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Pertuzumab and Cetuximab in Treating Patients With Previously Treated Locally Advanced or Metastatic Colorectal Cancer

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ClinicalTrials.gov Identifier: NCT00551421
Recruitment Status : Completed
First Posted : October 31, 2007
Results First Posted : February 23, 2015
Last Update Posted : March 31, 2015
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Tracking Information
First Submitted Date  ICMJE October 30, 2007
First Posted Date  ICMJE October 31, 2007
Results First Submitted Date  ICMJE December 17, 2014
Results First Posted Date  ICMJE February 23, 2015
Last Update Posted Date March 31, 2015
Study Start Date  ICMJE October 2007
Actual Primary Completion Date November 2010   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: February 20, 2015)
  • Recommended Phase II Dose of Pertuzumab When Administered in Combination With Cetuximab (Phase I) [ Time Frame: 28 days ]
    The regimen was deemed intolerable so there was no recommended phase II dose.
  • Objective Tumor Response Rate Defined as the Proportion of Patients With a Best Overall Response of CR or PR, Per RECIST Criteria (Phase II) [ Time Frame: Best tumor response from time period of start of study treatment to study discontinuation. ]
    Objective tumor response rate defined as the proportion of patients with a best overall response of CR or PR, per RECIST criteria (Phase II).
Original Primary Outcome Measures  ICMJE
 (submitted: October 30, 2007)
  • Recommended phase II dose of pertuzumab when administered in combination with cetuximab and irinotecan
  • Objective tumor response rate
Change History Complete list of historical versions of study NCT00551421 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: February 20, 2015)
  • Progression-free Survival [ Time Frame: The duration of time from start of study treatment to time of objective disease progression or death. ]
    The duration of time from start of study treatment to time of objective disease progression or death.
  • Overall Survival [ Time Frame: The duration of time from start of study treatment to death from any cause. ]
    The duration of time from start of study treatment to death from any cause.
Original Secondary Outcome Measures  ICMJE
 (submitted: October 30, 2007)
  • Progression-free Survival
  • Overall Survival
  • Correlation of skin rash, objective tumor response on positron emission tomography (PET) scan after course two, and laboratory correlates with efficacy outcomes
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Pertuzumab and Cetuximab in Treating Patients With Previously Treated Locally Advanced or Metastatic Colorectal Cancer
Official Title  ICMJE A Phase I/II Trial of Pertuzumab in Combination With Cetuximab and Irinotecan in Previously Treated Metastatic Colorectal Cancer
Brief Summary Monoclonal antibodies, such as pertuzumab and cetuximab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Giving pertuzumab together with cetuximab may kill more tumor cells. This phase I/II trial is studying the side effects and best dose of pertuzumab when given together with cetuximab and to see how well they work in treating patients with previously treated locally advanced or metastatic colorectal cancer
Detailed Description

PRIMARY OBJECTIVES:

I. To determine the safety, tolerability, and recommended phase II dose of pertuzumab when administered in combination with cetuximab in patients with cetuximab-refractory locally advanced or metastatic colorectal cancer.

II. To evaluate the objective tumor response rate (RR) in patients treated with this regimen.

SECONDARY OBJECTIVES:

I. To evaluate the median progression-free survival (PFS) of patients treated with this regimen.

II. To evaluate the median overall survival (OS) of patients treated with this regimen.

III. To evaluate the RR, PFS, and OS in a subgroup of patients who are EGFR-positive by immunohistochemistry.

IV. To explore the relationship between skin rash and the efficacy outcomes of RR, PFS, and OS in these patients.

V. To explore the relationship between objective tumor response on positron emission tomography (PET) scan after course two and the efficacy outcomes of RR, PFS, and OS in these patients.

VI. To explore the relationship between a variety of laboratory correlates and the efficacy outcomes of RR, PFS, and OS in these patients.

OUTLINE: This is a multicenter, phase I dose-escalation study of pertuzumab followed by a phase II study.

PHASE I: Patients receive pertuzumab IV over 30-60 minutes on day 1. Patients also receive cetuximab IV over 60-120 minutes on days 2, 8, and 15 of course 1 and on days 1, 8, and 15 in all subsequent courses.

Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

PHASE II: Patients receive treatment as in phase I. Pertuzumab is administered at the recommended phase II dose (determined in phase I). Previously collected tumor tissue samples are analyzed for correlative studies. Samples are analyzed for KRAS mutations via polymerase chain reaction and pyrosequencing; EGFR expression via immunohistochemistry and fluorescent in situ hybridization (FISH); HER receptor and ligand gene expression; and circulating tumor cells. Additional blood samples are collected periodically to isolate circulating tumor cells and are analyzed via FISH analysis.

