Panitumumab in Combination With Trametinib in Cetuximab-Refractory Stage IV Colorectal Cancer

Study Groups:

If participant is found to be eligible to take part in this study, participant will be
assigned to 1 of 3 groups based on the results of the genetic testing done at screening.

- If participant is in Group 1 or 3, participant will receive panitumumab alone.

- If participant is in Group 2, participant will receive will receive panitumumab and
trametinib.

If participant is in Group 1 or 3 and the disease appears to get worse, participant may be
able to cross-over to group 2 and begin to receive the panitumumab and trametinib combination
therapy.

Study Drug Administration:

Each study cycle is 14 days.

Participant will receive panitumumab by vein over about 60-90 minutes on Day 1 of each cycle.
After the first dose, participant will be checked for side effects for about 60 minutes after
the dose. If no intolerable side effects occur, participant's next dose will last about 30
minutes and participant will be checked for side effects for 30 minutes afterward.

If participant is in Group 2, participant will take trametinib by mouth 1 time every day.

Participant should take the trametinib tablets in the morning at about the same time each
day, at least 1 hour before or 2 hours after a meal. Participant should swallow the capsules
with about 1 cup (8 ounces) of water. Participant should swallow each capsule whole (without
chewing), one right after the other.

At the end of each study cycle or if participant stops taking the study drug, participant
should return any unused trametinib capsules to the study nurse.

Length of Study:

Participant may continue receiving the study drug(s) for as long as the doctor thinks it is
in participant's best interest. Participant will no longer be able to receive the study
drug(s) if the disease gets worse, if intolerable side effects occur, or if participant is
unable to follow study directions.

Study Visits:

On Day 1 of every cycle:

- Blood (about 6 tablespoons) will be drawn for routine and biomarker testing.

- If the doctor thinks it is needed, participant will have an eye exam.

- Participant will have a physical exam (Cycles 1-4, and every even-numbered cycle after
that)

- Participant will have an EKG (Cycles 1-4, and every even-numbered cycle after that).

- Participant will have either an ECHO or MUGA scan (Cycles 2, 4, and 10, and then every 6
cycles after that)

On Day 10 of Cycle 2, if the doctor thinks it is needed, participant will have an eye exam.

On Day 10 of Cycle 4 and every 4 cycles after that (Cycles 8, 12, 16, and so on):

- Participant will have a CT of participant's chest and CT/MRI of participant's abdomen
and pelvis.

- If the doctor thinks it is needed, participant will have an eye exam.

End of Treatment Visit:

Within 28-35 days after participant's last dose of study drug, participant will have an
end-of-treatment visit. The following tests and procedures will be performed:

- Participant will have a physical exam.

- Blood (about 5 tablespoons) will be drawn for routine and biomarker testing.

- Participant will have an EKG and either an ECHO or MUGA scan.

- Participant will have a CT scan of participant's chest and a CT scan or MRI of
participant's abdomen and pelvis.

- If the doctor thinks it is needed, participant will have an eye exam.

- If participant can become pregnant, blood (about 1 teaspoon) will be collected for a
pregnancy test.

Long-Term Follow-Up:

Every 3 months after the end of treatment visit, a member of the study staff will contact
participant to ask how participant is doing. This contact will take place either during a
regularly scheduled clinic visit or by phone. Each phone call should last about 10 minutes.

This is an investigational study. Panitumumab is FDA approved and commercially available for
the treatment of colorectal cancer. Trametinib is FDA approved and commercially available for
the treatment of melanoma. The combination of these drugs is considered investigational in
the treatment of advanced colorectal cancer.The study doctor can explain how the study drugs
are designed to work.

Up to 84 participants will be enrolled in this study. All will take part at MD Anderson.

Inclusion Criteria:

1. Histologically or cytologically confirmed colorectal adenocarcinoma, with metastatic
disease documented on diagnostic imaging studies

2. Progression during or within 6 months after fluoropyrimidine, irinotecan, and
oxaliplatin. For oxaliplatin-based therapy, failure of therapy will also include
patients who progressed within 12 months of adjuvant therapy and patients who had
oxaliplatin discontinued secondary to toxicity or allergic reaction. Patients with a
known history of Gilbert's disease who cannot receive irinotecan or patients who are
intolerant of irinotecan or fluoropyrimidine are eligible.

3. Confirmed wild-type status in KRAS exons 2, 3, and 4; NRAS exons 2, 3, and 4; and
BRAF, by standard of care testing of tumor specimen. Tissue used for testing may have
been collected prior to treatment with cetuximab.

4. Patient must have been already tested and have available results of the mutations
status of KRAS/NRAS/BRAF and EGFR from the circulating tumor DNA within 10 weeks prior
to starting study therapy.

5. Previous treatment with cetuximab with evidence of clinical benefit, as defined by
complete response, partial response, or prolonged stable disease with 16 or more weeks
of treatment without radiographic progression, as assessed by the treating physician
and documented in the medical record. This treatment may have occurred at any point in
the patient's clinical course for treatment of metastatic colorectal cancer.

6. Ultimate progression through previous treatment with cetuximab, with documented
clinical progression. Patients who discontinued cetuximab for any other reason, such
as decline in performance status, hypersensitivity, or other adverse effects of
therapy, are not eligible.

