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S1613, Trastuzumab and Pertuzumab or Cetuximab and Irinotecan Hydrochloride in Treating Patients With Locally Advanced or Metastatic HER2/Neu Amplified Colorectal Cancer That Cannot Be Removed by Surgery

NCT03365882

Description:

This randomized phase II trial studies how well trastuzumab and pertuzumab work compared to cetuximab and irinotecan hydrochloride in treating patients with HER2/neu amplified colorectal cancer that has spread from where it started to other places in the body and cannot be removed by surgery. Monoclonal antibodies, such as trastuzumab and pertuzumab, may interfere with the ability of tumor cells to grow and spread. Drugs used in chemotherapy, such as cetuximab and irinotecan hydrochloride, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving trastuzumab and pertuzumab may work better compared to cetuximab and irinotecan hydrochloride in treating patients with colorectal cancer.

Related Conditions:
  • Colorectal Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: S1613, Trastuzumab and Pertuzumab or Cetuximab and Irinotecan Hydrochloride in Treating Patients With Locally Advanced or Metastatic HER2/Neu Amplified Colorectal Cancer That Cannot Be Removed by Surgery
  • Official Title: S1613, A Randomized Phase II Study of Trastuzumab and Pertuzumab (TP) Compared to Cetuximab and Irinotecan (CETIRI) in Advanced/Metastatic Colorectal Cancer (mCRC) With HER-2 Amplification

Clinical Trial IDs

  • ORG STUDY ID: S1613
  • SECONDARY ID: NCI-2016-01422
  • SECONDARY ID: S1613
  • SECONDARY ID: S1613
  • SECONDARY ID: S1613
  • SECONDARY ID: U10CA180888
  • NCT ID: NCT03365882

Conditions

  • Colon Adenocarcinoma
  • ERBB2 Gene Amplification
  • Rectal Adenocarcinoma
  • Recurrent Colon Carcinoma
  • Recurrent Rectal Carcinoma
  • Stage III Colon Cancer AJCC v7
  • Stage III Rectal Cancer AJCC v7
  • Stage IIIA Colon Cancer AJCC v7
  • Stage IIIA Rectal Cancer AJCC v7
  • Stage IIIB Colon Cancer AJCC v7
  • Stage IIIB Rectal Cancer AJCC v7
  • Stage IIIC Colon Cancer AJCC v7
  • Stage IIIC Rectal Cancer AJCC v7
  • Stage IV Colon Cancer AJCC v7
  • Stage IV Rectal Cancer AJCC v7
  • Stage IVA Colon Cancer AJCC v7
  • Stage IVA Rectal Cancer AJCC v7
  • Stage IVB Colon Cancer AJCC v7
  • Stage IVB Rectal Cancer AJCC v7

Interventions

DrugSynonymsArms
CetuximabChimeric Anti-EGFR Monoclonal Antibody, Chimeric MoAb C225, Chimeric Monoclonal Antibody C225, Erbitux, IMC-C225Arm II (cetuximab, irinotecan hydrochloride)
Irinotecan HydrochlorideCampto, Camptosar, Camptothecin 11, Camptothecin-11, CPT 11, CPT-11, Irinomedac, U-101440EArm II (cetuximab, irinotecan hydrochloride)
Pertuzumab2C4, 2C4 Antibody, MoAb 2C4, Monoclonal Antibody 2C4, Perjeta, rhuMAb2C4, RO4368451Arm I (pertuzumab, trastuzumab)
TrastuzumabABP 980, Anti-c-ERB-2, Anti-c-erbB2 Monoclonal Antibody, Anti-ERB-2, Anti-erbB-2, Anti-erbB2 Monoclonal Antibody, Anti-HER2/c-erbB2 Monoclonal Antibody, Anti-p185-HER2, c-erb-2 Monoclonal Antibody, HER2 Monoclonal Antibody, Herceptin, Herceptin Biosimilar PF-05280014, Herceptin Trastuzumab Biosimilar PF-05280014, MoAb HER2, Monoclonal Antibody c-erb-2, Monoclonal Antibody HER2, PF-05280014, rhuMAb HER2, RO0452317, Trastuzumab Biosimilar ABP 980, Trastuzumab Biosimilar PF-05280014Arm I (pertuzumab, trastuzumab)

Purpose

This randomized phase II trial studies how well trastuzumab and pertuzumab work compared to cetuximab and irinotecan hydrochloride in treating patients with HER2/neu amplified colorectal cancer that has spread from where it started to other places in the body and cannot be removed by surgery. Monoclonal antibodies, such as trastuzumab and pertuzumab, may interfere with the ability of tumor cells to grow and spread. Drugs used in chemotherapy, such as cetuximab and irinotecan hydrochloride, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving trastuzumab and pertuzumab may work better compared to cetuximab and irinotecan hydrochloride in treating patients with colorectal cancer.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To evaluate the efficacy of trastuzumab and pertuzumab (TP) (Arm 1) in HER-2 amplified
      metastatic colorectal cancer (mCRC) by comparing progression-free survival (PFS) on TP
      compared to control arm (Arm 2) of cetuximab and irinotecan hydrochloride (irinotecan)
      (CETIRI).

