Study of Neratinib +Trastuzumab or Neratinib + Cetuximab in Patients With KRAS/NRAS/BRAF/PIK3CA Wild-Type Metastatic Colorectal Cancer by HER2 Status
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|ClinicalTrials.gov Identifier: NCT03457896|
Recruitment Status : Recruiting
First Posted : March 8, 2018
Last Update Posted : March 11, 2019
|Condition or disease||Intervention/treatment||Phase|
|Metastatic Colorectal Cancer||Drug: Trastuzumab Drug: Cetuximab Drug: Neratinib Diagnostic Test: Guardant360 Diagnostic Test||Phase 2|
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.
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||35 participants|
|Intervention Model:||Parallel Assignment|
|Masking:||None (Open Label)|
|Official Title:||A Phase II Study Evaluating the Combination of Neratinib Plus Trastuzumab or Neratinib Plus Cetuximab in Patients With "Quadruple Wild-Type" (KRAS/NRAS/BRAF/PIK3CA Wild-Type) Metastatic Colorectal Cancer Based on HER2 Status: Amplified, Non-Amplified (Wild-Type) or Mutated|
|Actual Study Start Date :||May 18, 2018|
|Estimated Primary Completion Date :||December 2020|
|Estimated Study Completion Date :||January 2021|
Experimental: 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
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.
240 mg taken by mouth daily until disease progression.
Other Name: Nerlynx
Diagnostic Test: 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.
Experimental: 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
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.
240 mg taken by mouth daily until disease progression.
Other Name: Nerlynx
- Progression free survival with neratinib plus trastuzumab therapy [ Time Frame: 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). Percentage of patients alive with absence of progression assessed using RECIST 1.1 criteria.
- Progression free survival (PFS) with neratinib plus cetuximab therapy [ Time Frame: 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 ]Progression free survival (PFS). Percentage of patients alive with absence of progression assessed using RECIST 1.1 criteria
- Overall response rate to study therapy [ Time Frame: From initiation of study therapy until disease progression, approximately 6 months. ]Rate of best overall response using measurement of tumor in patients with measurable metastatic disease
- Clinical benefit rate [ Time Frame: From initiation of study therapy until disease progression, approximately 6 months. ]Rate of disease status by continuous tumor measurement.
- Frequency of adverse events assessed using CTCAE 4.0 [ Time Frame: From beginning of study therapy until disease progression, approximately 6 months. ]Frequency of adverse events categorized using the NCI Common Terminology Criteria for Adverse Events version 4.0.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03457896
|Contact: Diana Gosik, RN, BSNemail@example.com|
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|Principal Investigator:||Norman Wolmark, MD||NSABP Foundation Inc|