Study of Proton Therapy in Adjuvant Pancreatic Cancer

The investigators hypothesize that resected pancreatic cancer patients will benefit from
enhanced local control with the addition of radiation therapy to adjuvant FFX. The recently
reported PRODIGE 24 study, demonstrated that 12 cycles of adjuvant FFX without radiation
therapy significantly improved survival and time to metastatic failure rates as compared to
GEM alone. Excessive distant failures rates using prior adjuvant systemic therapies, may have
limited the impact of radiation therapy; therefore, improvements in systemic control can
increase the benefit of local control.

In this study, the investigators utilize 5 fraction PRT, delivered over 1 week, during
adjuvant FFX (between cycles 6 and 7) to minimize the interruptions in chemotherapy as well
as to reduce the length of time from surgical resection to initiating adjuvant radiation
therapy. Conventional radiation therapy is typically delivered over 5 weeks and is commonly
given after the completion of adjuvant chemotherapy. Conventional radiation therapy cannot be
given concurrently with FFX due to the synergistic toxicities. In contrast, PRT significantly
reduces the exposure of normal tissues to the effects of radiation therapy and has been
safely delivered using a 5 fraction schedule with chemotherapy, as previously discussed.

Chemotherapy will consist of mFOLFIRINOX in 14-day cycles x 12 as used in the PRODIGE 24
study:

- Irinotecan 150 mg/m2 IV day 1

- Oxaliplatin 85 mg/m2 IV day 1

- Leucovorin 400 mg/m2 IV day 1

- 5-fluorouracil 2,400 mg/m2 IV days 1-3 (no bolus)

- Pegfilgrastim 6 mg SC on-body injector day 3 (optional, up to investigator's discretion,
can alternatively do day 4 without on-body injector)

- Suggested supportive care medications: fosaprepitant 150 mg IV day 1, dexamethasone 12
mg IV day 1, ondansetron 16 mg IV day 1, dexamethasone 4 mg PO q AM days 2-3,
ondansetron 8 mg PO BID days 2-3.

- Dose adjustments will be permitted at the discretion of the treating oncologist based on
patients' prior tolerability to FFX

- Proton radiation will consistent of 5 daily doses of 5 GyE total, ideally administered
Monday through Friday but can be administered within 7 business days, between cycles 6
and 7

Inclusion Criteria:

- Undergone pancreaticoduodenectomy with curative intent

- Pathologically-confirmed pancreatic adenocarcinoma of the pancreatic head
(adenocarcinoma must be the predominant component of the histology)

- Completed 2 cycles of adjuvant chemotherapy composed of 5-fluorouracil, leucovorin,
oxaliplatin, and irinotecan

- Complete resection (R0) or resection with microscopic positive magins (R1)

- Adequate healing post-operatively

- Bone marrow function: absolute neutrophil count (ANC) ≥ 1,500/mm3; Platelets ≥ 100 ×
109/L; hemoglobin ≥ 9.0 g/dL. Patients may have a transfusion of red blood cells to
meet the hemoglobin requirement.

- Renal function: serum creatinine ≤ 1.5 × upper normal limit of institution's normal
range or creatinine clearance ≥ 30 mL/min for subjects with creatinine levels above
institutional normal

- Hepatic function: AST and ALT ≤ 3.0 × the upper normal limit of institution's normal
range. Total bilirubin ≤ 1.5 × the upper normal limit of institution's normal range.

- Partial Thromboplastin Time (PTT) must be ≤ 1.5 × upper normal limit of institution's
normal range and INR (International Normalized Ratio) < 1.5. Subjects on anticoagulant
(such as warfarin) will be permitted to enroll as long as the INR is in the acceptable
therapeutic range as determined by the investigator.

- Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0-1

- Prior neoadjuvant chemotherapy is alllowed

- Patients must have fully recovered from all effects of surgery. Patients must have had
at least two weeks after minor surgery and four weeks after major surgery before
starting therapy. Minor procedures requiring "Twilight" sedation such as endoscopies
or mediport placement may only require a 24-hour waiting period, but this must be
discussed with an investigator.

- Women of childbearing potential must have a negative serum pregnancy test within 14
days prior to initiation of treatment and/or postmenopausal women must be amenorrheic
for at least 12 months to be considered of non-childbearing potential

- Patient is capable of understanding and complying with parameters as outlined in the
protocol and able to sign and date the informed consent, approved by the Institutional
Review Board (IRB), prior to the initiation of any screening or study-specific
procedures

Exclusion Criteria:

- Ampullary adenocarcinoma

- Women who are pregnant or breastfeeding

- Macroscopic positive margins (R2) or evidence of residual local or metastatic disease

- Resection not including pancreaticoduodenectomy

- Known allergy or intolerance to leucovorin, 5-fluorouracil, oxaliplatin, or irinotecan

- Prior radiation to the upper abdomen

- Inability to swallow pills or bowel obstruction

- Any invasive cancer in the previous 3 years requiring chemotherapy, radiation, or
anticancer therapy following surgery

- Insurance unwilling to pre-authorize PRT, FFX, and (if necessary) pegfilgrastim

- Clinically significant liver disease (Patients with resolved hepatitis B infection are
eligible if HBsAg testing is negative; Patients with resolved hepatitis C infection
are eligible if viral RNA PCR is negative)

- Uncontrolled HIV infection (CD4 count must be at least 200 and viral load undectable
on a stable antiretroviral regimen to be eligible for enrollment)

- Major surgery within 4 weeks prior to enrollment