Nivolumab and Ipilimumab and Radiation Therapy in MSS and MSI High Colorectal and Pancreatic Cancer

This research study is a Phase II clinical trial. Phase II clinical trials test the safety
and effectiveness of an investigational intervention to learn whether the intervention works
in treating a specific disease. "Investigational" means that the intervention is being
studied.

The FDA (the U.S. Food and Drug Administration) has not approved nivolumab for this specific
disease but it has been approved for other uses.

The FDA (the U.S. Food and Drug Administration) has not approved ipilimumab for this specific
disease but it has been approved for other uses.

Researchers hope to study the effects of the combination of Nivolumab and Ipilimumab. Many
cancers use specific pathways (such as PD-1/PD-L1 and CTLA-4) to evade the body's immune
system. Nivolumab and ipilimumab work by blocking the PD-1/PD-L1 and CTLA-4 pathways and thus
releasing the brakes on the immune system so it can stop or slow cancer.

Ipilimumab and Nivolumab are both antibodies. An antibody is a cell that attaches to other
cells to fight off infection. The antibodies in ipilimumab work by not allowing cancer cell
growth. The antibodies in nivolumab work by causing programmed cell death of the cancer
cells. Radiation therapy is believed to increase the likelihood of response of immunotherapy
(the prevention/treatment of a disease through an immune response).

In this research study, the investigators are studying the combination of nivolumab,
ipilimumab and radiation therapy on participants with microsatellite stable colorectal
cancer, pancreatic cancer, or MSI high colorectal cancer. The combination of these study
drugs have been tested and optimized for safety and is currently being tested in multiple
disease types. The study drugs have not been tested and optimized in combination with
radiation therapy. The investigators believe that through the combination of the study drugs
and radiation therapy the body may produce an immune response to stop the cancer cells from
growing.

Inclusion Criteria:

- Participants must have histologically or cytologically confirmed adenocarcinoma of
colorectal or pancreatic origin

- Age >18 years.

- Eastern Cooperative Oncology Group (ECOG) performance status ≤1

- Life expectancy of greater than 3 months

- Participants must have normal organ and marrow function as defined in Table 1, all
screening labs should be performed within 14 days of protocol registration.

Table 1 Adequate Organ Function Laboratory Values

System Laboratory Value

- Hematological

- Absolute neutrophil count (ANC) ≥1500 /mcL

- White blood count (WBC) ≥2000 /mcL

- Platelets ≥100,000 / mcL

- Hemoglobin ≥9 g/dL

- Renal

- Serum creatinine OR Measured or calculated creatinine clearance (GFR can also be
used in place of creatinine or CrCl) ≤ Serum creatinine ≤ 1.5 x ULN or creatinine
clearance (CrCl) ≥ 40 mL/min (if using the Cockcroft-Gault formula below):

- Female CrCl = (140 - age in years) x weight in kg x 0.85 72 x serum creatinine in
mg/dL

- Male CrCl = (140 - age in years) x weight in kg x 1.00 72 x serum creatinine in
mg/dL

- Hepatic

- Serum total bilirubin ≤ 1.5 X ULN (upper limit of normal) (subjects with Gilbert
Syndrome can have a total bilirubin <3 mg/dL

- aspartate aminotransferase (AST) serum glutamic oxaloacetic transaminase (SGOT)
and Alanine Aminotransferase ALT (SGPT) ≤ 3 X ULN OR ≤ 5 X ULN for subjects with
liver metastases

- Coagulation

- International Normalized Ratio (INR) or Prothrombin Time (PT)

- Activated Partial Thromboplastin Time (aPTT) ≤1.5 X ULN unless subject is
receiving anticoagulant therapy

- as long as PT or PTT is within therapeutic range of intended use of
anticoagulants

≤1.5 X ULN unless subject is receiving anticoagulant therapy

- as long as PT or PTT is within therapeutic range of intended use of
anticoagulants

- Creatinine clearance should be calculated per institutional standard.

- Women of childbearing potential (WOCBP) must use appropriate method(s) of
contraception. WOCBP should use an adequate method to avoid pregnancy for 5 months (30
days plus the time required for nivolumab to undergo five half-lives) after the last
dose of investigational drug.

