Study of Neratinib +Trastuzumab or Neratinib + Cetuximab in Patients With KRAS/NRAS/BRAF/PIK3CA Wild-Type Metastatic Colorectal Cancer by HER2 Status
NCT ID: NCT03457896
Last Updated: 2022-03-31
Study Results
The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.
Basic Information
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UNKNOWN
PHASE2
35 participants
INTERVENTIONAL
2018-05-18
2022-09-30
Brief Summary
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Detailed Description
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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.
Conditions
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Study Design
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NON_RANDOMIZED
PARALLEL
TREATMENT
NONE
Study Groups
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Arm 1
Guardant360 test on blood from select patients with known HER2 status.
Prior to assignment to Arm 1, HER2 test on blood obtained from Quadruple Wild-Type patients who received anti-EGFR therapy. Patients with HER2 amplified, HER2 Wild-Type or HER2 mutated will recieve:
• Neratinib daily + Trastuzumab weekly until disease progression
Trastuzumab
Patients with HER2 amplified tumors with prior anti-EGFR therapy and/or HER2 mutated colorectal cancer with/or without prior anti-EGFR therapy will receive 4 mg/kg IV loading dose; then 2 mg/kg IV weekly until disease progression. Neratinib: 240 mg taken by mouth daily until disease progression.
Neratinib
240 mg taken by mouth daily until disease progression.
Guardant360 Diagnostic Test
Prior to assignment to Arm 1, the Guardant360 diagnostic test will be conducted in blood to confirm known HER2 status for select patients.
Arm 2
Patients with HER2 Wild Type or HER2 amplified with no prior anti-EGFR therapy will receive:
• Neratinib daily + Cetuximab weekly until disease progression
Cetuximab
Patients with HER2 WT or HER2 amplified with no prior anti-EGFR therapy: 400 mg/m2 IV loading dose; then 250 mg/m2 IV weekly. Neratinib 240 mg taken by mouth daily until disease progression.
Neratinib
240 mg taken by mouth daily until disease progression.
Interventions
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Trastuzumab
Patients with HER2 amplified tumors with prior anti-EGFR therapy and/or HER2 mutated colorectal cancer with/or without prior anti-EGFR therapy will receive 4 mg/kg IV loading dose; then 2 mg/kg IV weekly until disease progression. Neratinib: 240 mg taken by mouth daily until disease progression.
Cetuximab
Patients with HER2 WT or HER2 amplified with no prior anti-EGFR therapy: 400 mg/m2 IV loading dose; then 250 mg/m2 IV weekly. Neratinib 240 mg taken by mouth daily until disease progression.
Neratinib
240 mg taken by mouth daily until disease progression.
Guardant360 Diagnostic Test
Prior to assignment to Arm 1, the Guardant360 diagnostic test will be conducted in blood to confirm known HER2 status for select patients.
Other Intervention Names
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Eligibility Criteria
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Inclusion Criteria
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 following criteria:
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 g/dL.
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
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 etiology.
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. (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 requirements.
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 therapy.
18 Years
ALL
No
Sponsors
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Puma Biotechnology, Inc.
INDUSTRY
NSABP Foundation Inc
NETWORK
Responsible Party
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Principal Investigators
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Norman Wolmark, MD
Role: PRINCIPAL_INVESTIGATOR
NSABP Foundation Inc
Locations
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Kaiser Permanente-Anaheim
Anaheim, California, United States
Kaiser Permanente-Baldwin
Baldwin Park, California, United States
Kaiser Permanente-Bellflower
Bellflower, California, United States
Kaiser Permanente-Fontana
Fontana, California, United States
Kaiser Permanente-Harbor City
Harbor City, California, United States
Kaiser Permanente-Irvine
Irvine, California, United States
Kaiser Permanente-Sunset
Los Angeles, California, United States
Kaiser Permanente-West Los Angeles (Cadillac)
Los Angeles, California, United States
Kaiser Permanente-Oakland
Oakland, California, United States
Kaiser Permanente-Panorama City
Panorama City, California, United States
Kaiser Permanente-Riverside
Riverside, California, United States
Kaiser Permanente-Roseville
Roseville, California, United States
Kaiser Permanente-Sacramento
Sacramento, California, United States
Kaiser Permanente-Medical Group
San Diego, California, United States
Kaiser Permanente-Zion
San Diego, California, United States
Kaiser Permanente-San Francisco
San Francisco, California, United States
Kaiser Permanente-San Jose
San Jose, California, United States
Kaiser Permanente-San Leandro
San Leandro, California, United States
Kaiser Permanente-San Marcos
San Marcos, California, United States
Kaiser Permanente Medical Center Santa Clara
Santa Clara, California, United States
Kaiser Permanente-South San Francisco
South San Francisco, California, United States
Kaiser Permanente-Vallejo
Vallejo, California, United States
Kaiser Permanente-Walnut Creek
Walnut Creek, California, United States
Kaiser Permanente-Woodland Hills
Woodland Hills, California, United States
UF Health Davis Cancer Pavilion and Shands Medical Plaza
Gainesville, Florida, United States
University of Florida
Gainesville, Florida, United States
Cancer Care Specialists of Central IL-Decatur
Decatur, Illinois, United States
Decatur Memorial Hospital
Decatur, Illinois, United States
Crosslands Cancer Center
Effingham, Illinois, United States
Cancer Care Specialists of Central IL-Swansea
Swansea, Illinois, United States
Trinity Health Michigan
Ann Arbor, Michigan, United States
Bronson Battle Creek
Battle Creek, Michigan, United States
St. Joseph Mercy Brighton
Brighton, Michigan, United States
St. Joseph Mercy Canton
Canton, Michigan, United States
St. Joseph Mercy Chelsea
Chelsea, Michigan, United States
Cancer Research Consortium of West Michigan
Grand Rapids, Michigan, United States
Spectrum Health Butterworth
Grand Rapids, Michigan, United States
St. Mary Mercy Hospital
Livonia, Michigan, United States
Mercy Health Mercy Campus
Muskegon, Michigan, United States
St. Mary's of Michigan
Saginaw, Michigan, United States
Lakeland Healthcare-Marie Yeager Cancer Center
Saint Joseph, Michigan, United States
Metro Health Hospital
Wyoming, Michigan, United States
Minnesota Oncology-Fridley
Saint Louis Park, Minnesota, United States
Thomas Jefferson University Hospital-Sidney Kimmel Cancer Network
Philadelphia, Pennsylvania, United States
Wellmont Cancer Institute
Johnson City, Tennessee, United States
Wellmont Cancer Institute
Kingston, Tennessee, United States
Wellmont Medical Associates-Oncology and Hematology
Bristol, Virginia, United States
Southwest Virginia Regional Cancer Center
Norton, Virginia, United States
Countries
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References
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Freeman TJ, George TJ, Jacobs SA, Yothers G, Kolevska T, Feng H, Lipchik C, Maley S, Song N, Srinivasan A, Finnigan M, Wade JL 3rd, Buchschacher GL Jr, Al Baghdadi T, Shipstone A, Lin D, Puhalla SL, Allegra CJ, Wolmark N, Pogue-Geile KL. NSABP FC-11: A phase II study of neratinib plus trastuzumab or neratinib plus cetuximab in patients with "quadruple wild-type" (KRAS/NRAS/BRAF/PIK3CA) metastatic colorectal cancer based on HER2 status: amplified, non-amplified (wild-type), or mutated. Cancer Chemother Pharmacol. 2025 Aug 9;95(1):80. doi: 10.1007/s00280-025-04802-8.
Other Identifiers
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NSABP FC-11
Identifier Type: -
Identifier Source: org_study_id
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