Clinical Trials /

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

NCT03457896

Description:

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.

Related Conditions:
  • Colorectal Adenocarcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: 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

Clinical Trial IDs

  • ORG STUDY ID: NSABP FC-11
  • NCT ID: NCT03457896

Conditions

  • Metastatic Colorectal Cancer

Interventions

DrugSynonymsArms
TrastuzumabArm 1
CetuximabArm 2
NeratinibNerlynxArm 1

Purpose

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.
    

Trial Arms

NameTypeDescriptionInterventions
Arm 1ExperimentalGuardant360 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
  • Neratinib
Arm 2ExperimentalPatients with HER2 Wild Type or HER2 amplified with no prior anti-EGFR therapy will receive: • Neratinib daily + Cetuximab weekly until disease progression
  • Cetuximab
  • Neratinib

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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure: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.
Safety Issue:
Description:Progression free survival (PFS). Percentage of patients alive with absence of progression assessed using RECIST 1.1 criteria.

Secondary Outcome Measures

Measure:Overall response rate to study therapy
Time Frame:From initiation of study therapy until disease progression, approximately 6 months.
Safety Issue:
Description:Rate of best overall response using measurement of tumor in patients with measurable metastatic disease
Measure:Clinical benefit rate
Time Frame:From initiation of study therapy until disease progression, approximately 6 months.
Safety Issue:
Description:Rate of disease status by continuous tumor measurement.
Measure:Frequency of adverse events assessed using CTCAE 4.0
Time Frame:From beginning of study therapy until disease progression, approximately 6 months.
Safety Issue:
Description:Frequency of adverse events categorized using the NCI Common Terminology Criteria for Adverse Events version 4.0.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:NSABP Foundation Inc

Trial Keywords

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

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