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

Background:

Tremelimumab is a monoclonal antibody against CTLA4. Anti-CTLA4 therapy has been shown to
enhance anti-tumor immunity by blocking tumor-induced immune suppression of cytotoxic T
cells.

Durvalumab is a human monoclonal antibody directed against PD-L1. Blockage of ligation
between PD-L1 and PD1 induces local immune activation and prevent anergy and exhaustion of
effectors T-cells.

Several studies have documented an increase in peripheral antitumor immunity following
radiation. This effect is evidently too weak to be clinically relevant, but has the potential
to be boosted by immune modulation.

The underlying hypothesis of this study is that the effect of Immune Checkpoint inhibitor
(Durvalumab with or without Tremelimumab) treatment can be enhanced by radiation in patients
with advanced pancreatic carcinoma.

Objective:

To determine the safety, tolerability and feasibility of immune checkpoint inhibition
[comprising either Durvalumab alone, or combined Durvalumab and Tremelimumab] in combination
with stereotactic body radiation therapy (SBRT) in patients with unresectable pancreatic
cancer.

Eligibility:

Histologically confirmed metastatic pancreatic cancer with primary in-situ (or
locally-recurrent) with at least 1 measurable metastatic lesion by RECIST 1.1 criteria and
accessible for biopsy. There is no limit to the number of prior chemotherapy regimens
received.

Patients must be greater than or equal to 18 years of age and have a performance status
(ECOG) less than or equal to 1

Life expectancy of greater than 3 months.

Acceptable organ and bone marrow function.

Patients must not have had standard of care chemotherapy, radiotherapy, or major surgery
within the last 2 weeks prior to entering the study. For recent experimental therapies a 28
day period of time must have elapsed before commencing protocol treatment.

No 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.

No active or history of inflammatory bowel disease (colitis, Crohn s), irritable bowel
disease, celiac disease, or other serious, chronic, gastrointestinal conditions associated
with diarrhea. No active or history of systemic lupus erythematosus, Wegener s
granulomatosis.

Design:

Subjects will be assigned to 4 arms

Anti-PDL1 (Durvalumab) in combination with radiation (8 Gy in fraction)

- Anti-PDL1 (Durvalumab) in combination with radiation (5 Gy in 5 fractions)

Anti-PDL1 (Durvalumab) and anti-CTLA4 (Tremelimumab) in combination with radiation (8 Gy in 1
fractions)

- Anti-PDL1 (Durvalumab) and anti-CTLA4 (Tremelimumab) in combination with radiation (5 Gy in
5 fractions).

- INCLUSION CRITERIA:

- Patients must have histopathological confirmation of pancreatic adenocarcinoma prior
to entering this study by the Laboratory of Pathology of the 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 RECIST1.1 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.

- 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 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 ALT or 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-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 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 (IgM positive). Subjects with a history of
hepatitis A with 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 Wegener
s 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, 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.

- 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.