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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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03365882
Recruitment Status : Recruiting
First Posted : December 7, 2017
Last Update Posted : February 28, 2020
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Southwest Oncology Group

Tracking Information
First Submitted Date  ICMJE October 2, 2017
First Posted Date  ICMJE December 7, 2017
Last Update Posted Date February 28, 2020
Actual Study Start Date  ICMJE October 9, 2017
Estimated Primary Completion Date April 1, 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: December 1, 2017)
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 ]
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.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: December 1, 2017)
  • Incidence of adverse events [ Time Frame: Up to 3 years ]
    Evaluated according to National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0.
  • Overall response rate (ORR) [ Time Frame: Up to 3 years ]
    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.
  • Overall survival (OS) [ Time Frame: From date of registration to date of death due to any cause, assessed up to 3 years ]
    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.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures
 (submitted: December 1, 2017)
  • Association between HER-2 gene copy number (GCN) and PFS [ Time Frame: Up to 3 years ]
    The associations between GCN and PFS will be explored via Kaplan-Meier curves and Cox regression.
  • Association between HER-2 gene copy number (GCN) and response [ Time Frame: Up to 3 years ]
    The associations between GCN and response will be explored via logistic regression.
  • Association between HER-2/CEP17 signal ratio and PFS [ Time Frame: Up to 3 years ]
    The associations between HER-2/CEP17 signal ratio and PFS will be explored via Kaplan-Meier curves and Cox regression.
  • Association between HER-2/CEP17 signal ratio and response [ Time Frame: Up to 3 years ]
    The associations between HER-2/CEP17 signal ratio and response will be explored via Logistic regression.
Original Other Pre-specified Outcome Measures Same as current
 
Descriptive Information
Brief Title  ICMJE 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  ICMJE 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
Brief Summary 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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • 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
Intervention  ICMJE
  • Biological: Cetuximab
    Given IV
    Other Names:
    • Chimeric Anti-EGFR Monoclonal Antibody
    • Chimeric MoAb C225
    • Chimeric Monoclonal Antibody C225
    • Erbitux
    • IMC-C225
  • Drug: Irinotecan Hydrochloride
    Given IV
    Other Names:
    • Campto
    • Camptosar
    • Camptothecin 11
    • Camptothecin-11
    • CPT 11
    • CPT-11
    • Irinomedac
    • U-101440E
  • Other: Laboratory Biomarker Analysis
    Correlative studies
  • Biological: Pertuzumab
    Given IV
    Other Names:
    • 2C4
    • 2C4 Antibody
    • MoAb 2C4
    • Monoclonal Antibody 2C4
    • Perjeta
    • rhuMAb2C4
    • RO4368451
  • Biological: Trastuzumab
    Given IV
    Other Names:
    • ABP 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-05280014
  • Device: HER-2 testing
    Central testing of HER-2 for eligibility
Study Arms  ICMJE
  • Experimental: Arm I (pertuzumab, trastuzumab)
    Patients 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.
    Interventions:
    • Other: Laboratory Biomarker Analysis
    • Biological: Pertuzumab
    • Biological: Trastuzumab
    • Device: HER-2 testing
  • Experimental: Arm II (cetuximab, irinotecan hydrochloride)
    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.
    Interventions:
    • Biological: Cetuximab
    • Drug: Irinotecan Hydrochloride
    • Other: Laboratory Biomarker Analysis
    • Device: HER-2 testing
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: December 1, 2017)
130
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE June 15, 2023
Estimated Primary Completion Date April 1, 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Danae Campos 2106148808 ext 1022 dcampos@swog.org
Contact: Dana Sparks 2106148808 ext 1004 dsparks@swog.org
Listed Location Countries  ICMJE Puerto Rico,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03365882
Other Study ID Numbers  ICMJE S1613
NCI-2016-01422 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
S1613
S1613 ( Other Identifier: SWOG )
S1613 ( Other Identifier: CTEP )
U10CA180888 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: Yes
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Southwest Oncology Group
Study Sponsor  ICMJE Southwest Oncology Group
Collaborators  ICMJE National Cancer Institute (NCI)
Investigators  ICMJE
Principal Investigator: Kanwal Raghav Southwest Oncology Group
PRS Account Southwest Oncology Group
Verification Date February 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP