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:

• 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.