Vemurafenib, Cetuximab, and Irinotecan in Advanced Solid Cancers

Study Groups:

If you are found to be eligible to take part in this study, your doctor will decide which
dose level of vemurafenib you will receive. All participants will receive the standard dose
of cetuximab and irinotecan.

Dose Escalation Group:

Up to 3 dose levels of vemurafenib will be tested in combination with cetuximab and
irinotecan. Up to 6 participants will be enrolled at each dose level.

The dose of any of the study drug combinations that you receive may be lowered if you have
intolerable side effects.

Dose Expansion Group:

After the highest tolerable dose of vemurafenib is found, additional participants will be
enrolled in the expansion group and will receive the study drug combination at that dose.
This group will have up to 15 participants with BRAF mutant, KRAS wild type colorectal
cancer.

Study Drug Administration:

You will take vemurafenib by mouth 2 times a day. If the doctor thinks it is needed, you may
take it less often. Vemurafenib can be taken with or without food. Always take it with food
or always take on an empty stomach. Take with full glass of water.

You will receive cetuximab and irinotecan by vein over 90 minutes on Day 1 of each cycle. You
will be monitored for at least 1 hour after the end of drug infusion.

Study Visits:

During Week 1 of Cycles 2 and beyond:

- You will have a physical exam and your skin will be checked.

- Your medical history will be recorded.

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

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

At Week 1 of Cycles 1-2, if you are in a certain group on study, blood (about 2 teaspoons
each time) will be drawn before your dose of irinotecan and 8 more times over the next 24
hours for pharmacokinetic (PK) testing. PK testing measures the amount of study drug in the
body at different time points.

If you are enrolled in the colorectal cancer dose expansion group, you will have a biopsy for
biomarker testing on Day 14 of Cycle 2.

Beginning at Week 1 of Cycle 3, you will have EKG every other cycle (once monthly) for 3
months, and then once every 3 months until the end of the study.

Beginning at Week 1 of Cycle 3, blood (about 2 teaspoons) will be drawn for biomarker testing
every other cycle (once monthly).

Beginning at Week 1 of Cycle 3, women who are able to become pregnant will have a blood
(about 2 teaspoons) or urine pregnancy test every other cycle.

At Week 1 of Cycle 3 and Cycle 5, urine will be collected for routine tests.

At Week 1 of Cycle 3, if you are in a certain group on study, blood (about 2 teaspoons) will
be drawn for PD testing.

Every 3 Cycles, you will have imaging to check the status of the disease. These tests can
include some or all of the following: a CT scan, MRI scan, PET scan, and/or bone scan. You
will also have a chest x-ray.

You will have an additional head and neck exam every 12 weeks while on study.

All patients will have a chest CT 6 months after their last dose of vemurafenib. SCC patients
will have additional chest CTs at screening and every 6 months while on study.

Length of Study:

You may continue taking the study drugs for as long as your doctor thinks it is in your best
interest. You will be taken off study early if the disease gets worse, if you continue to
have intolerable side effects, or if you are unable to follow study directions.

Your participation on the study will be over once you have completed the end-of-study visit.

End-of-Study Visit:

Within 30 days after your last dose of study drugs, you will have an end-of-study visit. At
this visit, the following tests and procedures will be performed:

- Your medical history will be recorded.

- You will have a physical exam, including measurement of your vital signs and weight.
°Your skin will be checked. You will also have a head and neck exam.

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

- Your performance status will be recorded.

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

- If the doctor thinks it is needed, blood (about 2 teaspoons) will be drawn to measure
tumor markers.

- If you are in a certain group on study, blood (about 2 teaspoons) will be drawn for PK
testing.

- You will have imaging to check the status of the disease. These tests can include some
or all of the following: a chest x-ray, CT scan, MRI scan, PET scan, and/or bone scan.

- If you are in the Dose Expansion group and the disease got worse while you were on
study, blood (about 2 teaspoons) will be drawn for biomarker testing.

Inclusion Criteria:

1. Patients must have histologically confirmed malignancy that is metastatic or
unresectable

2. Cancers with positive BRAF V600 mutation detected by a CLIA-certified laboratory

3. Age 18 years or older

4. ECOG performance status of 0 to 2

5. Life expectancy of greater than 3 months

6. Patients must have measurable disease per RECIST 1.1 criteria

7. Patients must have a K-RAS WT tumor

8. Patients must have normal organ and marrow function as defined below, within 14 days:
• Absolute neutrophils count >,=1500/mcl • Platelets >,=100000/mcl • Hb >,=9 mg/dl •
Total bilirubin =,<1.5 mg/dl • AST/ALT =,<5x upper limit of normal if liver metastases
present; otherwise, then =,< 2.5x upper limit • Estimated creatinine clearance by
Cockcroft-Gault equation > 30 mL/min

9. Current treatment may cause harm to the developing human fetus. For this reason women
of child-bearing age must have a negative pregnancy test at screening and both women
of child-bearing potential and men must agree to use adequate contraception (hormonal
or barrier method of birth control; abstinence) prior to study entry and for the
duration of study participation, and for 6 months after last dose. Should a woman
become pregnant or suspect she is pregnant while she or her partner is participating
in this study, she should inform her treating physician immediately

10. Signed informed consent approved by the Institutional Review Board prior to patient
entry

11. Expansion cohort: We propose a final expansion cohort for this study in a subset of
interest utilizing the recommended dosing of combination. This cohort will include
patients harboring characteristics that may predict response of combination or with
clinical features that proved to derive most benefit of the study combination during
preclinical studies. Cancers with positive BRAF (V600) mutation detected by a
CLIA-certified laboratory.

Exclusion Criteria:

1. Patient receiving any concurrent chemotherapy

2. Concurrent severe and/or uncontrolled medical disease including, but not limited to,
ongoing or active infection requiring intravenous antibiotics, bowel obstruction

3. Symptomatic congestive heart failure (NYHA Class III or IV), or unstable angina
pectoris

4. Patients who have had a myocardial infarction, transient ischemic attack, unstable
angina, or CVS within 6 months before treatment

5. Presence of symptomatic pleural and/or pericardial effusion not appropriately treated

6. Prolonged QTc interval (>,=450 msec) as calculated by Bazett's formula, or patients
with a history of congenital long QT syndrome or uncorrectable electrolyte
abnormalities

7. Medical and/or psychiatric problems of sufficient severity to limit full compliance
with the study or expose patients to undue risk

8. Known anaphylactic or severe hypersensitivity to the study drugs or their analogs

9. Patient has failed to recover from any prior surgery within 4 weeks of study entry

10. Patient is pregnant, lactating, or breastfeeding

11. Patient has had any treatment specific for tumor control within 3 weeks of dosing with
investigational drugs and cytotoxic agents, or within 2 weeks of cytotoxic agent given
weekly, or within 6 weeks of nitrosoureas or mitomycin C, or within 5 half-lives of
biological targeted agents with half-lives and pharmacodynamic effects lasting less
than 5 days

12. Patient is not able to swallow oral medication

13. Patients receiving any medications or substances that are strong inhibitors or
inducers of CYP3A4 complex are ineligible

14. Patients with known K-RAS mutant (codon 12 or 13) detected by an FDA-approved test in
a CLIA-certified laboratory

15. Patients with BRAF WT cancers