Clinical trial NCT03457896: Study of Neratinib +Trastuzumab or Neratinib + Cetuximab in Patients With KRAS/NRAS/BRAF/PIK3CA Wild-Type Metastatic Colorectal Cancer by HER2 Status
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
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE2
Conditions: Metastatic Colorectal Cancer
Keywords: NSABP
PUMA
Neratinib
Trastuzumab
Cetuximab
RAS
NRAS
BRAF
PIK3CA wild-type
Quadruple wild-type
HER2 status
Lead sponsor: NSABP Foundation Inc
Sponsor class: NETWORK
Collaborators: name: Puma Biotechnology, Inc.
First posted: 2018-03-08
Enrollment: 35
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Detailed description: 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.

Eligibility criteria: 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 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:

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.

Primary outcomes:
measure: Progression free survival with neratinib plus trastuzumab therapy
timeFrame: 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.
measure: Progression free survival (PFS) with neratinib plus cetuximab therapy
timeFrame: 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:
measure: Overall response rate to study therapy
timeFrame: From initiation of study therapy until disease progression, approximately 6 months.
measure: Clinical benefit rate
timeFrame: From initiation of study therapy until disease progression, approximately 6 months.
measure: Frequency of adverse events assessed using CTCAE 4.0
timeFrame: From beginning of study therapy until disease progression, approximately 6 months.
Other outcomes:
Locations:
city: Anaheim
country: United States
facility: Kaiser Permanente-Anaheim
state: California
city: Baldwin Park
country: United States
facility: Kaiser Permanente-Baldwin
state: California
city: Bellflower
country: United States
facility: Kaiser Permanente-Bellflower
state: California
city: Fontana
country: United States
facility: Kaiser Permanente-Fontana
state: California
city: Harbor City
country: United States
facility: Kaiser Permanente-Harbor City
state: California
city: Irvine
country: United States
facility: Kaiser Permanente-Irvine
state: California
city: Los Angeles
country: United States
facility: Kaiser Permanente-Sunset
state: California
city: Los Angeles
country: United States
facility: Kaiser Permanente-West Los Angeles (Cadillac)
state: California
city: Oakland
country: United States
facility: Kaiser Permanente-Oakland
state: California
city: Panorama City
country: United States
facility: Kaiser Permanente-Panorama City
state: California
city: Riverside
country: United States
facility: Kaiser Permanente-Riverside
state: California
city: Roseville
country: United States
facility: Kaiser Permanente-Roseville
state: California
city: Sacramento
country: United States
facility: Kaiser Permanente-Sacramento
state: California
city: San Diego
country: United States
facility: Kaiser Permanente-Medical Group
state: California
city: San Diego
country: United States
facility: Kaiser Permanente-Zion
state: California
city: San Francisco
country: United States
facility: Kaiser Permanente-San Francisco
state: California
city: San Jose
country: United States
facility: Kaiser Permanente-San Jose
state: California
city: San Leandro
country: United States
facility: Kaiser Permanente-San Leandro
state: California
city: San Marcos
country: United States
facility: Kaiser Permanente-San Marcos
state: California
city: Santa Clara
country: United States
facility: Kaiser Permanente Medical Center Santa Clara
state: California
city: South San Francisco
country: United States
facility: Kaiser Permanente-South San Francisco
state: California
city: Vallejo
country: United States
facility: Kaiser Permanente-Vallejo
state: California
city: Walnut Creek
country: United States
facility: Kaiser Permanente-Walnut Creek
state: California
city: Woodland Hills
country: United States
facility: Kaiser Permanente-Woodland Hills
state: California
city: Gainesville
country: United States
facility: UF Health Davis Cancer Pavilion and Shands Medical Plaza
state: Florida
city: Gainesville
country: United States
facility: University of Florida
state: Florida
city: Decatur
country: United States
facility: Cancer Care Specialists of Central IL-Decatur
state: Illinois
city: Decatur
country: United States
facility: Decatur Memorial Hospital
state: Illinois
city: Effingham
country: United States
facility: Crosslands Cancer Center
state: Illinois
city: Swansea
country: United States
facility: Cancer Care Specialists of Central IL-Swansea
state: Illinois
city: Ann Arbor
country: United States
facility: Trinity Health Michigan
state: Michigan
city: Battle Creek
country: United States
facility: Bronson Battle Creek
state: Michigan
city: Brighton
country: United States
facility: St. Joseph Mercy Brighton
state: Michigan
city: Canton
country: United States
facility: St. Joseph Mercy Canton
state: Michigan
city: Chelsea
country: United States
facility: St. Joseph Mercy Chelsea
state: Michigan
city: Grand Rapids
country: United States
facility: Cancer Research Consortium of West Michigan
state: Michigan
city: Grand Rapids
country: United States
facility: Spectrum Health Butterworth
state: Michigan
city: Livonia
country: United States
facility: St. Mary Mercy Hospital
state: Michigan
city: Muskegon
country: United States
facility: Mercy Health Mercy Campus
state: Michigan
city: Saginaw
country: United States
facility: St. Mary's of Michigan
state: Michigan
city: Saint Joseph
country: United States
facility: Lakeland Healthcare-Marie Yeager Cancer Center
state: Michigan
city: Wyoming
country: United States
facility: Metro Health Hospital
state: Michigan
city: Saint Louis Park
country: United States
facility: Minnesota Oncology-Fridley
state: Minnesota
city: Philadelphia
country: United States
facility: Thomas Jefferson University Hospital-Sidney Kimmel Cancer Network
state: Pennsylvania
city: Johnson City
country: United States
facility: Wellmont Cancer Institute
state: Tennessee
city: Kingston
country: United States
facility: Wellmont Cancer Institute
state: Tennessee
city: Bristol
country: United States
facility: Wellmont Medical Associates-Oncology and Hematology
state: Virginia
city: Norton
country: United States
facility: Southwest Virginia Regional Cancer Center
state: Virginia
Study officials:
affiliation: NSABP Foundation Inc
name: Norman Wolmark, MD
role: PRINCIPAL_INVESTIGATOR
References: