A Randomized Phase II Study of Pertuzumab and Trastuzumab (TP) compared to Cetuximab and Irinotecan (CETIRI) in Advanced/Metastatic Colorectal Cancer (mCRC) with HER2 Amplification

Eligibility Criteria for Step 1 Initial Registration: HER-2 Testing
- Zubrod Performance Status of 0 or 1.
- at least 18 years of age.

Disease Related Criteria
- Pts must have histologically or cytologically documented adenocarcinoma of
the colon or rectum that is metastatic or locally advanced and unresectable.
- Mutation results: All pts must have molecular testing performed in a CLIA certified lab which includes KRAS and NRAS gene and exon 15 of BRAF gene (BRAF V600E mutation). Pts 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.

Prior/Concurrent Therapy Criteria
- Pts 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. Ps 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.
- tPs must not have had history of severe toxicity and intolerance to or hypersensitivity to irinotecan or any other study drug. Pts must not have had a severe infusion-related reaction during any prior therapy with pertuzumab or trastuzumab.

Specimen and Data Submission Criteria
- Pts must have tumor slides available for submission for HER-2 testing as described in Section 15.1. HER-2 testing must be completed by the central lab prior to Step 2 Randomization. The central lab will perform HER-2 tests in accordance with instructions provided separately.

Regulatory Criteria
- Pts 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.

Eligibility Criteria for Step 2 Randomization
Results of HER-2 testing will be available on the SWOG Specimen Tracking Website and
sites will be notified by e-mail within 14 calendar days from submission of the tissue
specimen to the central lab.

Clinical/Laboratory Criteria for Step 2 Crossover
- Pts 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 greater than or equal to 2.0).
-Pts 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.
- Pts must have had at least one prior regimen of systemic chemotherapy for
metastatic or locally advanced, unresectable disease. Pts must have progressed following the most recent therapy. Prior treatment with irinotecan is allowed.

For pts that received adjuvant chemotherapy: Prior treatment for metastatic disease is not required for pt who experienced disease recurrence during or within 6 months of completion of adjuvant chemotherapy. If the pt received one line of adjuvant treatment and had disease recurrence
after 6 mo. of completing chemotherapy, pts will only be eligible after failing one additional line of chemotherapy used to treat the metastatic or locally advanced, unresectable disease. Pts who have received greater than or equal to 3 lines of systemic chemotherapy for metastatic or locally advanced, unresectable disease
are not eligible.
- Pts 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 CTCAE v4.0 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 pts must be neurologically asymptomatic and w/o corticosteroid treatment for at least 7 days prior to Step 2 Randomization.
-Pts must have a complete physical examination and medical history within
28 days prior to Step 2 Randomization.
- Pts who have had an echocardiogram performed within 6 months prior to
Step 2 Randomization, must have ventricular ejection fraction (LVEF) greater than or equal to 50% or greater than or equal to within normal limits for the institution.
- Pts must not have an uncontrolled intercurrent illness
- Pts must not have any known previous or concurrent condition suggesting
susceptibility to hypersensitivity or allergic reactions
- Pts must not be planning treatment with other systemic anti-cancer agents
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 pt has been disease and treatment free for two years.
Prostate cancer pts on active surveillance are eligible.
- Pts must not be pregnant or nursing due to risk of fetal or nursing infant
harm.



Clinical/Laboratory Criteria for Step 2 Randomization and Step 3 Crossover:
- Pts must have adequate hematologic function as evidenced by all of the
following within 14 days prior to Step 2 Randomization and Step 3 Crossover: ANC greater than or equal to 1,500/mcL; platelets greater than or equal to 75,000/mcL; and hemoglobin greater than or equal to 9 g/dL.
- Pts must have adequate hepatic function as evidenced by all of the following
within 14 days prior to Step 2 Randomization and Step 3 Crossover: AST and ALT both less than or equal to 5 x institutional upper limit of normal (IULN); bilirubin less than or equal to 1.5 mg/dL.
- Pts must have adequate kidney function as evidenced by calculated
creatinine clearance greater than 30 ml/min within 14 days prior to Step 2 Randomization.
Calculated creatinine clearance = (140 - age) x wt (kg) x 0.85 (if female)
72 x creatinine (mg/dl)

Eligibility Criteria for Step 3 Crossover Registration (Optional)
Clinical/Laboratory Criteria
- Pts must have documented disease progression as defined in Section 10.2d
while on CETIRI (Arm 2) on this protocol. The Follow-up Tumor Assessment
Form documenting disease progression must be submitted to SWOG prior to
Step 3 Crossover Registration. Registration to Step 3 Crossover must be within
28 days of discontinuation of CETIRI protocol treatment. Pts going off
treatment for any other reason are not eligible.
- Pts must have adequate hepatic function as evidenced by all of the following
within 14 days prior to Step 3 Crossover Registration: AST and ALT both less than or equal to 5 x
institutional upper limit of normal (IULN); bilirubin less than or equal to 1.5 mg/dL.
- Pts must have adequate kidney function as evidenced by calculated
creatinine clearance greater than 30 ml/min within 14 days prior to Step 3 Crossover
Registration.
Calculated creatinine clearance = (140 - age) x wt (kg) x 0.85 (if female)
72 x creatinine (mg/dl)
- Pts must have left ventricular ejection fraction (LVEF) greater than or equal to 50% or greater than or equal to lower limit
of normal for the institution by echocardiogram within 14 days prior to Step 3
Crossover Registration.
- Pts must have a magnesium, potassium, calcium, sodium, bicarbonate, and
chloride performed within 14 days prior to Step 3 Crossover Registration.
Additional timepoints are noted in Section 9.0.