S1406 Phase II Study of Irinotecan and Cetuximab With or Without Vemurafenib in BRAF Mutant Metastatic Colorectal Cancer

PRIMARY OBJECTIVES:

I. To evaluate the progression-free survival (PFS) of v-raf murine sarcoma viral oncogene
homolog B (BRAF) mutant metastatic colorectal cancer patients treated with irinotecan
(irinotecan hydrochloride), cetuximab, and vemurafenib, compared to a control arm of
irinotecan and cetuximab.

SECONDARY OBJECTIVES:

I. To evaluate the frequency and severity of toxicity associated with each of the treatment
arms in this patient population.

TERTIARY OBJECTIVES:

I. To evaluate overall survival (OS) in treatment Arms 1 and 2. II. To evaluate the overall
response rate (ORR), including confirmed and unconfirmed, complete and partial response, in
treatment Arms 1 and 2 in the subset of patients with measurable disease.

III. To estimate rates of OS, ORR, and PFS in patients who register to Arm 3 after disease
progression on Arm 1.

IV. To evaluate low-frequency Kirsten rat sarcoma viral oncogene homolog (KRAS) or
neuroblastoma RAS viral (v-ras) oncogene homolog (NRAS) mutations as detected by high-depth
sequencing as predictive biomarkers of efficacy.

V. To evaluate phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha
(PIK3CA) pathway activation through PIK3CA mutations or phosphatase and tensin homolog (PTEN)
protein loss as a predictive biomarker of innate resistance to this regimen.

VI. To evaluate gene expression signatures from screened patients with v-raf murine sarcoma
viral oncogene homolog B wild type (BRAFWT) and BRAFV600E tumors.

VII. To provide validation of BRAF immunohistochemistry (IHC) using complementary sequencing
methodology from screened patients with BRAFWT and BRAFV600E tumors.

VIII. To confirm the estimated sensitivity of detectable BRAF V600E circulating cell-free
deoxyribonucleic acid (DNA) as a non-invasive biomarker for BRAF V600E mutation as detected
by IHC in the primary tumor.

IX. To correlate radiographic tumor response with change in quantification of BRAFV600E
alleles in circulating cell-free DNA.

X. To monitor for known mechanism of acquired resistance to epidermal growth factor receptor
(EGFR) inhibition in circulating cell-free DNA (KRAS, NRAS mutations).

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive cetuximab intravenously (IV) and irinotecan hydrochloride IV on days
1 and 14. Courses repeat every 28 days in the absence of disease progression or unacceptable
toxicity. Patients with disease progression may cross over to Arm II.

ARM II: Patients receive cetuximab and irinotecan hydrochloride as in Arm I and vemurafenib
orally (PO) twice daily (BID) on days 1-28. Courses repeat every 28 days in the absence of
disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 2-6 months for 3 years.

- STEP I INITIAL REGISTRATION: BRAFV600E TESTING:

- Patients must have histologically or cytologically documented adenocarcinoma of the
colon or rectum that is either metastatic, or locally advanced and unresectable

- Patients must have BRAFV600E mutant status documented by a Clinical Laboratory
Improvements Amendments (CLIA) certified laboratory on a pathology report prior to
Step 2 registration; use of an Food and Drug Administration (FDA)-approved test is
preferred although other BRAF tests at a CLIA-certified laboratory may also be
accepted; if a BRAFV600E mutation is known, then the patient must be registered to
Step 2 Randomization immediately following Step 1 Initial Registration; if testing has
not been performed locally, BRAFV600E testing must be completed by the central lab
prior to Step 2 Randomization; if the specimen does not have a BRAFV600E mutation, the
patient is ineligible for Step 2 Randomization

- Brain metastases are allowed if they have been adequately treated with radiotherapy or
surgery and stable for at least 90 days prior to Step 1 Initial Registration; eligible
patients should be neurologically asymptomatic and without corticosteroid treatment
for at least 7 days prior to Step 1 Initial Registration

- Patients must have had one or two prior regimens of systemic chemotherapy for
metastatic disease; prior treatment with irinotecan is allowed; a maintenance regimen
of 5-fluorouracil or capecitabine, with or without bevacizumab, should not be counted
as a separate line of treatment; prior treatment for metastatic disease is not
required for patients who experienced disease recurrence during or within 6 months of
completion of adjuvant chemotherapy

- Patients must not have been treated with any of the following prior to Step 2
Randomization:

- Cetuximab, panitumumab, or any other monoclonal antibody against EGFR or
inhibitor of EGFR

- BRAF inhibitor including, but not limited to, vemurafenib or dabrafenib;
regorafenib is not considered a BRAF inhibitor for the purpose of determining
trial eligibility

- Mitogen-activated protein/extracellular signal-regulated kinase (MEK) inhibitor
including, but not limited to, trametinib or selumetinib

- Previous chemotherapy, immunotherapy, or radiation therapy must have been completed at
least 14 days prior to Step 1 Initial Registration and all toxicity must be resolved
to Common Terminology Criteria for Adverse Events version 4.0 (CTCAE v4.0) grade 1
(with the exception of CTCAE v4.0 grade 2 neuropathy) prior to Step 1 Initial
Registration

- Patients must not have a tumor with a mutation detected in codons 12 or 13 in KRAS;
patients must not have a tumor with a known mutation detected in codons 61, 117, or
146 of KRAS or NRAS