      SECONDARY OBJECTIVES:

      I. To evaluate the overall response rate (ORR), including confirmed complete and partial
      response per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, in treatment Arms 1
      and 2.

      II. To evaluate the overall survival (OS) in treatment Arms 1 and 2. III. To evaluate the
      safety and toxicity of TP compared to CETIRI.

      TERTIARY OBJECTIVES:

      I. To estimate the rates of PFS, OS, and ORR in patients who crossover to TP (Arm 3) after
      disease progression on CETIRI.

      II. To bank images for future retrospective analysis. III. To evaluate if HER-2/centromeric
      probe (CEP17) signal ratio and HER-2 gene copy number (GCN) are predictive of clinical
      efficacy for patients receiving TP versus CETIRI.

      IV. To bank tissue and blood samples for other future correlative studies from patients
      enrolled on the study.

      OUTLINE: Patients with HER2 gene amplification are randomized to 1 of 2 arms.

      ARM I: Patients receive pertuzumab intravenously (IV) over 30-60 minutes and trastuzumab IV
      over 30-120 minutes on day 1. Courses repeat every 21 days in the absence of disease
      progression or unacceptable toxicity.

      ARM II: Patients receive cetuximab IV over 60-120 minutes and irinotecan hydrochloride IV
      over 90 minutes on day 1. Courses repeat every 14 days in the absence of disease progression
      or unacceptable toxicity. Patients with documented disease progression may optionally
      crossover to Arm I.

      After completion of study treatment, patients are followed up for 3 years.
    

Trial Arms

NameTypeDescriptionInterventions
Arm I (pertuzumab, trastuzumab)ExperimentalPatients receive pertuzumab IV over 30-60 minutes and trastuzumab IV over 30-120 minutes on day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
    Arm II (cetuximab, irinotecan hydrochloride)ExperimentalPatients receive cetuximab IV over 60-120 minutes and irinotecan hydrochloride IV over 90 minutes on day 1. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity. Patients with documented disease progression may optionally crossover to Arm I.
    • Irinotecan Hydrochloride

    Eligibility Criteria

            Inclusion Criteria:
    
              -  STEP 1 INITIAL REGISTRATION: HER2 TESTING
    
              -  Patients must have histologically or cytologically documented adenocarcinoma of the
                 colon or rectum that is metastatic or locally advanced and unresectable
    
              -  Mutation results:
    
                   -  All patients must have molecular testing performed in a Clinical Laboratory
                      Improvement Act (CLIA) certified lab which includes which includes KRAS and NRAS
                      gene and exon 15 of BRAF gene (BRAF V600E mutation); patients with any known
                      activating mutation in exon 2 [codons 12 and 13], exon 3 [codons 59 and 61] and
                      exon 4 [codons 117 and 146]) of KRAS/NRAS genes and in exon 15 (BRAFV600E
                      mutation) of BRAF gene are not eligible
    
              -  Patients must not have been treated with any of the following prior to step 1 initial
                 registration:
    
                   -  Cetuximab, panitumumab, or any other monoclonal antibody against EGFR or
                      inhibitor of EGFR
    
                   -  HER-2 targeting for treatment of colorectal cancer; patients who have received
                      prior trastuzumab or pertuzumab for other indications such as prior history of
                      adjuvant or neoadjuvant breast cancer treatment prior to the development of
                      advanced colorectal cancer are eligible
    
              -  Patients must not have had history of severe toxicity and intolerance to or
                 hypersensitivity to irinotecan or any other study drug; patients must not have had a
                 severe infusion-related reaction during any prior therapy with pertuzumab or
                 trastuzumab
    
              -  Patients must have tumor slides available for submission for HER-2 testing; HER-2
                 testing must be completed by the central lab prior to step 2 randomization
    
              -  Patients must be informed of the investigational nature of this study and must sign
                 and give informed consent in accordance with institutional and federal guidelines; for
                 step 1 initial registration, the appropriate consent form is the step 1 consent form
    
              -  As a part of the OPEN registration process the treating institution's identity is
                 provided in order to ensure that the current (within 365 days) date of institutional
                 review board approval for this study has been entered in the system
    
              -  STEP 2 RANDOMIZATION
    
              -  Patients must have HER-2 amplification as determined by central testing (3+ or 2+ by
                 immunohistochemistry and HER-2 gene amplification by in situ hybridization with a
                 ratio of HER-2 gene signals to centromere 17 signals >= 2.0)
    
