Safety and Efficacy Study of Neratinib and Cetuximab to Treat Patients With Quadruple Wild-Type Metastatic Colorectal Cancer

The neratinib dose-escalation using a 3+3 design will include 4 dose levels (120 mg, 160 mg,
200 mg, and 240 mg) as a daily oral dose. Up to 12 patients will be treated at the maximum
tolerated dose (MTD).

The neratinib dose-escalation for the study will proceed on the basis of dose-limiting
toxicity (DLT) during cycle 1. DLT will be defined as the occurrence of 1 or more of the
following events during cycle 1: any grade diarrhea that is associated with fever or
dehydration requiring IV fluids; grade 3 diarrhea lasting more than 2 days on optimal medical
therapy; grade 4 diarrhea of any duration; grade 3 or 4 neutropenia associated with fever;
grade 4 neutropenia lasting more than 7 days; grade 4 thrombocytopenia; grade 3 or 4
non-hematological toxicity (excluding grade 3 rash or allergic reaction/hypersensitivity); or
any toxicity-related delay of more than 2 weeks to initiate cycle 2. Patients will be
enrolled at the next dose level when all evaluable patients at the same dose level have
completed the first treatment cycle. Enrolled patients will remain on the assigned dose level
treatment until toxicity or disease progression.

The Phase II part of this study will proceed with a two-stage design with a maximum of 46
patients. Between 6 and 12 patients at the Phase I MTD level will be included in the Phase
II, stage-one analysis.

Toxicity will be graded according to the National Cancer Institute (NCI) Common Terminology
Criteria for Adverse Events version 4.0.

Submission of tumor and blood samples for FC-7 correlative science studies will be a study
requirement for all patients. A core biopsy procedure to procure fresh tumor samples from an
accessible site of metastasis will be performed before study dose level assignment (after the
patient has signed the consent form and has been screened for eligibility).

Optional biopsy samples of metastatic disease will be procured from consenting patients after
Cycle 1 of treatment and at the time of disease progression.

Inclusion criteria:

- Patients with resected primary must be active participants of the NSABP Patient
Registry and Biospecimen Profiling Repository (MPR-1) study. Patients with intact
primary and metastatic KRAS wild-type disease at presentation (treatment naive), must
have signed consent for quadruple wild-type central testing for treatment-naive tumor
sample submission

- The Eastern Cooperative Oncology Group (ECOG) performance status must be 0, 1, or 2.

- Patients must have the ability to swallow oral medication.

- The tumor tissue must have been determined to be KRAS, NRAS, BRAF, PIK3CA wild-type by
central CLIA testing.

- There must be documentation by PET/CT scan, CT scan, or MRI, that the patient has
evidence of measurable metastatic disease per RECIST criteria.

- Patients must have an accessible metastatic lesion for pretreatment core biopsy
procurement.

- Unless either drug is medically contraindicated, patients must have received
oxaliplatin and irinotecan as part of standard chemotherapy regimens. (This includes
adjuvant therapy.)

- Patients must have had at least one prior treatment for metastatic disease with
standard chemotherapy and cetuximab in combination or as monotherapy. [Note: patients
who received panitumumab instead of cetuximab are eligible.]

- At the time of study entry, blood counts performed within 4 weeks prior to study entry
must meet the following criteria: absolute neutrophil count (ANC) must be greater than
or equal to 1000/mm3; Platelet count must be greater than or equal to 100,000/mm3;
Hemoglobin must be greater than or equal to 9 g/dL

- The following criteria for evidence of adequate hepatic function performed within 4
weeks prior to study entry must be met: Total bilirubin must be less than or equal to
1.5 x upper limit of normal (ULN); aspartate aminotransferase (AST) and ALT must be
less than or equal to 2.5 x ULN for the lab or less than or equal to 5 x ULN if liver
metastasis;

- Serum creatinine performed within 4 weeks prior to study entry must be less than or
equal to 1.5 x ULN for the lab.

- Female patients and male patients with female partners of reproductive potential must
agree to use an effective method of contraception during therapy and for at least 6
months after the last dose of study therapy.

- Patients with acquired immunodeficiency syndrome (AIDS-related illnesses) or known
human immunodeficiency virus (HIV) disease must: Have a CD4 count greater than or
equal to 200 cells/uL within 30 days prior to beginning study therapy; Be off all
antiretroviral therapy (prophylaxis/treatment) greater than 60 days prior to beginning
study therapy; Have no evidence of opportunistic infections.

Exclusion criteria:

- Diagnosis of anal or small bowel carcinoma.

- Colorectal cancer other than adenocarcinoma, e.g., sarcoma, lymphoma, carcinoid.

- Previous therapy with any HER2 TKI (such as trastuzumab, lapatinib, neratinib, etc.)
for any malignancy.

- Symptomatic brain metastases or brain metastases requiring chronic steroids to control
symptoms.

- Active hepatitis B or hepatitis C with abnormal liver function tests.

- Malabsorption syndrome, ulcerative colitis, inflammatory bowel disease, resection of
the stomach or small bowel, or other disease or condition significantly affecting
gastrointestinal function.

- Persistent Common Toxicity Criteria for Adverse Effects (CTCAE v4.0) greater than or
equal to grade 2 diarrhea regardless of etiology.

- Chronic daily treatment with corticosteroids with a dose of greater than or equal to
10 mg/day methylprednisolone equivalent (excluding inhaled steroids).

- CTCAE v4.0 grade 3 or 4 anorexia or nausea related to metastatic disease.

- CTCAE v4.0 greater than or equal to grade 2 vomiting related to metastatic disease.

- Any of the following cardiac conditions: Documented congestive heart failure;
Myocardial infarction within 6 months prior to study entry; Unstable angina within 6
months prior to study entry; Symptomatic arrhythmia

- Serious or non-healing wound, skin ulcer, or bone fracture.

- History of bleeding diathesis or coagulopathy. (Patients on stable anticoagulant
therapy are eligible.)

- Symptomatic interstitial lung disease or definitive evidence of interstitial lung
disease described on CT scan, MRI, or chest x-ray in asymptomatic patients; dyspnea at
rest requiring current continuous oxygen therapy.

- Other malignancies unless the patient is considered to be disease-free and has
completed therapy for the malignancy greater than or equal to 12 months prior to study
entry. Patients with the following cancers are eligible if diagnosed and treated
within the past 12 months: carcinoma in situ of the cervix, colorectal carcinoma in
situ, melanoma in situ, and basal cell and squamous cell carcinoma of the skin.

- Previous serious hypersensitivity reaction to monoclonal antibodies. (Determination of
"serious" hypersensitivity reaction is at the investigator's discretion.)

- Psychiatric or addictive disorders or other conditions that, in the opinion of the
investigator, would preclude the patient from meeting the study requirements.

- Pregnancy or lactation at the time of study entry.

- Use of any investigational agent within 4 weeks prior to study entry.