prior to Pancreatic Surgery

Pancreatic ductal adenocarcinoma (PDA) is one of the most difficult cancers and, unlike other
common cancers, annual deaths from PDA are rising. During the year 2017, it was estimated
that 53,670 people would be diagnosed with PDA and approximately 43,090 people would die in
the U.S. Despite recent advances, cytotoxic chemotherapy for PDA has been disappointing with
response rates of 20-30% for the most active regimens and little activity for targeted
therapies. Even among the small subset of patients who are suitable for surgical resection at
the time of diagnosis, complete resection is followed by recurrence in >90% of patients
without further systemic therapy, with a median time to recurrence of 6.9 months. Thus all
PDA patients require systemic chemotherapy and more effective regimens are urgently needed.

The purpose of this study is to determine whether the drug, bethanechol, could potentially be
used in combination with surgery to decrease the chance of cancer coming back after it is
removed. Bethanechol is a medication that is approved by the FDA and regulates the
parasympathetic nervous system. It is used to treat dry mouth and for patients who have
difficulty urinating. It has been used to manage the side effects of chemotherapy drugs. The
investigators planned this study in pancreatic cancer because animal models have shown that
treatment with bethanechol can inhibit cancer growth and spread. People with pancreatic
cancer localized to a small area usually undergo surgery to remove the tumor. The study is
designed to investigate that the medication is easy to tolerate and that it shows signs of
slowing cancer cell growth.

Inclusion Criteria:

- Be willing and able to provide written informed consent for the trial.

- Age ≥18 years of age on the day of signing informed consent.

- Have histologically or cytologically confirmed the diagnosis of resectable pancreatic
ductal adenocarcinoma or be willing to undergo a biopsy with confirmed pathology prior
to starting therapy.

- Have a predicted life expectancy of greater than 3 months.

- Have a performance status of 0 or 1 using the Eastern Cooperative Oncology Group
(ECOG) Performance Status Scale within 3 days of the first dose of study drug.

- Have a negative urine or serum pregnancy test within 7 days prior to receiving the
first dose of study medication (Cycle 1, Day 1) (female subjects of childbearing
potential). If the urine test is positive or cannot be confirmed as negative, a serum
pregnancy test will be required

Exclusion Criteria:

- Has received prior chemotherapy or radiotherapy for a current episode of pancreatic
adenocarcinoma.

- Has evidence of bacteruria on U/A within 7 days of study registration.

o Bacteriuria is defined by the presence of urinary nitrites or positive leukocyte
esterase test on a clean catch urine sample. In the event of a positive test, we will
delay registration and we will perform a urine culture (this is done reflexively in
our institution) and bacteriuria will be considered confirmed if there is the presence
of a bacterial species in a concentration greater than 100,000 colony-forming units
(CFUs) per milliliter. In an asymptomatic patient with fewer than 100,000 CFUs we will
consider them to be negative for bacteriuria and they will be eligible for the study

- Is currently using an acetylcholinesterase inhibitor or a beta-blocker.

- Has active peptic ulcer disease as defined by documented peptic ulcer and symptoms
uncontrolled with oral medication.

- Has a known hypersensitivity or allergy to bethanechol.

- Has uncontrolled hyperthyroidism, defined as clinical hyperthyroidism uncontrolled by
oral medication.

- Has bradycardia with resting heart rate < 55 beats per minute.

- Has chronic hypotension with resting systolic blood pressure < 90 mmHg.

- Has a history of coronary artery disease within 5 years prior to study entry.

- Has a history of vasomotor instability.

- Has a history of seizure disorder or required anti-seizure medication for seizure
prevention within 5 years prior to study entry.

- Has a history of Parkinson's disease.

- Has a history of latent or active bronchial asthma.

- Has a history of recent urinary bladder surgery within 12 months of study entry.

- Has a history of gastrointestinal resection and anastomosis within 12 months of study
entry.

- Has an active infection requiring systemic therapy.

- Has a history of current evidence of any condition, therapy, or laboratory abnormality
that might confound the results of the trial, interfere with the subject's
participation for the full duration of the trial, or is not in the best interest of
the subject to participate, in the opinion of the treating investigator.

- Has known psychiatric or substance abuse disorders that would interfere with
cooperation with the requirements of the trial.

- Is pregnant or breastfeeding, or expecting to conceive or father children within the
projected duration of the trial, starting with the screening visit through 120 days
after the last dose of trial treatment.