S1613, Trastuzumab and Pertuzumab or Cetuximab and Irinotecan Hydrochloride in Treating Patients With Locally Advanced or Metastatic HER2/Neu Amplified Colorectal Cancer That Cannot Be Removed by Surgery

PRIMARY OBJECTIVES:

I. To evaluate the efficacy of trastuzumab and pertuzumab (TP) (Arm 1) in HER-2 amplified
metastatic colorectal cancer (mCRC) by comparing progression-free survival (PFS) on TP
compared to control arm (Arm 2) of cetuximab and irinotecan hydrochloride (irinotecan)
(CETIRI).

SECONDARY OBJECTIVES:

I. To evaluate the overall response rate (ORR), including confirmed complete and partial
response per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, in treatment Arms 1
and 2.

II. To evaluate the overall survival (OS) in treatment Arms 1 and 2. III. To evaluate the
safety and toxicity of TP compared to CETIRI.

TERTIARY OBJECTIVES:

I. To estimate the rates of PFS, OS, and ORR in patients who crossover to TP (Arm 3) after
disease progression on CETIRI.

II. To bank images for future retrospective analysis. III. To evaluate if HER-2/centromeric
probe (CEP17) signal ratio and HER-2 gene copy number (GCN) are predictive of clinical
efficacy for patients receiving TP versus CETIRI.

IV. To bank tissue and blood samples for other future correlative studies from patients
enrolled on the study.

OUTLINE: Patients with HER2 gene amplification are randomized to 1 of 2 arms.

ARM I: Patients receive pertuzumab intravenously (IV) over 30-60 minutes and trastuzumab IV
over 30-120 minutes on day 1. Courses repeat every 21 days in the absence of disease
progression or unacceptable toxicity.

ARM II: Patients receive cetuximab IV over 60-120 minutes and irinotecan hydrochloride IV
over 90 minutes on day 1. Courses repeat every 14 days in the absence of disease progression
or unacceptable toxicity. Patients with documented disease progression may optionally
crossover to Arm I.

After completion of study treatment, patients are followed up for 3 years.

Inclusion Criteria:

- STEP 1 INITIAL REGISTRATION: HER2 TESTING

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

- Mutation results:

- All patients must have molecular testing performed in a Clinical Laboratory
Improvement Act (CLIA) certified lab which includes which includes KRAS and NRAS
gene and exon 15 of BRAF gene (BRAF V600E mutation); patients with any known
activating mutation in exon 2 [codons 12 and 13], exon 3 [codons 59 and 61] and
exon 4 [codons 117 and 146]) of KRAS/NRAS genes and in exon 15 (BRAFV600E
mutation) of BRAF gene are not eligible

- Patients must not have been treated with any of the following prior to step 1 initial
registration:

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

- HER-2 targeting for treatment of colorectal cancer; patients who have received
prior trastuzumab or pertuzumab for other indications such as prior history of
adjuvant or neoadjuvant breast cancer treatment prior to the development of
advanced colorectal cancer are eligible

- Patients must not have had history of severe toxicity and intolerance to or
hypersensitivity to irinotecan or any other study drug; patients must not have had a
severe infusion-related reaction during any prior therapy with pertuzumab or
trastuzumab

- Patients must have tumor slides available for submission for HER-2 testing; HER-2
testing must be completed by the central lab prior to step 2 randomization

- Patients must be informed of the investigational nature of this study and must sign
and give informed consent in accordance with institutional and federal guidelines; for
step 1 initial registration, the appropriate consent form is the step 1 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 2 RANDOMIZATION

- Patients must have HER-2 amplification as determined by central testing (3+ or 2+ by
immunohistochemistry and HER-2 gene amplification by in situ hybridization with a
ratio of HER-2 gene signals to centromere 17 signals >= 2.0)

- Patients must have measurable disease that is metastatic or locally advanced and
unresectable; imaging used to assess all disease per RECIST 1.1 must have been
completed within 28 days prior to step 2 randomization; all disease must be assessed
and documented on the Baseline Tumor Assessment Form

- Patients must have had at least one prior regimen of systemic chemotherapy for
metastatic or locally advanced, unresectable disease; patients must have progressed
following the most recent therapy; prior treatment with irinotecan is allowed; for
patients that received adjuvant chemotherapy: prior treatment for metastatic disease
is not required for patient who experienced disease recurrence during or within 6
months of completion of adjuvant chemotherapy; if the patient received one line of
adjuvant treatment and had disease recurrence after 6 months of completing
chemotherapy, patients will only be eligible after failing one additional line of
chemotherapy used to treat the metastatic or locally advanced, unresectable disease;
patients who have received >= 3 lines of systemic chemotherapy for metastatic or
locally advanced, unresectable disease are not eligible