- Women of childbearing potential must have a negative serum or urine pregnancy test
(minimum sensitivity 25 IU/L or equivalent units of HCG)

- Women must not be breastfeeding

- Men who are sexually active with WOCBP must use any contraceptive method with a
failure rate of less than 1% per year. Men receiving nivolumab and who are sexually
active with WOCBP will be instructed to adhere to contraception for a period of 7
months after the last dose of investigational product. Women who are not of
childbearing potential, ie, who are postmenopausal or surgically sterile as well as
azoospermic men do not require contraception

- Ability to understand and the willingness to sign a written informed consent document.

- Stable dose of dexamethasone 2 mg or less for 7 days prior to initiation of treatment

- One previously unirradiated lesion amenable to radiotherapy 8 Gy x 3 and can meet dose
constraints, and another unirradiated measurable lesion > 1 cm in size outside the
radiation field that can be used as measurable disease

- Colorectal patients must have documentation of microsatellite status.
Immunohistochemistry (IHC) is acceptable.

- Colorectal patients must have received prior Fluorouracil (5FU), Irinotecan and
Oxaliplatin (any combination) or have a contraindication to receiving these agents.

- Pancreas patients must have progressed on at least 1 prior line of chemotherapy

Exclusion Criteria:

- Participants who have had chemotherapy, targeted small molecule therapy or study
therapy within 14 days of protocol treatment, or those who have not recovered (i.e., ≤
Grade 1 or at baseline) from adverse events due to agents administered more than 2
weeks earlier. Subjects with ≤ Grade 2 neuropathy are an exception to this criterion
and may qualify for the study. If subject received major surgery, they must have
recovered adequately from the toxicity and/or complications from the intervention
prior to starting therapy.

- Participants who are receiving any other investigational agents.

- Patients are excluded if they have an active, known or suspected autoimmune disease
other than those listed below. Subjects are permitted to enroll if they have vitiligo,
type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only
requiring hormone replacement, psoriasis not requiring systemic treatment, or
conditions not expected to recur in the absence of an external trigger

- Patients are excluded if they have a condition requiring systemic treatment with
either corticosteroids (> 10 mg daily prednisone equivalents) or other
immunosuppressive medications within 14 days of study drug administration. Inhaled or
topical steroids and adrenal replacement doses > 10 mg daily prednisone equivalents
are permitted in the absence of active autoimmune disease. Subjects are permitted to
use topical, ocular, intra-articular, intranasal, and inhalational corticosteroids
(with minimal systemic absorption). Physiologic replacement doses of systemic
corticosteroids are permitted, even if > 10 mg/day prednisone equivalents. A brief
course of corticosteroids for prophylaxis (eg, contrast dye allergy) or for treatment
of non-autoimmune conditions (eg, delayed-type hypersensitivity reaction caused by
contact allergen) is permitted.

- Colorectal patients are excluded if they have had prior systemic treatment with an
anti-CTLA4, anti-PD1 (Programmed cell death protein 1) or PDL1 (Programmed
death-ligand 1) antibody. Pancreatic patients are excluded if they have previously
received anti-CTLA-4 therapy. Prior PD-1 or PDL1 therapy will be permitted for
pancreas patients

- Has a known history of active TB (Bacillus Tuberculosis)

- Patients are excluded if they are positive test for hepatitis B virus surface antigen
(HBV sAg) or hepatitis C virus ribonucleic acid (HCV antibody) indicating acute or
chronic infection

- Patients are excluded if they have known history of testing positive for human
immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS). These
participants are at increased risk of lethal infections when treated with
marrow-suppressive therapy. Appropriate studies will be undertaken in participants
receiving combination antiretroviral therapy when indicated.

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance with
study requirements.

- Has known psychiatric or substance abuse disorders that would interfere with
cooperation with the requirements of the trial.

- Is pregnant or breastfeeding, or expecting to conceive or father children within the
projected duration of the trial, starting with the pre-screening or screening visit
through 5 months for woman and 7 months for men, after the last dose of trial
treatment.

- Has a known additional malignancy that is progressing or requires active treatment.
Exceptions include basal cell carcinoma of the skin and squamous cell carcinoma of the
skin that has undergone potentially curative therapy or in situ cervical cancer.

- Has known history of, or any evidence of active, non-infectious pneumonitis.

- Has an active infection requiring systemic therapy.

- Has received a live vaccine within 30 days of planned start of study therapy. Note:
Seasonal influenza vaccines for injection are generally inactivated flu vaccines and
are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live
attenuated vaccines, and are not allowed.

- History of allergy to study drug components

- History of severe hypersensitivity reaction to any monoclonal antibody

- Uncontrolled brain metastases. Patients treated with radiation > 4 weeks prior with
follow up imaging showing control are eligible