- SPECIMEN SUBMISSION CRITERIA:

- Patients must have tumor (slides or block) available for submission for V600E BRAF
testing

- Patients must have additional tumor available and be willing to submit tissue and
blood samples

- SPECIMEN SUBMISSION CRITERIA REGULATORY CRITERIA:

- Patients or their legally authorized representative must be informed of the
investigational nature of this study and must sign and give written informed consent
in accordance with institutional and federal guidelines; for Step 1 Initial
Registration of patients who have not yet submitted specimens for the central
BRAFV600E testing, the appropriate consent form is the Step 1 Consent Form; for both
Step 1 Initial Registration and Step 2 Randomization of patients whose BRAF mutation
status is already known, the appropriate consent form is the Step 2 Consent Form

- STEP 2 RANDOMIZATION:

- Patients must have BRAFV600E mutation

- Patients must have measurable or non-measurable metastatic disease; computed
tomography (CT) scans or magnetic resonance imaging (MRIs) used to assess all disease
must have been completed within 28 days prior to Step 2 Randomization; CT scans or
MRIs must be assessed and documented on the Baseline Tumor Assessment Form (Response
Evaluation Criteria in Solid Tumors [RECIST] 1.1)

- Patients must have a Zubrod performance status of 0-1

- Absolute neutrophil count (ANC) >= 1,500/mcL

- Platelets >= 100,00/mcL

- Hemoglobin >= 9 g/dL

- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x
institutional upper limit of normal (IULN) or =< 5 x IULN if liver metastases are
present

- Total bilirubin =< 1.5 x IULN

- Serum creatinine =< 1.5 x IULN within 14 days prior to Step 2 Randomization OR

- Calculated creatinine clearance > 60 ml/min; the serum creatinine value used in the
calculation must have been obtained within 14 days prior to Step 2 Randomization

- Patients must have an electrocardiogram (ECG) within 14 days prior to Step 2
Randomization

- Patients must have corrected QT (QTc) =< 500 msec

- Patients must not have a known history of Gilbert's Syndrome or known homozygosity for
the UDP glucuronosyltransferase 1 family, polypeptide A1 (UGT1A1)*28 allele

- Patients must not have interstitial pneumonia or extensive symptomatic interstitial
fibrosis of the lung

- Patients must not have an uncontrolled intercurrent illness including, but not limited
to, active bleeding diathesis, uncontrolled infection/disorders, nonmalignant medical
illnesses that are uncontrolled or whose control may be jeopardized by the treatment
with the study therapy, or psychiatric illness/social situations which would limit
compliance with study requirements

- Patients must be able to swallow pill/tablet and have no refractory nausea, vomiting,
malabsorption, external biliary shunt, or significant small bowel resection that would
preclude adequate absorption

- Patients must not be pregnant or nursing; women/men of reproductive potential must
have agreed to use an effective contraceptive method while on study and for 30 days
after study treatment; a woman is considered to be of "reproductive potential" if she
has had menses at any time in the preceding 12 consecutive months; in addition to
routine contraceptive methods, "effective contraception" also includes heterosexual
celibacy and surgery intended to prevent pregnancy (or with a side-effect of pregnancy
prevention) defined as a hysterectomy, bilateral oophorectomy or bilateral tubal
ligation; however, if at any point a previously celibate patient chooses to become
heterosexually active during the time period for use of contraceptive measures, he/she
is responsible for beginning contraceptive measures

- No other prior malignancy is allowed except for the following: adequately treated
basal cell or squamous cell skin cancer, in situ cervical cancer, adequately treated
stage I or II cancer from which the patient is currently in complete remission, or any
other cancer from which the patient has been disease free for three years

- STEP 2 RANDOMIZATION REGULATORY CRITERIA:

- Patients or their legally authorized representative must be informed of the
investigational nature of this study and must sign and give written informed consent
in accordance with institutional and federal guidelines; for all patients, the
appropriate consent form for this registration is the Step 2 Consent Form

- As a part of the OPEN registration process the treating institution's identity is
provided in order to ensure that the current (within 365 days) date of institutional
review board approval for this study has been entered in the system

- STEP 3 CROSSOVER REGISTRATION:

- Patients must have documented disease progression while on Arm 1 of this protocol; the
follow-up tumor assessment form documenting disease progression must be submitted to
Southwestern Oncology Group (SWOG) prior to Step 3

- Registration to Step 3 Crossover must be within 28 days of discontinuation of Arm 1
protocol treatment; patients going off treatment for any other reason are not eligible

- ANC >= 1,500/mcL within 14 days prior to Step 3 registration

- Platelets >= 100,00/mcL within 14 days prior to Step 3 registration

- Hemoglobin >= 9 g/dL within 14 days prior to Step 3 registration

- AST and ALT =< 2.5 x institutional upper limit of normal (IULN) or =< 5 x IULN if
liver metastases are present within 14 days prior to Step 3 registration

- Total bilirubin =< 1.5 x IULN within 14 days prior to Step 3 registration

- Serum creatinine =< 1.5 x IULN within 14 days prior to Step 3 registration OR

- Calculated creatinine clearance > 60 ml/min; the serum creatinine value used in the
calculation must have been obtained within 14 days prior to Step 3 registration