High or Standard Intensity Radiation Therapy After Gemcitabine Hydrochloride and Nab-paclitaxel in Treating Patients With Pancreatic Cancer That Cannot Be Removed by Surgery

PRIMARY OBJECTIVES:

- I. To determine if intensified radiochemotherapy following gemcitabine and
nab-paclitaxel in patients with unresectable pancreatic cancer will show a signal for
improved 2-year overall survival (OS) from 10% to 22.5% as compared to chemotherapy with
gemcitabine and nab-paclitaxel alone.

- II. To determine if standard radiochemotherapy, following gemcitabine and
nab-paclitaxel, in patients with unresectable pancreatic cancer will show a signal for
improved 2-year OS from 10% to 22.5% as compared to chemotherapy with gemcitabine and
nab-paclitaxel alone.

SECONDARY OBJECTIVES:

- I. To evaluate patterns of failure (local and systemic progression) by SMAD family
member 4 (SMAD4) status and intensity of radiation therapy.

- II. To evaluate the impact of radiochemotherapy on OS for the subset of SMAD4 intact
patients.

- III. To evaluate adverse events associated with the treatments.

- IV. To evaluate correlation between SMAD4 status determined by immunohistochemistry
(IHC) and genetic SMAD4 status.

Patients are randomized to 1 of 3 treatment arms.

After completion of study treatment, patients are followed up at 1 month and then every 3
months.

Inclusion Criteria:

1. Histologically or cytologically proven diagnosis of adenocarcinoma of the pancreas
prior to registration

2. Tumor diameter ≤ 7 cm

3. Unresectable by radiographic criteria (pancreas protocol CT or MRI) or exploration
within 30 days prior to registration.

4. A cell block or core biopsy must be submitted for central review and analysis of SMAD4
status as soon as possible following step 1 registration.

5. No distant metastases, based upon the following minimum diagnostic workup:

- History/physical examination within 30 days prior to registration

- Whole body fluorodeoxyglucose-positron emission tomography/computerized
tomography (FDG-PET/CT) within 30 days prior to registration NOTE: If whole-body
FDG-PET/CT is not performed, CT of the chest and CT (or MRI) of abdomen and
pelvis must be obtained (imaging of abdomen and pelvis need not be repeated if
already included in pancreas protocol study)

6. Zubrod Performance Status 0-1 within 30 days prior to registration

7. Age ≥ 18;

8. Complete blood count (CBC)/differential obtained within 14 days prior to step 1
registration, with adequate bone marrow function defined as follows:

- Absolute neutrophil count (ANC) ≥ 1,500 cells/mm3

- Platelets ≥ 100,000 cells/mm3

- Hemoglobin ≥ 8.0 g/dl (NOTE: The use of transfusion or other intervention to
achieve Hgb ≥ 8.0 g/dl is acceptable)

9. Additional laboratory studies within 14 days prior to registration:

- carbohydrate antigen 19-9 (CA19-9); NOTE: in the event that a stent has been
placed and biliary obstruction has been relieved, the CA19-9 should be drawn post
stent placement

- Creatinine < 2 mg/dl; Glomerular filtration rate (GFR) > 50 mL/min (Cockroft and
Gault formula)

- Bilirubin < 1.5 x ULN

- Alanine aminotransferase (ALT) and aminotransferase (AST) ≤ 2.5 x ULN

- Activated partial thromboplastin time (aPTT), prothrombin time (PT) ≤1.2 x upper
limit of normal (ULN)

10. Patient must provide study specific informed consent prior to study entry

11. Women of childbearing potential and male participants must practice adequate
contraception during protocol treatment and for at least 6 months following treatment

12. For females of child-bearing potential, negative serum pregnancy test within 30 days
prior to registration

Exclusion Criteria:

1. More than one primary lesion

2. Prior invasive malignancy (unless disease free for a minimum of 1095 days [3 years]);
Non-melanomatous skin cancer and previous early prostate cancer that had a non-rising
prostate-specific antigen (PSA) are eligible

3. Prior systemic anti-cancer therapy for pancreatic cancer; note that prior chemotherapy
for a different cancer is allowable

4. Prior radiation therapy to the abdomen that would result in overlap of radiation
therapy fields

5. Severe, active co-morbidity, defined as follows:

- Unstable angina and/or congestive heart failure requiring hospitalization within
the last 6 months

- Transmural myocardial infarction within the last 6 months

- Acute bacterial or fungal infection requiring intravenous antibiotics at the time
of registration

- Chronic Obstructive Pulmonary Disease exacerbation or other respiratory illness
requiring hospitalization or precluding study therapy within 30 days before
registration

- Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects;
note, however, that laboratory tests for liver function and coagulation
parameters are not required for entry into this protocol

- Acquired Immune Deficiency Syndrome (AIDS) based upon current Centers for Disease
Control (CDC) definition; note, however, that HIV testing is not required for
entry into this protocol. The need to exclude patients with AIDS from this
protocol is necessary because the treatments involved in this protocol may be
significantly immunosuppressive. Protocol-specific requirements may also exclude
immuno-compromised patients

6. Pregnancy or women of childbearing potential, women who cannot discontinue
breastfeeding and men who are sexually active and not willing/able to use medically
acceptable forms of contraception; this exclusion is necessary because the treatment
involved in this study may be significantly teratogenic

7. Prior allergic reaction to the study drug(s) involved in this protocol

8. Pre-existing Grade 2 or greater neuropathy

9. Distant metastases