CHARM II: Chemotherapy for Ablation and Resolution of Mucinous Pancreatic Cysts

Pancreatic cystic lesions are increasingly encountered and typically discovered incidentally
on cross-sectional imaging, occurring in approximately 2% of all American adults with a 37%
prevalence in individuals over 80. Most of these cysts are mucinous (neoplastic) in origin
and represent precursor lesions for pancreatic adenocarcinoma.

Discovering a pancreatic cyst typically presents a treatment dilemma, with options including
either indefinite radiographic surveillance with MR (magnetic resonance) or CT imaging or
surgical resection, both of which have significant limitations. Surveillance carries
significant economic and possible psychological burdens while waiting for signs of malignancy
to develop, as well as radiation exposure with computed tomography. On the other hand,
surgical resection possesses a significant risk of serious adverse events (20%-40%) and
mortality (1-2%). This clinical dilemma delineates the pressing need to develop effective,
but more minimally invasive approaches for the elimination of these premalignant pancreatic
cysts, and among these, endoscopic ultrasound guided fine needle infusion (EUS-FNI) has
emerged as an innovative and promising approach. Between November 2011 and December 30, 2015,
investigators from interventional endoscopy, surgical oncology, hematology oncology, and
pathology of the Penn State Hershey Medical Center conducted the CHARM I clinical trial. This
was a prospective, randomized, double-blind, single-center study with an N of 46 patients
required for 80% power to prove non-inferiority. Final results from CHARM I were as follows:
Patients treated included 23 females and 16 males with the majority of lesions located in the
body and head of the pancreas. Both the alcohol and alcohol-free groups recorded a 47% rate
of complete ablation at 6 months, which increased to 64% for both groups at the 1 year
follow-up. One subject experienced a complication in the alcohol arm (6%), and no subjects
experienced complications in the alcohol-free arm.

The overall objectives of CHARM II are to verify the significant findings of CHARM I in a
multi-center clinical trial as requested by national investigators in this field. We expect
that administering a specifically designed chemotherapeutic cocktail without prior ethanol
lavage will result in an equivalent rate of cyst resolution with fewer complications when
compared with lavage using alcohol. The results of this study will provide important
information about the most efficient and safest method for treating premalignant pancreatic
cysts, an important step for treating these lesions with a minimally invasive technique and
preventing their progression to pancreatic cancer. Standard alternative treatment options for
this patient group (if not taking part in this study) would be ongoing periodic radiographic
surveillance with MR or CT imaging waiting for signs of malignancy to develop or to consider
surgical resection (an option with significant rates of morbidity and mortality).

This is an investigator-initiated, prospective, randomized, double-blinded, multi-center
study evaluating ethanol lavage and chemotherapy for the ablation of mucinous and
indeterminate type pancreatic cysts with malignant potential. Participants will be screened
for the study according to inclusion and exclusion criteria. After confirming their
eligibility, patients will be randomized to one of the following EUS-FNI treatment arms in a
1:1 ratio:

Control arm: After removal of cyst fluid, cysts will be lavaged for 3 to 5 minutes with 98%
ethanol and then infused with an admixture of 3 mg/ml paclitaxel and 19 mg/ml gemcitabine.

Experimental arm: After removal of cyst fluid, cysts will be lavaged for 3 to 5 minutes with
normal saline and then infused with an admixture of 3 mg/ml paclitaxel and 19 mg/ml
gemcitabine.

Patients will be contacted by the study team via phone call at both 72 hours and 30 days
after their EUS procedure to assess any adverse events that may have occurred. Within 2-3
weeks of the having the EUS procedure, patients will receive the cyst fluid pathology
results. At 3 months after the initial procedure, patients will undergo a follow-up EUS
examination in the same manner as the initial EUS exam. During this exam, a complete
pancreaticobiliary evaluation will be conducted, and the diameter of the previously treated
cyst will be measured in the x and y dimensions to assess the 3 month response. Any cyst
still >15mm and amenable to repeat ablation will undergo a second EUS-guided chemoablation
treatment using the same lavage that the patient was randomized to initially. At both 12
months and 24 months after the initial procedure, the patient will be seen in the GI clinic
and undergo either an MRI-MRCP (magnetic resonance cholangiopancreatography) or enhanced CT
scan for a full pancreaticobiliary evaluation to assess the end-point treatment response.

Inclusion Criteria:

- Adult subjects over the age of 18.

- Patients with a previously detected pancreatic cyst(s) 2-5 cm in diameter which is
consistent with a mucinous type cyst as per ASGE guidelines, including indeterminate
type cysts.

- Ability to give written informed consent.

- Capable of safely undergoing endoscopy with deep sedation or general anesthesia.

Exclusion Criteria:

- Lesions which are consistent with a benign cyst by clinical, cytological, chemical,
and radiographic evaluation as per ASGE guidelines (i.e., consistent with a pseudocyst
or serous cystadenoma).

- Known or suspected pancreatic cancer or pathologic lymphadenopathy.

- Cysts with the following high risk features: main pancreatic duct dilation of > 5mm,
epithelial type mural nodules, pathologically thick wall/septation (> 2mm), cytology
showing high grade dysplasia or "suspicious for malignancy", signs of common bile duct
or pancreatic duct obstruction, solid mass component within or associated with the
cyst, pancreatic duct stricture associated with tail atrophy, or previous fine needle
aspiration failure due to excessive cyst fluid viscosity.

- Septated cysts with > 4 compartments.

- Confirmed pancreatitis within the last 3 months.

- Baseline lab values at the time of consent of: white blood cells (K/uL) > 14 or < 2,
hematocrit < 30, platelets (K/uL) <30,000, non-pharmacologic INR > 1.7, CA19-9 >2X
ULN(unit/ml), lipase (U/L) > 2 X the upper limit of normal, creatinine (mg/dl) > 3.0
unless stable on renal replacement therapy, ALT (U/L) > 500, total bilirubin (mg/dl) >
2.5.

- Any pre-existing or discovered medical condition that would, at the discretion of the
investigator, interfere with the completion of and/or participation in the existing
protocol. This includes severe pre-existing medical conditions which would preclude a
reasonable 5 year life expectancy (and thus neutralize the patient's benefit from
ablating a premalignant type pancreatic cyst).

- Pregnancy, breastfeeding, or incarcerated individual.