Immune Checkpoint Inhibition (Tremelimumab and/or MEDI4736) in Combination With Radiation Therapy in Patients With Unresectable Pancreatic Cancer

* INCLUSION CRITERIA:
* Patients must have histopathological confirmation of pancreatic adenocarcinoma prior to entering this study by the Laboratory of Pathology of the National Cancer Institute (NCI) to entering this study by the Laboratory of Pathology of the NCI prior to entering this study
* Patients must have disease that is not amenable to potentially curative resection. Primary in-situ (or locally-recurrent) tumor must be present and, in the opinion of radiation oncology, be amenable to radiation therapy as planned in the protocol. Each case will be discussed at GI tumor board with multidisciplinary team.
* Patients must have at least 1 measurable metastatic lesion by Response Evaluation in Solid Tumors (RECIST) 1.1 criteria.
* There is no limit to the number of prior chemotherapy regimens received. Patients must have received at least one line of prior systemic chemotherapy for advanced unresectable and/or metastatic disease.
* Age greater than or equal to 18 years
* Life expectancy of greater than 3 months.
* Eastern Cooperative Oncology Group (ECOG) performance status 0-1
* Patients must have normal organ and marrow function as defined below:

  * absolute neutrophil count - \> 1,000/mcL
  * Platelets - greater than or equal to 100,000/mcL
  * total bilirubin - Bili should be less than or equal to 2 x upper limit of normal (ULN) (patients with Gilbert's Syndrome must have a total bilirubin less than 3.0 mg/dL)
  * serum albumin - greater than or equal 2.5 g/dL

Patients are eligible with alanine aminotransferase (ALT) or aspartate aminotransaminase (AST) up to 3 x ULN. (up to 5 x ULN if liver metastases present)

--Creatinine - \< 2X institution upper limit of normal

OR

--creatinine clearance - \>45 mL/min/1.73 m(2), for patients with creatinine levels above institutional normal

* Patients must have recovered from any acute toxicity related to prior therapy, including surgery. Toxicity should be less than or equal to grade 1 or returned to baseline.
* Patient must be able to understand and willing to sign a written informed consent document.

EXCLUSION CRITERIA:

* Malignant ascites that is clinically detectable by physical examination or is symptomatic. Evidence of radiographic ascites that is not clinically significant will not be an exclusion criterion.
* Any prior Grade greater than or equal to 3 imAE while receiving immunotherapy, including anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA4) treatment, or any unresolved imAE \> Grade 1. Note: Active or history of vitiligo will not be a basis for exclusion.
* Patients must not have had standard of care chemotherapy, radiotherapy, or major surgery within the last 2 weeks prior to entering the study. Note: Local surgeries for isolated lesions for palliative intent are acceptable. For recent experimental therapies a 28 day period of time must have elapsed before commencing protocol treatment.
* Patients with known brain metastases will be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events.
* Uncontrolled intercurrent illness, including, but not limited to, ongoing or active infection, current pneumonitis, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, interstitial lung disease, or psychiatric illness/social situations that would limit compliance with study requirement, substantially increase risk of incurring adverse events from Durvalumab (MEDI4736) or tremelimumab, or compromise the ability of the subject to give written informed consent.
* Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease, diverticulitis with the exception of diverticulosis, celiac disease, irritable bowel disease; Wegner syndrome; Hashimoto syndrome; Graves disease; rheumatoid arthritis, hypophysitis, uveitis, etc.) within the past 3 years prior to the start of treatment. The following are exceptions to this criterion:

  * Subjects with vitiligo or alopecia
  * Requirement for intermittent use of bronchodilators or local steroid injections
  * Subjects with hypothyroidism (eg, following Hashimoto syndrome) stable on hormone replacement, or psoriasis not requiring systemic treatment
* History of primary immunodeficiency or history of active tuberculosis. Note: Latent tuberculosis will not be a basis for exclusion.
* Diverticulitis (either active or history of) within the past 2 years. Note that diverticulosis is permitted.
* Dementia or significantly altered mental status that would prohibit the understanding or rendering of Information and Consent and compliance with the requirements of the protocol.
* True positive test results for hepatitis A (Immunoglobulin M (IgM) positive). Subjects with a history of hepatitis A with Immunoglobulin G (IgG) blood test are not excluded. True positive test results hepatitis B, or C infection.
* Active or history of inflammatory bowel disease (colitis, Crohn's), irritable bowel disease, celiac disease, or other serious, chronic, gastrointestinal conditions associated with diarrhea. Active or history of systemic lupus erythematosus or Wegeners granulomatosis.
* Current or prior use of immunosuppressive medication within 14 days before the first dose of MEDI4736 and tremelimumab. The following are exceptions to this criterion:

  * Intranasal, inhaled, and topical steroids
  * Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or equivalent
  * Steroids as premedication for hypersensitivity reactions (eg, computed tomography (CT) scan premedication)
* History of sarcoidosis syndrome.
* Patients should not be vaccinated with live attenuated vaccines within 1 month of starting Tremelimumab and MEDI4736 treatment. Subjects, if enrolled, should not receive live vaccine during the study and 180 days after the last dose of both drugs.
* Human immunodeficiency virus (HIV)-positive patients receiving anti-retroviral therapy are excluded from this study due to the possibility of pharmacokinetic interactions between antiretroviral medications and Tremelimumab or MEDI4736. HIV positive patients not receiving antiretroviral therapy are excluded due to the possibility that Tremelimumab or MEDI4736 may worsen their condition and the likelihood that the underlying condition may obscure the attribution of adverse events.
* History of hypersensitivity reaction to human or mouse antibody products.
* Pregnancy and breast feeding are exclusion factors. The effects of Tremelimumab and MEDI4736 on the developing human fetus are unknown. Enrolled patients must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, the duration of study participation and 180 days (female patients) or 90 days (male patients) after the end of the treatment. In addition male patients must refrain from sperm donation for 90 days after the final dose of investigational product. Female patients must refrain from egg cell donation for 180 days after the final dose of investigational product. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately.
* Any condition that, in the opinion of the investigator, would interfere with evaluation of the investigational product or interpretation of subject safety or study results.