Trial of Carbon Ion Versus Photon Radiotherapy for Locally Advanced, Unresectable Pancreatic Cancer

A significant percentage of patients with incurable pancreatic cancer die with predominantly
local disease. Conventional chemoradiotherapy (i.e. using photon therapy) leads to inadequate
locoregional control rates, despite concurrent chemotherapy and modern radiation techniques.
Carbon ion radiation therapy holds the promise of a novel biological mechanism for
eradicating local-only disease (heavy ion therapy), and preliminary data are extremely
encouraging. Thus, evaluating the comparative effectiveness of a novel and more potent
radiotherapy modality in this known radioresistant, lethal disease is a natural question.

This is a randomized phase III trial comparing photon-based (IMRT) and carbon-ion based
(CIRT) chemoradiotherapy treatments. Patients will be randomized in a 2:1 ratio (CIRT:IMRT)
to one of the following two treatment arms following non-progressive disease during induction
chemotherapy:

- Carbon ion-based irradiation (CIRT). Patients will be treated with carbon ion
irradiation plus concurrent gemcitabine chemotherapy. This chemoradiation course is
followed by treatment with gemcitabine and nab-paclitaxel chemotherapy.

- Photon-based irradiation (IMRT). Patients will be treated with x-ray irradiation (IMRT)
plus concurrent gemcitabine chemotherapy. This chemoradiation course is followed by
treatment with gemcitabine and nab-paclitaxel chemotherapy.

Inclusion Criteria:

1. All patients must be willing and capable to provide informed consent within the 30
days prior to registration to participate in the protocol.

2. Histological and/or cytological diagnosis of pancreas adenocarcinoma must be done at
any point prior to registration

3. Unresectable by radiographic or exploration within 30 days of registration

4. Age ≥ 18 years.

5. Distance from the pancreas tumor edge to the bowel and stomach > 3 mm (in both the
prone and supine positions)

6. Tumor does not exceed 15 cm in greatest dimension

7. No evidence for metastatic disease as assessed by CT imaging of the chest, abdomen and
pelvis OR by PET-CT within the 30 days prior to registration.

8. Zubrod performance status of 0-1, within 30 days prior to registration.

9. CMP and CBC with differential obtained within 14 days prior to registration (may be
taken after stent placement), with adequate hematologic variables as defined by:

Absolute neutrophil count > 1500 cells/mm3 Creatinine <1.5 mg/dL Hemoglobin >8.0 g/dL
AST and ALT < 2.5 X ULN Bilirubin < 1.5 times the ULN (after stent placement, if
necessary)

10. Patients must complete all required pretreatment evaluations

11. Able to travel to a foreign country within approximately 2 weeks of randomization (for
patients enrolled at UTSW)?

12. Women of childbearing potential and male participants must agree to use an effective
method of contraception.

A female of child-bearing potential is any woman (regardless of sexual orientation, having
undergone a tubal ligation, or remaining celibate by choice) who meets the following
criteria:

- Has not undergone a hysterectomy or bilateral oophorectomy; or

- Has not been naturally postmenopausal for at least 12 consecutive months (i.e., has
had menses at any time in the preceding 12 consecutive months).

Exclusion Criteria:

1. Subjects receiving other investigational agents.

2. History of allergic reactions attributed to compounds of similar chemical or biologic
composition to gemcitabine or nab-paclitaxel or other agents used in study.

3. Subjects who are pregnant or nursing due to the potential for congenital abnormalities
and the potential of this regimen to harm nursing infants.

4. Prior treatment for pancreatic cancer preceding registration

5. Prior radiation to the upper abdomen

6. Placement of a metal stent for relief of biliary obstruction (metal stents may be
placed following completion of radiation therapy).

7. Body weight >100 kg

8. Active inflammatory bowel disease or active gastric/duodenal ulcer

9. Metal implants in the upper abdomen

10. Expected medical intolerance of radiotherapy, concurrent chemotherapy, and/or adjuvant
chemotherapy.

11. History of HIV or hepatitis B or C