Clinical Trial Evaluating the Safety and Response With PF-05082566, Cetuximab and Irinotecan in Patients With Advanced Colorectal Cancer

Study Groups:

If you are found to be eligible to take part in this study, you will be assigned to a dose
level of irinotecan based on when you join this study. Up to 3 dose levels of irinotecan will
be tested. Up to 6 participants will be enrolled at each dose level. The first group of
participants will receive the lowest dose level. Each new group will receive a higher dose
than the group before it, if no intolerable side effects were seen. This will continue until
the highest tolerable dose of Irinotecan is found.

After the highest tolerable dose level of irinotecan is found, an additional 20 participants
will be enrolled on the study and will receive this dose.

All participants will receive the same dose of cetuximab and PF-05082566.

Study Drug Administration:

You will receive irinotecan and cetuximab by vein on Days 1 and 15 of each 28-day cycle. The
first time you receive cetuximab, it will be given over about 2 hours. If you tolerate it
well, you will receive it over about 1 hour each time after that. Irinotecan will be given
over about 90 minutes.

On Day 2 of each cycle, you will receive PF-05082566 by vein over about 1 hour.

You will also be given standard drugs to help decrease the risk of side effects. You may ask
the study staff for information about how the drugs are given and their risks.

Length of Study:

You may continue receiving the study drugs for as long as your study doctor thinks it is in
your best interest. 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 the study will be over after the end-of-study visit.

Study Visits:

On Day 1 of each Cycle:

- You will have a physical exam.

- Blood (about 1-2 tablespoons) will be drawn for routine tests and biomarker testing. If
you can become pregnant, part of this sample will also be used for a pregnancy test.

- Urine will be collected for routine tests.

On Day 2 of each Cycle:

- Blood (about 1-2 tablespoons) will be drawn for pharmacodynamic (PD) testing. PD testing
measures how the level of study drug in your body may affect the disease. At Cycle 1,
this will be done before and 3 times over the 6 hours after the dose. At Cycles 2 and
beyond, this will only be done before the dose.

- You will have an EKG before you receive the study drug.

On Days 3, 4, 9, and 22 of Cycle 1, blood (about 1-2 tablespoons) will be drawn for PD
testing.

On Day 15 of each Cycle, blood (about 1-2 tablespoons) will be drawn for routine tests and PD
testing.

If you had a core needle biopsy at screening, you will have another biopsy about 6-8 weeks
after screening.

Every 8 weeks, you will have the same imaging scan(s) you had at screening.

End-of-Study Visit:

After you stop receiving the study drugs:

- You will have a physical exam.

- Blood (about 1-2 tablespoons) will be drawn for routine tests, PD testing, and biomarker
testing.

- You will have the same imaging scan(s) you had at screening.

Follow-Up:

Every 3 months (+/- 1 month) after the end-of-study visit, you will be called and asked about
how you are doing and any other treatments you may be receiving. These calls should last
about 10 minutes each time.

Inclusion Criteria:

1. Patients must have histologically and or cytologically confirmed metastatic colorectal
cancer

2. Age 16 years or older.

3. Patients must have a wild type or mutated RAS tumor status known prior to enrollment

4. Metastatic colorectal cancer patients have progressed following at least one line of
5-FU-based chemotherapy.

5. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2.

6. Patients must have measurable disease per irRECIST criteria for part 2 (dose
expansion).

7. Adequate bone marrow function, defined as ANC ≥ 1.0 x 10^9/L (≥ 1,000/uL), platelet
count ≥ 75 x 10^9/L (≥ 75000/μL), and hemoglobin ≥ 8.0 g/dL (≥ 5.0 mmol/L). Patients
must be transfusion independent (i.e., no blood product transfusions for a period of
at least 14 days prior to screening).

8. Adequate Renal Function, including serum creatinine < 2 x upper limit of normal (ULN)
or estimated creatinine clearance > 30 ml/min as calculated using the method standard
for the institution.

9. Adequate Liver Function, including: a) Total serum bilirubin < 1.5 x ULN, unless the
patient has documented Gilbert syndrome; b) Aspartate and Alanine Aminotransferase
(AST and ALT) < 3 x ULN

10. Adequate Cardiac Function, as measured by left ventricular ejection fraction (LVEF)
that is greater than 40%, or the absence of New York Heart Association (NYHA)
classification of greater than stage II congestive heart failure.