After completion of study treatment, patients are followed at 30 days and then periodically thereafter.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Adenocarcinoma of the Colon
  • Adenocarcinoma of the Rectum
  • Recurrent Colon Cancer
  • Recurrent Rectal Cancer
  • Stage III Colon Cancer
  • Stage III Rectal Cancer
  • Stage IV Colon Cancer
  • Stage IV Rectal Cancer
Intervention  ICMJE
  • Biological: pertuzumab
    Given IV
    Other Names:
    • 2C4 antibody
    • monoclonal antibody 2C4
    • Perjeta
    • rhuMAb-2C4
  • Biological: cetuximab
    Given IV
    Other Names:
    • C225
    • C225 monoclonal antibody
    • IMC-C225
    • MOAB C225
    • monoclonal antibody C225
  • Drug: irinotecan hydrochloride
    Given IV
    Other Names:
    • Campto
    • Camptosar
    • CPT-11
    • irinotecan
    • U-101440E
  • Other: immunohistochemistry staining method
    Correlative study
    Other Name: immunohistochemistry
  • Other: fluorescence in situ hybridization
    Correlative study
    Other Name: fluorescence in situ hybridization (FISH)
  • Other: gene expression analysis
    Correlative study
  • Other: mutation analysis
    Correlative study
  • Other: polymerase chain reaction
    Correlative study
    Other Name: PCR
  • Other: laboratory biomarker analysis
    Correlative study
Study Arms  ICMJE Experimental: Arm I

Phase I: Patients receive pertuzumab IV over 30-60 minutes on day 1. Patients also receive cetuximab IV over 60-120 minutes on days 2, 8, and 15 of course 1 and on days 1, 8, and 15 in all subsequent courses. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Phase II: Patients receive treatment as in phase I. Pertuzumab is administered at the recommended phase II dose (determined in phase I).

Interventions:
  • Biological: pertuzumab
  • Biological: cetuximab
  • Drug: irinotecan hydrochloride
  • Other: immunohistochemistry staining method
  • Other: fluorescence in situ hybridization
  • Other: gene expression analysis
  • Other: mutation analysis
  • Other: polymerase chain reaction
  • Other: laboratory biomarker analysis
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 Completed
Actual Enrollment  ICMJE
 (submitted: February 20, 2015)
17
Original Enrollment  ICMJE
 (submitted: October 30, 2007)
62
Actual Study Completion Date  ICMJE June 2012
Actual Primary Completion Date November 2010   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Patients with a history of colorectal cancer (CRC) treated by surgical resection and who develop radiological or clinical evidence of metastatic disease do not require separate histological or cytological confirmation of metastatic disease unless 1 of the following criteria are met:

    • More than 5 years has elapsed between the primary surgery and the development of metastatic disease
    • The primary cancer was stage I
  • Patients must have representative tumor specimens in paraffin blocks or at least 15 unstained slides with an associated pathology report obtained at any time prior to study entry:

    • Cytology specimens are not acceptable replacements
  • Patients must have their tumor tissue screened for KRAS mutation status, and be found to have a KRAS wild-type tumor:

    • No KRAS-mutated tumor
  • Locally advanced or metastatic disease
  • Not curable by surgery or amenable to radiotherapy with curative intent
  • Must have received an cetuximab-containing regimen for at least 6 weeks for treatment of metastatic disease
  • Documented progression of disease or intolerable toxicity during or within 3 months of receiving this regimen
  • Patients who have received an cetuximab-containing regimen as adjuvant therapy for resected stage II or III CRC are eligible provided recurrent disease is documented < 6 months after completion of adjuvant treatment
  • Must have received >= 1 prior chemotherapeutic regimen for treatment of metastatic disease with any of the following:

    • Cetuximab
    • Must have resolution of any skin rash related to prior treatment with cetuximab
    • No prior cetuximab which required a dose reduction for toxicity
    • 5-fluorouracil or capecitabine
    • Irinotecan hydrochloride or oxaliplatin
  • Measurable disease by CT scan or physical exam
  • ECOG performance status (PS) 0-1 (Karnofsky PS 70-100%)
  • Life expectancy > 12 weeks
  • Absolute neutrophil count >= 1,500/mcL
  • Platelet count >= 100,000/mcL
  • Leukocytes >= 3,000/mcL
  • Hemoglobin >= 9 g/dL (transfusion, erythropoietin, or other approved hematopoietic growth factors allowed)
  • Total bilirubin =< 1.5 times upper limit of normal (ULN)
  • AST and ALT =< 5 times ULN
  • Creatinine normal OR Creatinine clearance >= 60 mL/min
  • Not pregnant or nursing
  • Negative pregnancy test
  • Fertile patients must use effective contraception prior to and during study therapy
  • Cardiac left ventricular ejection fraction >= 50% OR >= lower limit of normal
  • No evidence of left ventricular wall motion abnormalities as measured by ECHO or MUGA scan
  • None of the following cardiac conditions:

