Stereotactic Radiosurgery and Metformin in Patients With Borderline-Resectable or Locally-Advanced Pancreatic Cancer

This is an open label pilot, single-center, non-randomized trial is designed to evaluate the
tolerability and preliminary activity of the combination of stereotactic body radiation
therapy (SBRT) with metformin for resectable and locally-advanced pancreatic/periampullary
cancers.

PRIMARY OBJECTIVES:

The primary objectives of this study are to:

1) To determine if the addition of metformin to SBRT adds minimal additional toxicity for
patients with A). borderline-resectable or B). not surgically resectable pancreatic
adenocarcinomas.

SECONDARY OBJECTIVES:

I. Evaluate the clinical/pathological response and resectability rates associated with these
regimens.

OUTLINE:

Patients receive metformin hydrochloride orally (PO) daily or twice daily (BID) on days -11
to -1. Patients then undergo stereotactic radiosurgery 5 days a week for 5 weeks and receive
concurrent metformin hydrochloride* by mouth, two times a day for 5 weeks. Patients undergo
laparotomy on week 6 (or weeks 5-7). ). Systemic therapy continues as soon as it is
considered feasible by the treating physicians.

*NOTE: Metformin hydrochloride should be stopped 2 days before laparotomy.

After completion of study treatment, patients are followed up every 3 months for 2 years.

Inclusion Criteria:

- Subjects must be able to provide written informed consent

- Histologically and/or cytologically confirmed adenocarcinoma of the pancreas, clinical
stage T1-4, N0-1, M0

- Eastern Cooperative Oncology Group (ECOG) performance status 0-2

- Hemoglobin ≥ 9.0 g/dl

- Alkaline phosphatase < 3 x upper limit of normal (ULN)

- Albumin > 2.5 g/dL

- Absolute neutrophil count ≥ 1500/mm^3

- Platelet count ≥ 75,000/mm^3

- Total bilirubin < 1.5 x upper limit of normal (ULN)

- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) ≤
2.5 x institutional upper limit of normal

- Alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) ≤ 2.5 x
institutional upper limit of normal

- Creatinine ≤ 1.5

- Borderline-resectable or locally-advanced pancreatic cancer (based upon impression of
the surgical oncologist, in conjunction with radiologic consultations) as defined per
the Alliance consensus :

- Borderline-resectable

- An interface between the primary tumor and superior mesenteric vein
(SMV)/portal vein measuring 180 degrees or greater of the circumference of
the vein wall

- Short-segment occlusion of the SMV/portal vein but with suitable vessel
proximal and distal to the obstruction to allow safe resection and
reconstruction

- Short-segment interface (of any degree) between the tumor and the hepatic
artery with normal artery proximal and distal to the interface that is
amenable to resection and arterial reconstruction

- An interface between the tumor and the SMA or celiac trunk measuring less
than 180 degrees of the circumference of the artery wall

- Not surgically resectable due to one or more of the following things

- Patient is not a surgical candidate due to medical comorbidities and/or poor
performance status

- Patient elects not to undergo surgical therapy

- Patient has locally-advanced pancreatic cancer based on having one of the
following:

- Encasement of the SMA/celiac artery (>180 degrees).

- Involvement of the SMV/portal vein without options for reconstruction.

- Aortic invasion or encasement.

- Women of child-bearing potential and men must agree to use adequate contraception
(double barrier method of birth control or abstinence) 6 weeks prior to study entry,
for the duration of study participation and for 6 months after completing treatment;
should a woman become pregnant or suspect that she is pregnant while she or her
partner is participating in this study, she should inform the treating physician
immediately

- Patients previously treated with chemotherapy are eligible unless they have evidence
of local or distant disease progression; patients must have completed their last cycle
of chemotherapy at least two weeks prior to study enrollment

- Patients currently taking metformin are eligible for participation.

- Women of child-bearing potential and male patients who are sexually-active must agree
to use effective methods of birth control throughout protocol treatment.

- Patients must not have poorly-controlled diarrhea (no more than 4 loose stools per
day). Patients may be reconsidered for the study if the diarrhea resolves.

Exclusion Criteria:

- Evidence of gross duodenal invasion, gastric outlet obstruction

- Gastrointestinal perforation or intra-abdominal abscess (< 3 months); recent (< 3
months) gastrointestinal (GI) bleeding from gastric or duodenal ulcer

- Systemic collagen vascular disease including scleroderma or systemic lupus
erythematosus (SLE); rheumatoid arthritis is eligible

- Serious active infection requiring intravenous (IV) antibiotics

- Conditions leading to inadequate gastrointestinal tract absorption as determined by
the treating physician and/or investigator

- Patients with uncontrolled intercurrent illness including, but not limited to ongoing
or active infection, symptomatic congestive heart failure, unstable angina pectoris,
uncontrolled cardiac arrhythmia, or psychiatric illness/social situations that would
limit compliance with study requirements

- Poorly-controlled diarrhea (> 4 loose bowel movement [BM]/day without use of
anti-motility agents) within 7 days of study enrollment; patients may be reconsidered
for the study if the diarrhea resolves

- Comorbid conditions that, in the opinion of the investigator, would complicate safety
or compliance such as known human immunodeficiency virus (HIV) or current substance
abuse

- Patients who are pregnant or lactating

- Patients who are unwilling or unable to comply with study and/or follow-up procedures

- Treatment for other carcinomas within the last two years, except cured non-melanoma
skin cancer, curatively treated in-situ cervical cancer, or localized prostate cancer
with stable prostate-specific antigen (PSA)

- Multi-focal pancreatic lesions concerning for cancer.