Study of Durvalumab and Tremelimumab After Radiation for Microsatellite Stable Metastatic Colorectal Cancer Progressing on Chemotherapy

The FC-9 study is designed as a phase II, open label, single arm study of the dual immune
checkpoint blockade with the combination of durvalumab and tremelimumab following
hypofractionated palliative radiation in patients with microsatellite stable (MSS) metastatic
colorectal cancer (mCRC) who have progressed on chemotherapy. The primary aim is to determine
the anti-tumor efficacy of the dual immune checkpoint blockade with durvalumab plus
tremelimumab. The secondary aims are to determine the clinical benefit rate, duration of
response, tolerability and correlates of response. Tumor response at unirradiated target
lesions will be measured at baseline and every 2 cycles using RECIST 1.1.

Following three doses of hypofractionated palliative radiation (Days −2, −1, and Day 0 prior
to Cycle 1), patients will receive the combination of tremelimumab (75 mg IV infusion) and
durvalumab (1500 mg IV infusion) on Day 1 for 4 cycles. Beginning with Cycle 5 through Cycle
12, patients will receive durvalumab alone (1500 mg/IV infusion) on Day 1 of each 28 day
cycle.

The sample size will be between 12 and 21 evaluable patients. Twelve evaluable patients will
be treated in the first stage of the study. If there are no responses among the 12 evaluable
patients, the study will be terminated. If the study goes on to the second stage, a total of
21 evaluable patients will be studied.

Submission of tumor tissue and blood samples for FC-9 correlative science studies will be a
study requirement for all patients. Requirements will include archived tumor samples from the
diagnostic biopsy; additional biopsies of fresh tissue from an accessible lesion prior to
radiation therapy and after 2 cycles of study therapy; and blood sample collections.

Inclusion Criteria:

- The ECOG performance status must be 0 or 1.

- There must be histologic confirmation of a diagnosis of colorectal adenocarcinoma.

- The tumor must have been determined to be microsatellite stable (MSS).

- There must be documentation by PET/CT scan, CT scan, or MRI, that the patient has
evidence of measurable metastatic disease per RECIST 1.1.

- Patients must have an accessible metastatic lesion for pretreatment core biopsy.

- Unless either drug is medically contraindicated, patients must have received
oxaliplatin and irinotecan as part of standard metastatic chemotherapy regimens.

- The patient must have multiple sites of metastatic disease with at least one lesion
amenable to treatment with stereotactic radiation therapy (SBRT) in the lung or liver
and at least one lesion not being irradiated and meeting RECIST 1.1.

- At the time of study entry, blood counts performed within 2 weeks prior to study entry
must meet the following criteria:

- ANC must be greater than or equal to 1500/mm3,

- Platelet count must be greater than or equal to 100,000/mm3; and

- Hemoglobin must be greater than or equal to 9 g/dL.

- The following criteria for evidence of adequate hepatic function performed within 2
weeks prior to study entry must be met:

- Total bilirubin must be less than or equal to 1.5 x ULN (upper limit of normal)
for the lab unless the patient has a bilirubin elevation greater than 1.5 x ULN
to 3 x ULN due to Gilbert's disease or similar syndrome involving slow
conjugation of bilirubin; and

- AST and ALT must be less than or equal to 2.5 x ULN for the lab with the
following exception: for patients with documented liver metastases, AST and ALT
must be less than or equal to 5 x ULN.

- Adequate renal function within 4 weeks prior to study entry, defined as serum
creatinine less than or equal to 1.5 x ULN for the lab or measured or calculated
creatinine clearance greater than 40 mL/min by Cockcroft-Gault formula.

- All hematologic, gastrointestinal, and genitourinary chemotherapy toxicities must be
less than Grade 2 at the time study therapy is to begin. (Note: Transfusions may be
used to correct hemoglobin for patients experiencing anemia from therapy who otherwise
would be eligible for the study.

- Patients with reproductive potential (male/female) must agree to use accepted and
highly effective methods of contraception while receiving study therapy and for at
least 6 months after the completion of study therapy. The definition of effective
method of contraception will be based on the investigator's discretion.

