Tremelimumab (Anti-CTLA-4) Plus Durvalumab (MEDI4736) (Anti-PD-L1) in the Treatment of Resectable Colorectal Cancer Liver Metastases

Study Drug Administration:

If you are found to be eligible to take part in this study, you will receive tremelimumab by
vein over about 1 hour and MEDI4736 by vein over about 4 hours during Week 11. After Week 11,
you will receive MEDI4736 alone by vein over about 1 hour during Weeks 21, 25, 29, and 33.

Between Weeks 15 and 17, you will have your already scheduled liver surgery. This means you
will receive tremelimumab before your surgery and MEDI4736 after your surgery.

Study Visits:

During Week 1:

- You will have a physical exam.

- Blood (about 6 tablespoons) will be drawn for routine tests and for testing related to
your immune system.

- If you can become pregnant, part of the above routine blood sample will be used for a
pregnancy test. Urine may also be collected for this test.

During Week 4 :

- You will have a physical exam.

- Blood (about 6 teaspoons) will be drawn for routine tests and for testing related to
your immune system.

- You will have a CT scan.

- If you can become pregnant, part of the above routine blood sample will be used for a
pregnancy test. Urine may also be collected for this test.

Between Weeks 4 and 8:

- You will have a physical exam.

- Blood (about 4 tablespoons) will be drawn for tests related to the immune system.

- You will have liver surgery as part of your standard care. You will sign a separate
consent form for this procedure.

After your liver surgery

Between 0-2 weeks after your liver surgery:

- You will also have a physical exam.

- Blood (about 7 tablespoons) will be drawn for routine tests, to check the status of the
disease, and for tests related to your immune system.

During Week 1:

- You will have a physical exam.

- Blood (about 4 teaspoons) will be drawn for routine tests.

- If you can become pregnant, part of the above routine blood sample will be used for a
pregnancy test. Urine may also be collected for this test.

During Weeks 5 and 9:

- You will have a physical exam.

- Blood (about 4 teaspoons) will be drawn for routine tests.

During Week 13 and every 14 weeks after that until 2 years:

- You will have a physical exam.

- Blood (about 8 teaspoons) will be drawn for routine tests and to check the status of the
disease.

- You will have a CT scan or MRI.

At Week 17, instead of coming into the clinic, the study staff may call you to ask how you
are doing. If you are called, it should last about 5-10 minutes.

Length of Study:

You may receive tremelimumab and MEDI4736 for 1 week and MEDI4736 alone for up to an
additional 4 weeks. You will no longer be able to take the study drugs if the disease gets
worse, if intolerable side effects occur, or if you are unable to follow study directions.

Your participation on this study will be over after follow-up.

Follow-Up:

If you stop treatment for any reason, you will be asked to come to the hospital so your study
doctor may check your health and follow up any ongoing side effects or discomfort until they
get better.

If the disease has gotten better or remained the same, your doctor will continue to check on
the status of the disease as part of your standard of care, which may include imaging scans
and/or blood draws for routine tests.

The study staff will call you 2 times every year starting about 2 years after surgery to ask
you how you are doing. These calls should last about 5-10 minutes.

Follow-up will continue for 5 years or until you withdraw from the study, whichever happens
first.

Inclusion Criteria:

1. Patients must have histologically or cytologically confirmed colorectal cancer with
liver metastases deemed resectable by a general or liver surgeon (resectability may
involve the use of ablative techniques to some but not all liver metastases). Those
patients with known disease outside of the liver are not eligible (except for patients
with primary lesions in place that are planned for resection or nonspecific lung
metastases <1cm).

2. Patients must have measurable disease, defined as at least one lesion that can be
accurately measured in at least one dimension (longest diameter to be recorded) as
=/>10 mm with spiral CT scan.

3. All lines of prior therapy accepted. Subjects with prior hepatic or extra-hepatic
resections of metastatic disease will be included.

4. Age =/>18 years. Because no dosing or adverse event data are currently available on
the use of tremelimumab in combination with durvalumab in patients <18 years of age,
children are excluded from this study.

5. Life expectancy of greater than 6 months.

6. ECOG performance status =/<1 (Karnofsky =/>70%).

7. Patients must have normal organ and marrow function as defined: a) leukocytes
=/>3,000/mcL; b) absolute neutrophil count =/>1,500/mcL; c) platelets =/>100,000/mcL;
d) total bilirubin < 1.5 X institutional normal limits (subjects with known Gilbert
syndrome are eligible with total bilirubin < 3.0 mg/dL); e) AST(SGOT)/ALT(SGPT) =/< 3
X institutional upper limit of normal; f) creatinine within normal institutional
limits OR g) creatinine clearance =/>60 mL/min/1.73 m^2 for patients with creatinine
levels above institutional normal.