    • Uncontrolled high blood pressure
    • Unstable angina
    • Symptomatic congestive heart failure
    • Congestive heart failure, cardiac dysfunction, or cardiomyopathy requiring medication treatment
    • Myocardial infarction within the past 6 months
    • Serious uncontrolled cardiac arrhythmia
    • New York Heart Association class III or IV heart disease
  • No active or uncontrolled infection
  • No predisposing colonic or small bowel disorders in which the symptoms are uncontrolled as indicated by baseline pattern of > 3 loose stools/day (in patients without a colostomy or ileostomy)
  • Patients with a colostomy or ileostomy may be eligible at investigator discretion
  • No psychiatric illness/social situation that would limit compliance with study requirements
  • No other prior or concurrent malignancy, except for adequately treated basal cell or squamous cell skin cancer, in situ carcinoma of the cervix, lobular carcinoma in situ in one breast, or other cancer from which the patient has been disease-free for at least 5 years
  • No other medical or psychiatric disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that may affect the interpretation of the study results or render the patient at high risk for treatment complications
  • No history of allergic reactions, hypersensitivity, or intolerance to cetuximab, and/or compounds of similar chemical or biologic composition to pertuzumab or cetuximab (i.e., other monoclonal antibodies such as bevacizumab) that led to discontinuation of the drug
  • Patients able to tolerate subsequent infusions after a reaction are eligible
  • At least 4 weeks since prior major surgery (e.g., laparotomy) and recovered (Insertion of a vascular access device is not considered major or minor surgery)
  • At least 2 weeks since prior minor surgery and recovered (Insertion of a vascular access device is not considered major or minor surgery)
  • At least 4 weeks since prior major radiotherapy (e.g., chest or bone palliative radiotherapy)
  • At least 4 weeks since prior bevacizumab
  • More than 4 weeks since prior chemotherapy (6 weeks for nitrosoureas or mitomycin C) and recovered
  • No prior agents directed against EGFR and/or HER2
  • No more than one prior treatment regimen for metastatic disease; Prior chemotherapy in the adjuvant setting following resection of stage II or III disease allowed provided the regimen did not contain irinotecan hydrochloride and/or an agent directed against EGFR and/or HER2
  • No prior doxorubicin or liposomal doxorubicin at doses > 360 mg/m^2; epirubicin at doses > 720 mg/m^2; mitoxantrone at doses > 120 mg/m^2; or idarubicin at doses > 90 mg/m^2
  • No prior radiotherapy to > 15% of the bone marrow
  • No prior standard adjuvant chemoradiotherapy for rectal cancer
  • No phenytoin, phenobarbital, carbamazepine, or any other enzyme-inducing anti-convulsant drugs (EIACDs) for at least 7 days before, during, and for 7 days after the final dose of irinotecan hydrochloride
  • Concurrent gabapentin or other non-EIACDs are allowed
  • No St. John's wort for at least 14 days before, during, and for 7 days after the final dose of irinotecan hydrochloride
  • No concurrent corticosteroids, except for stable doses of prednisone (< 20 mg/day or equivalent), topical or inhaled corticosteroids, or corticosteroids for reasons unrelated to treatment of colorectal cancer
  • No concurrent combination antiretroviral therapy for HIV-positive patients
  • No concurrent filgrastim (G-CSF) or sargramostim (GM-CSF) for any of the following reasons:

    • To avoid dose reductions or delays
    • Prophylactic treatment
    • Treatment of febrile neutropenia
  • No other concurrent HER family-targeted therapy
  • No concurrent rifampin
  • No concurrent herbal remedies unless initiated prior to study entry
  • No other concurrent investigational agents
  • No other concurrent anticancer therapy, including cytotoxic chemotherapy, radiotherapy, immunotherapy, hormonal therapy, or biological anticancer therapy
  • Histologically or cytologically confirmed adenocarcinoma of the colon or rectum
  • Site of the primary lesion must be or have been confirmed endoscopically, radiologically, or surgically to be or have been in the large bowel
  • No known brain metastases
  • No concurrent fluconazole
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 information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries Canada
 
Administrative Information
NCT Number  ICMJE NCT00551421
Other Study ID Numbers  ICMJE NCI-2009-00241
07-070
U01CA062490 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party National Cancer Institute (NCI)
Study Sponsor  ICMJE National Cancer Institute (NCI)
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Kimmie Ng Dana-Farber Cancer Institute
PRS Account National Cancer Institute (NCI)
Verification Date July 2014

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