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

- Brain metastases are allowed if they have been adequately treated with radiotherapy or
surgery and stable for at least 30 days prior to step 2 randomization; eligible
patients must be neurologically asymptomatic and without corticosteroid treatment for
at least 7 days prior to step 2 randomization

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

- Patients must have a complete physical examination and medical history within 28 days
prior to step 2 randomization

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

- Platelets >= 75,000/mcL

- Hemoglobin >= 9 g/dL

- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) both =< 5 x
institutional upper limit of normal (IULN)

- Bilirubin =< 1.5 mg/dL

- Calculated creatinine clearance > 30 ml/min within 14 days prior to step 2
randomization

- Patients who have had an echocardiogram performed within 6 months prior to step 2
randomization must have ventricular ejection fraction (left ventricular ejection
fraction [LVEF]) >= 50% or >= within normal limits for the institution

- Patients must not have an uncontrolled intercurrent illness including, but not limited
to diabetes, hypertension, severe infection, severe malnutrition, unstable angina,
class III-IV New York Heart Association (NYHA) congestive heart failure, ventricular
arrhythmias, active ischemic heart disease, or myocardial infarction within 6 months
prior to step 2 randomization

- Patients must not have any known previous or concurrent condition suggesting
susceptibility to hypersensitivity or allergic reactions, including, but not limited
to: known hypersensitivity to any of the study treatments or to excipients of
recombinant human or humanized antibodies; patients with mild or seasonal allergies
may be included after discussion with the study chairs

- Patients must not be planning treatment with other systemic anti-cancer agents (e.g.,
chemotherapy, hormonal therapy, immunotherapy) or other treatments not part of
protocol-specified anti-cancer therapy including concurrent investigational agents of
any type

- No prior malignancy is allowed except for adequately treated basal cell or squamous
cell skin cancer, in situ cervical cancer, ductal carcinoma in situ, other low grade
lesions such as incidental appendix carcinoid, or any other cancer from which the
patient has been disease and treatment free for two years; prostate cancer patients on
active surveillance are eligible

- Patients must not be pregnant or nursing; females of child-bearing potential must have
a negative serum pregnancy test within 7 days prior to registration; women/men of
reproductive potential must have agreed to use an effective contraceptive method while
on study and for at least 7 months after the last dose of 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 outlined in the protocol, he/she is
responsible for beginning contraceptive measures

- Patients must be given the opportunity to consent to the optional submission of tissue
for future research

- Patients 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; the appropriate consent form for this registration is the step 2 consent
form

- STEP 2 RANDOMIZATION: As a part of the Oncology Patient Enrollment Network (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 (OPTIONAL): Patients must have documented disease
progression while on CETIRI (Arm 2) on this protocol; the Follow-up Tumor Assessment
Form documenting disease progression must be submitted to Southwest Oncology Group
(SWOG) prior to step 3 crossover registration; registration to step 3 crossover must
be within 28 days of discontinuation of CETIRI protocol treatment; patients going off
treatment for any other reason are not eligible

- STEP 3 CROSSOVER REGISTRATION (OPTIONAL): Patients must have a Zubrod performance
status of 0 or 1

- STEP 3 CROSSOVER REGISTRATION (OPTIONAL): ANC >= 1,500/mcL

- STEP 3 CROSSOVER REGISTRATION (OPTIONAL): Platelets >= 75,000/mcL

- STEP 3 CROSSOVER REGISTRATION (OPTIONAL): Hemoglobin >= 9 g/dL

- STEP 3 CROSSOVER REGISTRATION (OPTIONAL): AST and ALT both =< 5 x institutional upper
limit of normal (IULN)

- STEP 3 CROSSOVER REGISTRATION (OPTIONAL): Bilirubin =< 1.5 mg/dL

- STEP 3 CROSSOVER REGISTRATION (OPTIONAL): Calculated creatinine clearance > 30 ml/min
within 14 days prior to step 3 crossover registration

- STEP 3 CROSSOVER REGISTRATION (OPTIONAL): Patients must have left ventricular ejection
fraction (LVEF) >= 50% or >= lower limit of normal for the institution by
echocardiogram within 14 days prior to step 3 crossover registration

- STEP 3 CROSSOVER REGISTRATION (OPTIONAL): Patients must have a magnesium, potassium,
calcium, sodium, bicarbonate, and chloride performed within 14 days prior to step 3
crossover registration

- STEP 3 CROSSOVER REGISTRATION (OPTIONAL): Patients 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; the appropriate consent form
for this registration is the step 2 consent form

- STEP 3 CROSSOVER REGISTRATION (OPTIONAL): 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