              -  Patients must have measurable disease that is metastatic or locally advanced and
                 unresectable; imaging used to assess all disease per RECIST 1.1 must have been
                 completed within 28 days prior to step 2 randomization; all disease must be assessed
                 and documented on the Baseline Tumor Assessment Form
    
              -  Patients must have had at least one prior regimen of systemic chemotherapy for
                 metastatic or locally advanced, unresectable disease; patients must have progressed
                 following the most recent therapy; prior treatment with irinotecan is allowed; for
                 patients that received adjuvant chemotherapy: prior treatment for metastatic disease
                 is not required for patient who experienced disease recurrence during or within 6
                 months of completion of adjuvant chemotherapy; if the patient received one line of
                 adjuvant treatment and had disease recurrence after 6 months of completing
                 chemotherapy, patients will only be eligible after failing one additional line of
                 chemotherapy used to treat the metastatic or locally advanced, unresectable disease;
                 patients who have received >= 3 lines of systemic chemotherapy for metastatic or
                 locally advanced, unresectable disease are not eligible
    
              -  Patients must have completed prior chemotherapy, immunotherapy, or radiation therapy
                 at least 14 days prior to step 2 randomization and all toxicity must be resolved to
                 Common Terminology Criteria for Adverse Events (CTCAE) version (v)4.0 grade 1 (with
                 the exception of CTCAE v4.0 grade 2 neuropathy) prior to step 2 randomization
    
              -  Brain metastases are allowed if they have been adequately treated with radiotherapy or
                 surgery and stable for at least 30 days prior to step 2 randomization; eligible
                 patients must be neurologically asymptomatic and without corticosteroid treatment for
                 at least 7 days prior to step 2 randomization
    
              -  Patients must have a Zubrod performance status of 0 or 1
    
              -  Patients must have a complete physical examination and medical history within 28 days
                 prior to step 2 randomization
    
              -  Absolute neutrophil count (ANC) >= 1,500/mcL
    
              -  Platelets >= 75,000/mcL
    
              -  Hemoglobin >= 9 g/dL
    
              -  Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) both =< 5 x
                 institutional upper limit of normal (IULN)
    
              -  Bilirubin =< 1.5 mg/dL
    
              -  Calculated creatinine clearance > 30 ml/min within 14 days prior to step 2
                 randomization
    
              -  Patients who have had an echocardiogram performed within 6 months prior to step 2
                 randomization must have ventricular ejection fraction (left ventricular ejection
                 fraction [LVEF]) >= 50% or >= within normal limits for the institution
    
              -  Patients must not have an uncontrolled intercurrent illness including, but not limited
                 to diabetes, hypertension, severe infection, severe malnutrition, unstable angina,
                 class III-IV New York Heart Association (NYHA) congestive heart failure, ventricular
                 arrhythmias, active ischemic heart disease, or myocardial infarction within 6 months
                 prior to step 2 randomization
    
              -  Patients must not have any known previous or concurrent condition suggesting
                 susceptibility to hypersensitivity or allergic reactions, including, but not limited
                 to: known hypersensitivity to any of the study treatments or to excipients of
                 recombinant human or humanized antibodies; patients with mild or seasonal allergies
                 may be included after discussion with the study chairs
    
              -  Patients must not be planning treatment with other systemic anti-cancer agents (e.g.,
                 chemotherapy, hormonal therapy, immunotherapy) or other treatments not part of
                 protocol-specified anti-cancer therapy including concurrent investigational agents of
                 any type
    
              -  No prior malignancy is allowed except for adequately treated basal cell or squamous
                 cell skin cancer, in situ cervical cancer, ductal carcinoma in situ, other low grade
                 lesions such as incidental appendix carcinoid, or any other cancer from which the
                 patient has been disease and treatment free for two years; prostate cancer patients on
                 active surveillance are eligible
    
              -  Patients must not be pregnant or nursing; females of child-bearing potential must have
                 a negative serum pregnancy test within 7 days prior to registration; women/men of
                 reproductive potential must have agreed to use an effective contraceptive method while
                 on study and for at least 7 months after the last dose of study treatment; a woman is
                 considered to be of "reproductive potential" if she has had menses at any time in the
                 preceding 12 consecutive months; in addition to routine contraceptive methods,
                 "effective contraception" also includes heterosexual celibacy and surgery intended to
                 prevent pregnancy (or with a side-effect of pregnancy prevention) defined as a
                 hysterectomy, bilateral oophorectomy or bilateral tubal ligation; however, if at any
                 point a previously celibate patient chooses to become heterosexually active during the
                 time period for use of contraceptive measures outlined in the protocol, he/she is
                 responsible for beginning contraceptive measures
    