8. Known or ordered molecular testing for MSI, BRAF, and KRAS status.

9. Evidence of post-menopausal status or negative urinary or serum pregnancy test for
female pre-menopausal patients. Women will be considered post-menopausal if they have
been amenorrheic for 12 months without an alternative medical cause. The following
age-specific requirements apply: Women <50 years of age would be considered
post-menopausal if they have been amenorrheic for 12 months or more following
cessation of exogenous hormonal treatments and if they have luteinizing hormone and
follicle-stimulating hormone levels in the post-menopausal range for the institution
or underwent surgical sterilization (bilateral oophorectomy or hysterectomy).

10. Continuation from criteria above: Women >/= 50 years of age would be considered
post-menopausal if they have been amenorrheic for 12 months or more following
cessation of all exogenous hormonal treatments, had radiation-induced menopause with
last menses >1 year ago, had chemotherapy-induced menopause with last menses >1 year
ago, or underwent surgical sterilization (bilateral oophorectomy, bilateral
salpingectomy or hysterectomy).

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

12. Weight >30kg (required for flat dose-based administration of study agents)

Exclusion Criteria:

1. Prior chemotherapy < 2 weeks prior to study drug treatment and treatment related
adverse events that have not recovered to baseline or grade 1 (alopecia excluded).
Prior radiation therapy <4weeks prior to study drug treatment.

2. Patients may not be receiving any other investigational agents.

3. Active or prior documented autoimmune or inflammatory disorders (including
inflammatory bowel disease [eg, colitis or Crohn's disease], diverticulitis [with the
exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome, or
Wegener syndrome [granulomatosis with polyangiitis, Graves' disease, rheumatoid
arthritis, hypophysitis, uveitis, etc.]). The following are exceptions to this
criterion: a) Patients with vitiligo or alopecia; b) Patients with hypothyroidism (eg,
following Hashimoto syndrome) stable on hormone replacement; c) Any chronic skin
condition that does not require systemic therapy; d) Patients without active disease
in the last 5 years may be included but only after consultation with the study
physician; d) Patients with celiac disease controlled by diet alone.

4. Subjects with a condition requiring systemic treatment with either corticosteroids
(>10mg daily prednisone equivalents) or other immunosuppressive medications within 14
days of study drug administration. Inhaled or topical steroids and adrenal replacement
doses > 10mg daily prednisone equivalents are permitted in the absence of active
autoimmune disease.

5. Prior exposure to T cell checkpoint inhibitor therapies, including durvalumab and
tremelimumab.

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

7. Known allergy or hypersensitivity to any of the study drugs or any of the study drug
excipients.

8. History of active primary immunodeficiency

9. Women who are pregnant, which includes women with a positive pregnancy test at
enrollment or prior to the administration of study medication, or breastfeeding are
not allowed on study.

10. Receipt of a live vaccine within 30 days of study entry.

11. Any unresolved toxicity NCI CTCAE Grade >/=2 from previous anticancer therapy with the
exception of alopecia, vitiligo, and the laboratory values defined in the inclusion
criteria: a) Patients with Grade >/=2 neuropathy will be evaluated on a case-by-case
basis after consultation with the Study Physician; b) Patients with irreversible
toxicity not reasonably expected to be exacerbated by treatment with durvalumab or
tremelimumab may be included only after consultation with the Study Physician.

12. Any concurrent chemotherapy, biologic, or hormonal therapy for cancer treatment.
Concurrent use of hormonal therapy for non-cancer-related conditions (e.g., hormone
replacement therapy) is acceptable.

13. Major surgical procedure within 28 days prior to the first dose of IP. Note: Local
surgery of isolated lesions for palliative intent is acceptable.

14. History of allogenic organ transplantation.

15. Known active infection including tuberculosis (clinical evaluation that includes
clinical history, physical examination and radiographic findings, and TB testing in
line with local practice), hepatitis B (known positive HBV surface antigen (HBsAg)
result), hepatitis C, or human immunodeficiency virus (positive HIV 1/2 antibodies).
Patients with a past or resolved HBV infection (defined as the presence of hepatitis B
core antibody [anti-HBc] and absence of HBsAg) are eligible. Patients positive for
hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative
for HCV RNA.

16. Female patients who are pregnant or breastfeeding or male or female patients of
reproductive potential who are not willing to employ effective birth control from
screening to 90 days after the last dose of durvalumab monotherapy or180 days after
the last dose of durvalumab + tremelimumab combination therapy.