Irinotecan Plus Brivanib in Metastatic Colorectal Cancer (CRC) Enriched for Elevated Levels of Plasma FGF

Study Drugs:

Brivanib is designed to keep cancer cells from receiving the blood supply they need. This may
slow down the growth of cancer cells.

Irinotecan is designed to interfere with the DNA (genetic material) of cancer cells. This may
slow down the growth and spread of cancer cells.

Study Drug Administration:

If you are found to be eligible to take part in this study, you will take brivanib by mouth 1
time every day. The study drug should be taken at the same time each day with a glass (about
8 ounces) of water. You can take it with or without food.

You will be given irinotecan by vein over about 1½ hours on Day 1 of each 14-day cycle. You
may be given other drugs to help prevent side effects. The study staff will tell you about
these drugs, how they will be given, and the possible risks.

If you have a side effect, you should tell your doctor or study nurse right away. Your study
doctor may prescribe drugs for your side effects, delay future treatments, lower the dose of
the study drugs, or stop your treatment with the study drugs.

Study Visits:

On Day 7 of Cycle 1:

- Your vital signs will be measured.

- Blood (about 2 tablespoons) will be drawn for routine tests and to check your thyroid
function. If the doctor thinks it is needed, part of the blood may be used to check your
blood's ability to clot.

Before all cycles, starting with Cycle 2:

- You will have a physical exam, including measurement of your vital signs.

- Your performance status will be recorded.

- Blood (about 1-2 tablespoons) will be collected for routine tests. If the doctor thinks
it is needed, part of the blood may be used to check your blood's ability to clot if
needed.

- You will be asked about any drugs you may have taken and side effects you may have had.

- Before Cycles 2 and 3 only, blood (about 1 tablespoon) will be drawn to check your
thyroid function.

Every 8 weeks:

- You will have a CT scan or MRI scan to check the status of the disease.

- Blood (about 2-3 tablespoons) will be drawn for thyroid, CEA, and cytokine testing.

- Urine will be collected for routine tests.

Every 12 weeks (Weeks 12, 24, 36, and so on), you will have an ECHO to check your heart
function.

Length of Study:

You may continue taking the study drugs for as long as the doctor thinks it is in your best
interest. You will no longer be able to take the study drugs if the disease gets worse or
intolerable side effects occur.

End-of-Treatment Visit:

Within 2 weeks after you stop taking the study drugs, the following tests and procedures will
be performed if not done in the last 14 days:

- You will be asked about any side effects you may have had and any drugs you may be
taking.

- You will have a physical exam, including measurement of your vital signs.

- Your performance status will be recorded.

- You will have a CT scan or MRI scan to check the status of the disease.

- Blood (about 1-2 tablespoons) and urine will be collected for routine tests.

- Blood (about 2-3 tablespoons) will be drawn for thyroid, CEA, and cytokine testing.

Long-Term Follow-Up:

After you stop taking the study drugs, you will be called every 3 months. You will be asked
questions about your health. These calls should last about 15 minutes each time.

This is an investigational study. Brivanib is not FDA approved or commercially available. It
is currently being used for research purposes only. Irinotecan is FDA approved and
commercially available for the treatment of colorectal cancer. The combination of brivanib
and irinotecan is considered investigational.

Up to 60 patients will take part in this study. All will be enrolled at MD Anderson.

Inclusion Criteria:

1. Signed written Informed Consent.

2. Patient must have progressed on front-line chemotherapy treatment containing
bevacizumab for histologically confirmed colorectal adenocarcinoma that is
unresectable or metastatic. Progression is defined as either radiographic or clinical
progression.

3. Patient must have measurable lesions as defined by RECIST version 1.1 criteria.

4. ECOG performance status 0-2.

5. Known bFGF level performed by a CLIA-certified laboratory performed during or within
12 weeks of last bevacizumab treatment

6. Enrollment in the "Assessment of Targeted Therapies Against Colorectal Cancer"
(ATTACC) protocol 2009-0091.

7. LVEF > 50% measured by 2-D echocardiogram

8. Bone marrow function defined as the following: An absolute neutrophil count (ANC)
=/>1,500/mcl; Platelets =/>100,000/mcl; Hemoglobin =/> 8.5 g/dl.

9. Renal function defined as the following: Serum creatinine less than or equal to 1.5 x
institutional upper limit normal (ULN).

10. Hepatic function defined as the following: Serum total bilirubin < 1.5 x ULN; AST
(SGOT), ALT (SGPT) and alkaline phosphatase =/< 2.5 x ULN; Serum albumin =/> 2.5 g/dl;
If liver involvement, AST, ALT, and alkaline phosphatase =/< 5.0 x ULN.