7. All prior treatment- related toxicities must be CTCAE (Version 4.0) (except
8. Radiographically measurable disease present per RECIST 1.1

9. Age >/= 18 years

10. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1

11. Blood counts performed within 3 weeks prior to starting study therapy must have
absolute neutrophil count >/= 1,500/mm3, platelets >/= 100,000/mm3, and hemoglobin >/=
9 g/dL

12. Liver function tests performed within 3 weeks prior to starting study therapy must
have total bilirubin and aspartate aminotransferase present), and albumin >/= 2.5 g/dL

13. Serum creatinine performed within 3 weeks prior to starting study therapy must be 1.5 x ULN, or have calculated creatinine clearance (using Cockcroft-Gault formula) of
>/= 50 mL/minute.

14. PT/INR and PTT performed within 3 weeks prior to starting study therapy must be 1.5 x ULN

15. Left Ventricular Ejection fraction (LVEF) >/= LLN by ECHO or MUGA within 3 weeks prior
to starting study therapy.

16. Women of childbearing potential must have a negative serum pregnancy test within 14
days prior to randomization and must agree to use effective contraception throughout
the treatment period and for 4 months after the last dose of study treatment.

17. Ability to sign informed consent form. Informed consent form for this study must be
signed prior to the performance of any study-specific procedures and initiation of any
study therapy.

18. Ability to swallow and retain oral medication, with no clinically significant
gastrointestinal abnormalities that may alter absorption such as malabsorption
syndrome or major resection of the stomach or bowels.

19. In cohort 1, must have EGFR S492R or other ectodomain mutation detected from
circulating tumor DNA from plasma collected after progression to prior cetuximab. May
have a concomitant mutation in KRAS, NRAS, or BRAF, if there is at least a 5-fold
higher allele frequency of the most prevalent EGFR mutation than the most prevalent
KRAS/NRAS/BRAF mutation.

20. In cohort 2, must have one or more mutations found in KRAS exon 2, 3, or 4; NRAS exon
2, 3, or 4; BRAF codon 600. May have a concomitant EGFR ectodomain mutation, if the
most prevalent EGFR ectodomain mutation does not have over a 5-fold higher allele
frequency than the most prevalent KRAS/NRAS/BRAF mutation.

21. In cohort 3, must not have EGFR ectodomain mutation or any mutations in KRAS, NRAS, or
BRAF.

22. Patients must have consented to the MD Anderson ATTACC protocol prior to inclusion.

Exclusion Criteria:

1. Past treatment with any MEK or ERK inhibitor or with panitumumab

2. Previous retreatment with cetuximab following progression on initial course of
cetuximab therapy

3. Known untreated brain metastasis or brain metastasis treated within 3 months prior to
enrollment in this trial

4. Symptomatic or untreated leptomeningeal or brain metastases or spinal cord
compression.

5. History of interstitial lung disease or pneumonitis

6. History of any other malignancy within 3 years, except for adequately treated
carcinoma in situ of the cervix or non-melanoma skin cancer and/or subjects with
indolent second malignancies are eligible.

7. Prior treatment within 21 days of the first dose of study drug with any other
chemotherapy, immunotherapy, biologic therapy, vaccine therapy, or investigational
treatment, or failure to recover from adverse effects of prior therapies administered
over 4 weeks prior to Study Day 1. All toxicities from prior therapies must be Grade 1 (or treatment in the adjuvant setting is allowed.

8. Any major surgery, extensive radiotherapy, chemotherapy with delayed toxicity,
biologic therapy, or immunotherapy within 21 days prior to randomization and/or daily
chemotherapy without the potential for delayed toxicity within 14 days prior to
randomization.

9. Impaired cardiac function or clinically significant cardiac disease, as defined: a)
Left ventricular ejection fraction < lower limit of normal (LLN) on multiple gated
acquisition scan (MUGA) or echocardiogram; b) Congenital long QT syndrome or family
history of unexpected sudden cardiac death; c) QTc corrected with Bazett's formula
(QTcB) >/= 480 ms.; d) History or evidence of current clinically significant
uncontrolled arrhythmias. Note subjects with atrial fibrillation controlled for >30
days prior to dosing are eligible;

10. Continuation of criteria above: e) History of acute coronary syndromes (including
myocardial infarction and unstable angina), coronary angioplasty, or stenting within 6
months prior to randomization; f) History or evidence of current >/= Class II
congestive heart failure as defined by New York Heart Association (NYHA); g) Treatment
refractory hypertension defined as a blood pressure of systolic> 140 mmHg and/or
diastolic > 90 mm Hg which cannot be controlled by anti-hypertensive therapy; h)
Patients with intra-cardiac defibrillators.

11. Any serious and/or unstable pre-existing medical disorder (aside from malignancy
exception above), psychiatric disorder, or other conditions that could interfere with
subject's safety, obtaining informed consent, or compliance to the study procedures.

12. History of retinal vein occlusion (RVO)

13. Pregnant or breastfeeding, or planning to become pregnant within 6 months after the
end of treatment.

14. History of organ allograft or other history of immunodeficiency.

15. Inability or unwillingness to comply with study and/or follow-up requirements

16. Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs
chemically related to study drug, or excipients or to dimethyl sulfoxide (DMSO).

17. Known Human Immunodeficiency Virus (HIV), Hepatitis B virus (HBV), or Hepatitis C
virus (HCV) infection. Subjects with laboratory evidence of cleared HBV and HCV
infection will be permitted.

18. Current use of a prohibited medication.