              -  Patients must be given the opportunity to consent to the optional submission of tissue
                 for future research
    
              -  Patients must be informed of the investigational nature of this study and must sign
                 and give written informed consent in accordance with institutional and federal
                 guidelines; the appropriate consent form for this registration is the step 2 consent
                 form
    
              -  STEP 2 RANDOMIZATION: As a part of the Oncology Patient Enrollment Network (OPEN)
                 registration process the treating institution's identity is provided in order to
                 ensure that the current (within 365 days) date of institutional review board approval
                 for this study has been entered in the system
    
              -  STEP 3 CROSSOVER REGISTRATION (OPTIONAL): Patients must have documented disease
                 progression while on CETIRI (Arm 2) on this protocol; the Follow-up Tumor Assessment
                 Form documenting disease progression must be submitted to Southwest Oncology Group
                 (SWOG) prior to step 3 crossover registration; registration to step 3 crossover must
                 be within 28 days of discontinuation of CETIRI protocol treatment; patients going off
                 treatment for any other reason are not eligible
    
              -  STEP 3 CROSSOVER REGISTRATION (OPTIONAL): Patients must have a Zubrod performance
                 status of 0 or 1
    
              -  STEP 3 CROSSOVER REGISTRATION (OPTIONAL): ANC >= 1,500/mcL
    
              -  STEP 3 CROSSOVER REGISTRATION (OPTIONAL): Platelets >= 75,000/mcL
    
              -  STEP 3 CROSSOVER REGISTRATION (OPTIONAL): Hemoglobin >= 9 g/dL
    
              -  STEP 3 CROSSOVER REGISTRATION (OPTIONAL): AST and ALT both =< 5 x institutional upper
                 limit of normal (IULN)
    
              -  STEP 3 CROSSOVER REGISTRATION (OPTIONAL): Bilirubin =< 1.5 mg/dL
    
              -  STEP 3 CROSSOVER REGISTRATION (OPTIONAL): Calculated creatinine clearance > 30 ml/min
                 within 14 days prior to step 3 crossover registration
    
              -  STEP 3 CROSSOVER REGISTRATION (OPTIONAL): Patients must have left ventricular ejection
                 fraction (LVEF) >= 50% or >= lower limit of normal for the institution by
                 echocardiogram within 14 days prior to step 3 crossover registration
    
              -  STEP 3 CROSSOVER REGISTRATION (OPTIONAL): Patients must have a magnesium, potassium,
                 calcium, sodium, bicarbonate, and chloride performed within 14 days prior to step 3
                 crossover registration
    
              -  STEP 3 CROSSOVER REGISTRATION (OPTIONAL): Patients must be informed of the
                 investigational nature of this study and must sign and give written informed consent
                 in accordance with institutional and federal guidelines; the appropriate consent form
                 for this registration is the step 2 consent form
    
              -  STEP 3 CROSSOVER REGISTRATION (OPTIONAL): As a part of the OPEN registration process
                 the treating institution's identity is provided in order to ensure that the current
                 (within 365 days) date of institutional review board approval for this study has been
                 entered in the system
          
    Maximum Eligible Age:N/A
    Minimum Eligible Age:18 Years
    Eligible Gender:All
    Healthy Volunteers:No

    Primary Outcome Measures

    Measure:Progression-free survival (PFS)
    Time Frame:From date of registration to date of first documentation of progression or symptomatic deterioration, or death due to any cause, assessed up to 3 years
    Safety Issue:
    Description:Analysis of PFS will be conducted using the stratified log rank test upon the observation of 115 PFS events. PFS among patients who register to Arm 3 will be summarized using descriptive statistics.

    Secondary Outcome Measures

    Measure:Incidence of adverse events
    Time Frame:Up to 3 years
    Safety Issue:
    Description:Evaluated according to National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0.
    Measure:Overall response rate (ORR)
    Time Frame:Up to 3 years
    Safety Issue:
    Description:ORR including confirmed complete and partial responses per Response Evaluation Criteria in Solid Tumors 1.1 will be compared using using the Cochran-Mantel-Haenszel test. ORR among patients who register to Arm 3 will be summarized using descriptive statistics.
    Measure:Overall survival (OS)
    Time Frame:From date of registration to date of death due to any cause, assessed up to 3 years
    Safety Issue:
    Description:Distributions of OS in each arm will be estimated using the method of Kaplan-Meier and compared using the stratified log-rank test. OS among patients who register to Arm 3 will be summarized using descriptive statistics.

    Details

    Phase:Phase 2
    Primary Purpose:Interventional
    Overall Status:Recruiting
    Lead Sponsor:Southwest Oncology Group

    Last Updated

    January 2, 2018