Bethanechol in Combination with Gemcitabine and Nab-paclitaxel for the Treatment of Borderline Resectable Pancreatic Cancer

Inclusion Criteria

• Be willing and able to provide written informed consent for the trial
• Age >= 18 years of age on day of signing informed consent
• Have histologically or cytologically confirmed diagnosis of pancreatic ductal adenocarcinoma or be willing to undergo a biopsy with confirmed pathology prior to starting therapy
• Study eligibility will be assessed by the primary surgeons of patients; all pancreatic surgeons are members of the Pancreas Center; will require a determination of “borderline resectable” (BR) pancreatic cancer, following definitions in the National Comprehensive Cancer Network (NCCN) guidelines, as used in the Columbia University Irving Medical Center (CUIMC) Pancreas Center. Briefly, the study will include patients with (1) venous involvement amenable to reconstruction; (2) tumor < 180° of the celiac and superior mesenteric arteries; or (3) hepatic artery amenable to reconstruction
• Have a predicted life expectancy of greater than 3 months
• Have a performance status of 0 -2 using the Eastern Cooperative Oncology Group (ECOG) Performance Scale within 3 days of 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
• Absolute neutrophil count (ANC) >= 1500/uL (within 14 days prior to the first dose of study intervention)
• Platelets >= 100 000/uL (within 14 days prior to the first dose of study intervention)
• Hemoglobin >= 9.0 g/dL or >= 5.6 mmol/L (within 14 days prior to the first dose of study intervention)
• Creatinine OR
 measured or calculated creatinine clearance (glomerular filtration rate [GFR] can also be used in place of creatinine or creatinine clearance [CrCl]) =< 1.5 x upper limit of normal (ULN) OR
 >= 60 mL/min for participant with creatinine levels > 1.5 x institutional ULN (within 14 days prior to the first dose of study intervention)
• Total bilirubin =< 1.5 x upper limit of normal (ULN) OR direct bilirubin =< ULN for participants with total bilirubin levels > 1.5 x ULN (within 14 days prior to the first dose of study intervention)
• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) =< 2.5 x ULN (=< 5 x ULN for participants with liver metastases) (within 14 days prior to the first dose of study intervention)
• International normalized ratio (INR) OR prothrombin time (PT) =< 1.5 x ULN unless participant is receiving anticoagulant therapy as long as PT or partial thromboplastin time (PTT) is within therapeutic range of intended use of anticoagulants (within 14 days prior to the first dose of study intervention)
• Activated partial thromboplastin time (aPTT) =< 1.5 x ULN unless participant is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants (within 14 days prior to the first dose of study intervention)

Exclusion Criteria

• Has received prior chemotherapy or radiotherapy for current episode of pancreatic adenocarcinoma
• Has evidence of bacteriuria on U/A within 7 days of study registration * 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 per milliliter. In an asymptomatic patient with fewer than 100,000 colony forming units (CFUs) we will consider them to be negative for bacteriuria and they will be eligible for the study. Patients may be registered after bacteriuria is cleared
• Is currently using an acetylcholinesterase inhibitor that cannot be discontinued
• 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 < 50 beats per minute
• Has chronic hypotension with resting systolic blood pressure < 90mmHg
• Has a history of symptomatic coronary artery disease, myocardial infarction, or percutaneous coronary intervention within 2 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 2 years prior to study entry
• Has a history of Parkinson’s disease
• Has a history of latent or active bronchial asthma requiring the use of daily preventative medication or use of emergency inhaler greater than once per week
• 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 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
• Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial and unwilling to use effective contraception, starting with the screening visit through 120 days after the last dose of trial treatment