Study of Neratinib +Trastuzumab or Neratinib + Cetuximab in Patients With KRAS/NRAS/BRAF/PIK3CA Wild-Type Metastatic Colorectal Cancer by HER2 Status

  • End date
    Jan 18, 2022
  • participants needed
  • sponsor
    NSABP Foundation Inc
Updated on 18 April 2021
ct scan
platelet count
liver metastasis
chemotherapy regimen
adjuvant therapy


This is a phase II trial to examine the efficacy of neratinib plus trastuzumab or neratinib plus cetuximab in patients with "quadruple wild-type" (all RAS/NRAS/BRAF/PIK3CA wild-type), metastatic colorectal cancer based on HER2 status (amplified, non-amplified [wild-type] or mutated). Patients must have confirmed quadruple wild-type (WT) genotype, via NSABP MPR-1 or from colonic biopsy or a metastatic biopsy taken prior to treatment, and known HER2 status.


The primary aim of this study is to determine the progression-free survival (PFS) in each of these HER2 populations. Secondary aims include overall response rate (ORR) and clinical benefit rate (CBR) defined as the objective tumor decrease and stable disease by RECIST 1.1 criteria; toxicity and safety profile. Exploratory analysis will be performed to assess for molecular predictors of response. The local site will make the primary determination of response and progression based on all radiographic images (e.g., MRI, CT, PET, bone scan, etc.) as well as other relevant reports documenting disease response or progression.

For patients identified as quadruple WT with prior cetuximab or panitumumab treatment, a pre-entry blood sample will be required from consenting patients to confirm HER2 amplification for study eligibility.

Patients with quadruple WT, HER2 amplified with prior anti-EGRF therapy and/or HER2 mutated colorectal cancer with/or without prior anti-EGRF therapy will receive concurrent therapy with trastuzumab 4 mg/kg IV loading dose followed by 2 mg/kg IV weekly and neratinib 240 mg taken by mouth daily until disease progression, (Arm 1).

Patients with quadruple WT, HER2 WT or HER2 amplified with no prior anti-EGRF therapy will be assigned to receive concurrent therapy with cetuximab (400 mg/m2 IV loading dose followed by 250 mg/m2 IV weekly), and neratinib 240 mg taken by mouth daily until disease progression (Arm 2).

Approximately thirty-five (35) patients will be accrued to this study; 15 patients with HER2 amplified, 15 patients with HER2 WT, and approximately 5 patients with HER2 mutated colorectal cancer. Patients with HER2 WT or HER2 amplified mCRC who drop out of the study before the first scan (for whatever reason) will be replaced. Patients who drop out of the study after the first scan but before the second scan will be considered to have progressive disease.

Toxicity will be graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events version 4.0 (CTCAE v4.0).

Required blood and tissue samples will be collected at entry into the study. A tumor biopsy will be procured from an accessible site of metastasis before study therapy is initiated (after the patient has signed the consent form and has been screened for eligibility). Tissue will be sent to Champions Oncology Laboratory for engraftment into an NOD/SCID mouse to develop a patient-derived xenograft (PDX) model, and to NSABP Pathology Division for correlative science. Tissue samples from PDX models will be sent to Celcuity for functional HER2 signaling assay. Additional blood samples will be collected during the course of treatment.

Optional tumor and blood samples will be collected from consenting patients at the time of disease progression.

Condition Metastatic Colorectal Cancer
Treatment Cetuximab, Trastuzumab, Neratinib, Celcuity CELx HSF, Guardant360 Diagnostic Test
Clinical Study IdentifierNCT03457896
SponsorNSABP Foundation Inc
Last Modified on18 April 2021


Yes No Not Sure

Inclusion Criteria

The tumor tissue must have been determined to be KRAS, NRAS, BRAF, PIK3CA (all
RAS quadruple) wild-type by CLIA testing
The ECOG performance status must be 0, 1 or 2. Patients must have the ability
to swallow and retain oral medication. There must be documentation by CT scan
or MRI, that the patient has evidence of measurable metastatic disease per
RECIST 1.1 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.)
Specific patient eligibility for quadruple WT and HER2 status
Arm 1
HER2 amplified confirmed by CLIA testing performed on blood samples, and prior
treatment with cetuximab or panitumumab
HER2 mutation confirmed by CLIA testing of tumor, and with or without prior
treatment with cetuximab or panitumumab
Arm 2
HER2 WT or HER2 amplified confirmed by CLIA testing of this tumor, and no
prior therapy with cetuximab or panitumumab
Blood counts performed within 2 weeks prior to study entry must meet the
ANC must be greater than or equal to 1000/mm3. Platelet count must be greater
than or equal to 75,000/mm3. Hemoglobin must be greater than or equal to 8
Adequate hepatic function performed within 2 weeks prior to study entry must
be met
Total bilirubin must be less than or equal to 1.5 x ULN (upper limit of normal) for the lab unless the patient has a bilirubin elevation greater than 1.5 x ULN to 3 x ULN due to Gilbert's disease or similar syndrome involving slow conjugation of bilirubin; and
Alkaline phosphatase must be less than or equal to 3 x ULN for the lab with the following exception: for patients with documented liver metastases or bone involvement alkaline phosphatase must be less than or equal to 5 x ULN; and
AST and ALT must be less than or equal to 3 x ULN for the lab with the following exception: for patients with documented liver metastases, AST and ALT must be less than or equal to 5 x ULN
Serum creatinine performed within 2 weeks prior to study entry must be less
than or equal to 1.5 x ULN for the lab
Patients eligible for Arm 1 (neratinib + trastuzumab): Left ventricular
ejection fraction must be greater than or equal to 50% or within normal range
for the institution (whichever is lowest)
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 7 months after the last dose of study therapy

Exclusion Criteria

Diagnosis of anal or small bowel carcinoma. Colorectal cancer histology other
than adenocarcinoma, e.g., sarcoma, lymphoma, carcinoid
Previous therapy with any HER2 targeting agents (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 CTCAE v4.0 greater than or equal to grade 2 diarrhea regardless of
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
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. (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
Previous serious hypersensitivity reaction to monoclonal antibodies
(Determination of "serious" hypersensitivity reaction is at the investigator's
discretion.) 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
Psychiatric or addictive disorders or other conditions that, in the opinion of
the investigator, would preclude the patient from meeting the study
Pregnancy or lactation at the time of study entry. (Note: Pregnancy testing
should be performed within 14 days prior to study entry according to
institutional standards for women of childbearing potential.) Use of any
investigational agent within 4 weeks prior to study entry. Note: Use of agents
known to be strong cytochrome P450 (CYP) 3A4 inducers or inhibitors, and
proton pump inhibitors (PPIs) should be avoided for the duration of study
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