11. Resolved acute effects of any prior therapy to baseline severity or Grade < /= 2 CTCAE
v. 4.03 except for AEs not constituting a safety risk by investigator judgment.

12. Serum or urine pregnancy test (for females of childbearing potential) negative at
screening and at the baseline visit (before the patient may receive the
investigational product).

13. Male and female patients of childbearing potential and at risk for pregnancy must
agree to use two highly effective methods of contraception throughout the study and
for at least 90 days after the last dose of assigned treatment. Female patients who
are not of childbearing potential (permanently sterilized or postmenopausal; i.e.,
meet at least one of the following criteria): - Have undergone a documented
hysterectomy and/or bilateral oophorectomy; or - Have medically confirmed ovarian
failure; or - Achieved postmenopausal status, defined as follows: cessation of regular
menses for at least 12 consecutive months with no alternative pathological or
physiological cause; status may be confirmed by having a serum follicle stimulating
hormone (FSH) level within the laboratory's reference range for postmenopausal women

14. High microsatellite instability (MSI-H) colorectal cancer patients must have received
an approved PD-1 targeted agent prior to enrolling in this trial.

15. Evidence of a personally signed and dated informed consent document indicating that
the patient has been informed of all pertinent aspects of the study

16. Willingness and ability to comply with the study scheduled visits, treatment plans,
laboratory tests and other procedures.

Exclusion Criteria:

1. Patients with known symptomatic brain metastases requiring steroids. Patients with
previously diagnosed brain metastases are eligible if they are asymptomatic or have
completed their treatment and have recovered from the acute effects of radiation
therapy or surgery prior to the start of study medication, have discontinued
corticosteroid treatment for these metastases for at least 4 weeks and are
neurologically stable

2. Patient has had any treatment specific for tumor control within 3 weeks of dosing, or
for investigational drugs and cytotoxic agents, within 5 half-lives or 3 weeks,
whichever is shorter

3. Patients receiving any medications or substances that are strong inhibitors or
inducers of CYP3A4 complex. Lists including medications and substances known or with
the potential to interact with the CYP3A4 isoenzymes

4. Prior therapy with a compound of the same mechanism as PF-05082566 (immunomodulation
of 4-1BB).

5. Major surgery within 28 days of starting study treatment.

6. Radiation therapy within 14 days of starting study treatment

7. Autoimmune disorders (e.g., Crohn's Disease, rheumatoid arthritis, scleroderma,
systemic lupus erythematosus) and other diseases that compromise or impair the immune
system except patients who have grade 1 psoriasis (in remission or controlled with
topical steroids) or mild degree of autoimmune thyroiditis that are controlled with
medications

8. Active and clinically significant bacterial, fungal or viral infection including
hepatitis B (HBV), hepatitis C (HCV), known human immunodeficiency virus (HIV) or
acquired immunodeficiency syndrome (AIDS)-related illness (HIV testing is not
required)

9. Unstable or serious concurrent medical conditions in the previous 6 months, eg,
pancreatitis, severe/unstable angina, prolonged QT interval corrected by Fridericia's
formula(QTcF) > 470 msec (calculated as average of triplicate readings, taken no
greater than 2 minutes apart, and no history of Torsades de Pointes or symptomatic QTc
abnormality), symptomatic congestive heart failure, myocardial infarction and/or
pulmonary hypertension, ongoing maintenance therapy for life-threatening ventricular
arrhythmia, stroke, and uncontrolled major seizure disorder

10. Concurrent active malignancy other than non-melanoma skin cancer or carcinoma in situ
of the cervix

11. Patients who are pregnant or breastfeeding

12. Patients with intolerance to or who have had a severe allergic or anaphylactic
reaction to antibodies or infused therapeutic proteins, or patients who have had a
severe allergic or anaphylactic reaction to any of the substances included in the
study drug (including excipients).

13. Other severe acute or chronic medical or psychiatric condition, including recent
(within the past year) or active suicidal ideation or behavior, or laboratory
abnormality that may increase the risk associated with study participation or
investigational product administration or may interfere with the interpretation of
study results and, in the judgment of the investigator, would make the patient
inappropriate for entry into this study.