- Female patients must either be of non-reproductive potential (i.e., post-menopausal by
history: greater than or equal to 60 years old and no menses for greater than or equal
to 1 year without an alternative medical cause; OR history of hysterectomy, OR history
of bilateral tubal ligation, OR history of bilateral oophorectomy) or must have a
negative serum pregnancy test upon study entry.

Exclusion Criteria:

- Diagnosis of anal or small bowel carcinoma.

- Colorectal cancer other than adenocarcinoma, e.g., sarcoma, lymphoma, carcinoid.

- Previous therapy with any PD-1 or PD-L1 inhibitor including durvalumab or anti-CTLA4
(including tremelimumab) for any malignancy.

- Receipt of live attenuated vaccination within 30 days prior to study entry or within
30 days of receiving study therapy.

- Active or chronic hepatitis B or hepatitis C.

- Symptomatic or uncontrolled brain metastases requiring concurrent treatments,
uncontrolled spinal cord compression, carcinomatous meningitis, or new evidence of
brain or leptomeningeal disease; uncontrolled seizures.

- Active infection or chronic infection requiring chronic suppressive antibiotics.

- Active or documented inflammatory disease.

- Known history of human immunodeficiency virus (HIV) or acquired
immunodeficiency-related (AIDS) illnesses.

- Current or prior use of immunosuppressive medication within 28 days before the first
dose of study therapy with the exceptions of intranasal corticosteroids or systemic
corticosteroids at physiological doses that do not exceed 10mg/day of prednisone or an
equivalent corticosteroid.

- History of allogeneic organ transplantation.

- Any of the following cardiac conditions:

- Documented NYHA Class III or IV congestive heart failure,

- Myocardial infarction within 6 months prior to study entry,

- Unstable angina within 6 months prior to study entry,

- Symptomatic arrhythmia. If QTc greater than or equal to 470ms, confirmation of
eligible QTc requires mean calculation from 2 additional electrocardiograms
(ECGs) 2−5 minutes apart using Fridericia's Correction Formula (mean less than
470 ms).

- Uncontrolled high blood pressure defined as systolic blood pressure (BP) greater than
or equal to 150 mmHg or diastolic BP greater than or equal to 100 mmHg with or without
anti-hypertensive medication. Patients with initial BP elevations are eligible if
initiation or adjustment of BP medication lowers pressure to meet entry criteria.

- Active or prior documented inflammatory bowel disease (e.g., Crohn's disease,
ulcerative colitis).

- Ongoing or active gastritis or peptic ulcer disease.

- Active bleeding diatheses.

- Known history of previous diagnosis of tuberculosis.

- History of hypersensitivity to durvalumab or tremelimumab or any excipients of these
drugs.

- Known history or confirmation of active pneumonia, pneumonitis, symptomatic
interstitial lung disease, or definitive evidence of interstitial lung disease
described on CT scan, MRI, or chest x-ray in asymptomatic patients; dyspnea at rest
requiring current continuous oxygen therapy.

- Active or prior documented autoimmune disease within the past 2 years. (Note: Patients
with vitiligo, Grave disease, or psoriasis not requiring systemic treatment within the
past 2 years are eligible.)

- Other malignancies unless the patient is considered to be disease-free and has
completed therapy for the malignancy greater than or equal to 12 months prior to study
entry. Patients with the following cancers are eligible if diagnosed and treated
within the past 12 months: carcinoma in situ of the cervix, and basal cell and
squamous cell carcinoma of the skin.

- Psychiatric or addictive disorders or other conditions that, in the opinion of the
investigator, would preclude the patient from meeting the study requirements or
interfere with interpretation of study results.

- Pregnancy or lactation at the time of study entry. (Note: Pregnancy testing should be
performed within 14 days prior to study entry according to institutional standards for
women of childbearing potential.)

- Use of any investigational agent. Use and/or receipt of the last dose of anti-cancer
therapy (chemotherapy, immunotherapy, endocrine therapy, targeted therapy, biologic
therapy, tumor embolization, monoclonal anti-bodies) within 14 days prior to the first
dose of study therapy.