11. International normalized ratio (INR) =/< 2.3 or Prothrombin Time (PT) =/< 6 seconds
above control unless patient is currently receiving warfarin therapy for the treatment
or prevention of venous thrombosis.

12. Men and women, age =/> 18 years.

13. A male subject of fathering potential must use an adequate method of contraception to
avoid conception throughout the study [and for up to 12 weeks after the last dose of
study drug] to minimize the risk of pregnancy. If the partner is pregnant or
breastfeeding, the subject must use a condom.

14. Women of childbearing potential (WOCBP) must be using an adequate method of
contraception to avoid pregnancy throughout the study and for up to 12 weeks after the
last dose of study drug to minimize the risk of pregnancy. WOCBP must have a negative
serum or urine pregnancy test within 72 hours before the start of the investigational
product.

Exclusion Criteria:

1. Women who are pregnant or breastfeeding.

2. Patients with brain metastases.

3. Patients with resectable colorectal cancer or non-adenocarcinoma cancer of the colon
or rectum.

4. Patients who have had prior therapy with brivanib, anti-PDGFR (platelet-derived growth
factor receptor) or anti-FGFR (fibroblast growth factor receptor) therapy.

5. Recent (within 4 weeks of the first study drug administration), or planned
participation in another experimental therapeutic drug study.

6. Recent (within 4 weeks of the first study drug administration) infusion of bevacizumab
therapy.

7. Prior irinotecan chemotherapy.

8. Prior full field radiotherapy =/<4 weeks or limited field radiotherapy =/<2 weeks
prior to first study drug administration.

9. Recent use (within 4 weeks of first study drug administration) of St. John's Wort.

10. Patients with a history of thrombotic or embolic events within the last six months
such as a cerebrovascular accident (including transient ischemic attacks), pulmonary
embolism.

11. Patients with gastrointestinal bleeding or any other hemorrhage/bleeding event CTCAE
(version 4.0) Grade 4 within 30 days prior to first study drug administration

12. Patients with uncontrolled or significant cardiovascular disease including: i) Active
coronary artery disease, unstable or newly diagnosed angina or myocardial infarction <
12 months prior to first study drug administration. ii) Class III-IV New York Heart
Association (NYHA) congestive heart failure. iii) Uncontrolled hypertension (Systolic
blood pressure [BP] > 150 mmHg and diastolic BP > 90 mmHg for 24 hours) despite
optimal medical management. Blood pressure must be below 140/90 mmHg at screening.
Subjects with a history of hypertension who are receiving treatment with calcium
channel blockers that are CYP3A4 substrates should be changed to an alternative
antihypertensive medication prior to first study drug administration. iv) Cardiac
arrhythmias requiring anti-arrhythmic therapy other than beta blockers or digoxin. v)
QTc (Fridericia) prolongation >450 msec. vi) Subjects with valvular heart disease =/>
CTCAE (Ver. 4.0) Gr 2. vii) Left ventricular ejection fraction (LVEF) < 50%.

13. Active infection, less than 7 days after completing systemic antibiotic therapy.

14. History of non-healing wounds or ulcers, or bone fractures within 3 months prior to
first study drug administration.

15. Major surgical procedure, open biopsy, or significant traumatic injury less than 3
weeks or those who receive minor surgical procedures (e.g. core biopsy or fine needle
aspiration) within 1 week from first dose of first study drug administration.

16. Inability to swallow tablets or untreated malabsorption syndrome.

17. Pre-existing thyroid abnormality with thyroid function that can not be maintained in
the normal range with medication.

18. History of human immunodeficiency virus (HIV).

19. Patients with centrally cavitating lung lesions.

20. Known bleeding diathesis.

21. Inability to comply with study and/or follow-up procedures.

22. Patients with known glomerular nephritis.

23. Patients with known polycythemia.

24. Patients with known Gilbert's syndrome.

25. Women with a positive pregnancy test.

26. Patients with hyponatremia (sodium < 130 mmol/L).

27. Baseline serum potassium < 3.5 mmol/L (potassium supplementation may be given to
restore the serum potassium above this level prior to study entry).

28. Baseline serum calcium < 8.4 mg/dL (calcium supplementation may be given to restore
the serum calcium above this level prior to study entry).

29. Baseline serum magnesium < 1.5 mg/dL (magnesium supplementation may be given to
restore the serum magnesium above this level prior to study entry).

30. Known or suspected history of allergy to brivanib or any agents given in association
with this study.

31. Prisoners or subjects who are involuntarily incarcerated. Patients who are
compulsorily detained for treatment of either a psychiatric or physical (eg,
infectious disease) illness.