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

NCT03457896 | Unknown Phase 2 FDA Drug

• 1 other identifier: NSABP FC-11
• Study Type: interventional
• Target: 35
• Locations: 1 country
• Sites: 48

Brief Summary

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.

Conditions

Metastatic Colorectal Cancer

Keywords

NSABP; PUMA; Neratinib; Trastuzumab; Cetuximab; RAS; NRAS; BRAF; PIK3CA wild-type; Quadruple wild-type; HER2 status

Outcome Measures

Primary Outcomes (2)

• Progression free survival with neratinib plus trastuzumab therapy

  Progression free survival (PFS). Percentage of patients alive with absence of progression assessed using RECIST 1.1 criteria.

  From initiation of neratinib plus trastuzumab therapy to time of tumor assessment, between cycle 6 and 7,which is usually six months after start of therapy.

• Progression free survival (PFS) with neratinib plus cetuximab therapy

  Progression free survival (PFS). Percentage of patients alive with absence of progression assessed using RECIST 1.1 criteria

  From initiation of neratinib plus cetuximab therapy to time of tumor assessment between cycles 6 and 7, which is usually 6 months after start of therapy

Secondary Outcomes (3)

• Overall response rate to study therapy

  From initiation of study therapy until disease progression, approximately 6 months.

• Clinical benefit rate

  From initiation of study therapy until disease progression, approximately 6 months.

• Frequency of adverse events assessed using CTCAE 4.0

  From beginning of study therapy until disease progression, approximately 6 months.

Study Arms (2)

Arm 1

EXPERIMENTAL

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

Drug: Trastuzumab; Drug: Neratinib; Diagnostic Test: Guardant360 Diagnostic Test

Arm 2

EXPERIMENTAL

Patients with HER2 Wild Type or HER2 amplified with no prior anti-EGFR therapy will receive: • Neratinib daily + Cetuximab weekly until disease progression

Drug: Cetuximab; Drug: Neratinib

Interventions

Trastuzumab DRUG

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.

Arm 1

Cetuximab DRUG

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.

Arm 2

Neratinib DRUG

240 mg taken by mouth daily until disease progression.

Also known as: Nerlynx

Arm 1; Arm 2

Guardant360 Diagnostic Test 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 1

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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 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

You may not qualify if:

• 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 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.

Sponsors & Collaborators

• NSABP Foundation Inc: lead
• Puma Biotechnology, Inc.: collaborator

Study Sites (48)

Kaiser Permanente-Anaheim

Anaheim, California, 92806, United States

Location

Kaiser Permanente-Baldwin

Baldwin Park, California, 91706, United States

Location

Kaiser Permanente-Bellflower

Bellflower, California, 90706, United States

Location

Kaiser Permanente-Fontana

Fontana, California, 92335, United States

Location

Kaiser Permanente-Harbor City

Harbor City, California, 90710, United States

Location

Kaiser Permanente-Irvine

Irvine, California, 92618, United States

Location

Kaiser Permanente-Sunset

Los Angeles, California, 90027, United States

Location

Kaiser Permanente-West Los Angeles (Cadillac)

Los Angeles, California, 90034, United States

Location

Kaiser Permanente-Oakland

Oakland, California, 94611, United States

Location

Kaiser Permanente-Panorama City

Panorama City, California, 91402, United States

Location

Kaiser Permanente-Riverside

Riverside, California, 92505, United States

Location

Kaiser Permanente-Roseville

Roseville, California, 95661, United States

Location

Kaiser Permanente-Sacramento

Sacramento, California, 95814, United States

Location

Kaiser Permanente-Medical Group

San Diego, California, 92108, United States

Location

Kaiser Permanente-Zion

San Diego, California, 92120, United States

Location

Kaiser Permanente-San Francisco

San Francisco, California, 94115, United States

Location

Kaiser Permanente-San Jose

San Jose, California, 95119, United States

Location

Kaiser Permanente-San Leandro

San Leandro, California, 94577, United States

Location

Kaiser Permanente-San Marcos

San Marcos, California, 92078, United States

Location

Kaiser Permanente Medical Center Santa Clara

Santa Clara, California, 95051, United States

Location

Kaiser Permanente-South San Francisco

South San Francisco, California, 94080, United States

Location

Kaiser Permanente-Vallejo

Vallejo, California, 94589, United States

Location

Kaiser Permanente-Walnut Creek

Walnut Creek, California, 94596, United States

Location

Kaiser Permanente-Woodland Hills

Woodland Hills, California, 91367, United States

Location

UF Health Davis Cancer Pavilion and Shands Medical Plaza

Gainesville, Florida, 32608, United States

Location

University of Florida

Gainesville, Florida, 32610, United States

Location

Cancer Care Specialists of Central IL-Decatur

Decatur, Illinois, 62526, United States

Location

Decatur Memorial Hospital

Decatur, Illinois, 62526, United States

Location

Crosslands Cancer Center

Effingham, Illinois, 62401, United States

Location

Cancer Care Specialists of Central IL-Swansea

Swansea, Illinois, 62226, United States

Location

Trinity Health Michigan

Ann Arbor, Michigan, 48106, United States

Location

Bronson Battle Creek

Battle Creek, Michigan, 49017, United States

Location

St. Joseph Mercy Brighton

Brighton, Michigan, 48114, United States

Location

St. Joseph Mercy Canton

Canton, Michigan, 48188, United States

Location

St. Joseph Mercy Chelsea

Chelsea, Michigan, 48118, United States

Location

Cancer Research Consortium of West Michigan

Grand Rapids, Michigan, 49503-2560, United States

Location

Spectrum Health Butterworth

Grand Rapids, Michigan, 49503, United States

Location

St. Mary Mercy Hospital

Livonia, Michigan, 48154, United States

Location

Mercy Health Mercy Campus

Muskegon, Michigan, 49444, United States

Location

St. Mary's of Michigan

Saginaw, Michigan, 48601, United States

Location

Lakeland Healthcare-Marie Yeager Cancer Center

Saint Joseph, Michigan, 49085, United States

Location

Metro Health Hospital

Wyoming, Michigan, 49519, United States

Location

Minnesota Oncology-Fridley

Saint Louis Park, Minnesota, 55432, United States

Location

Thomas Jefferson University Hospital-Sidney Kimmel Cancer Network

Philadelphia, Pennsylvania, 19107, United States

Location

Wellmont Cancer Institute

Johnson City, Tennessee, 37601, United States

Location

Wellmont Cancer Institute

Kingston, Tennessee, 37660, United States

Location

Wellmont Medical Associates-Oncology and Hematology

Bristol, Virginia, 24201, United States

Location

Southwest Virginia Regional Cancer Center

Norton, Virginia, 24273, United States

Location

Related Publications (1)

• 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.

  PMID: 40782152 DERIVED

MeSH Terms

Conditions

Colorectal Neoplasms

Interventions

Trastuzumab; Cetuximab; neratinib

Condition Hierarchy (Ancestors)

Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Rectal Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Study Officials

• Norman Wolmark, MD

  NSABP Foundation Inc

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NETWORK
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 1, 2018
• First Posted: March 8, 2018
• Study Start: May 18, 2018
• Primary Completion: September 30, 2021
• Study Completion: September 30, 2022
• Last Updated: March 31, 2022

Record last verified: 2022-03

Locations

US (48)