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Biomarker Directed Treatment in Metastatic Colorectal Cancer

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. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT01703390
Recruitment Status : Completed
First Posted : October 10, 2012
Last Update Posted : December 21, 2020
Sponsor:
Collaborator:
Merck Sharp & Dohme LLC
Information provided by (Responsible Party):
Arbeitsgemeinschaft medikamentoese Tumortherapie

Brief Summary:
This pilot study is being mounted to assess whether treatment assignment by ERCC-1 gene expression status suggests better clinical results from historical experience in metastatic colorectal cancer (mCRC). In wild type KRAS mCRC patients treated with either FOLFOX or FOLFIRI in combination with cetuximab the median response rate is approximately 60-65%. Biomarker directed treatment in this study may demonstrate that patients with low ERCC-1 treated with FOLFOX and cetuximab, and those with high ERCC-1 treated with FOLFIRI and cetuximab, will improve response rate to 70-75%. KRAS wild type patients will be treated with 6 cycles of one of the following regimens chosen for optimization based on patient characteristics (primary treatment phase). Patients with ERCC-1 < 1.7 relative gene expression of ERCC-1 over ß-actin (ERCC-1 low) will be assigned to treatment with mFOLFOX6 in combination with Cetuximab. Patients with ERCC-1 gene expression > 1.7 relative gene expression of ERCC-1 over over ß-actin (ERCC-1 high) will be assigned to treatment with FOLFIRI in combination with Cetuximab.

Condition or disease Intervention/treatment Phase
Metastatic Colorectal Cancer Drug: FOLFIRI + Cetuximab Drug: modifiedFOLFOX6 + Cetuximab Phase 2

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 47 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Pilot Study: Biomarker Directed Treatment in Metastatic Colorectal Cancer
Actual Study Start Date : December 4, 2012
Actual Primary Completion Date : February 23, 2018
Actual Study Completion Date : July 3, 2020

Resource links provided by the National Library of Medicine

Drug Information available for: Cetuximab

Arm Intervention/treatment
Experimental: ERCC-1 low
modifiedFOLFOX6 + Cetuximab oxaliplatin 85 mg/m2 on day 1, 15 q d29 for 6 cycles folinic acid (FA) 400 mg/m2 on days 1 and 15 and q d29 for 6 cycles fluorouracil (5-FU) 400 mg/m2 bolus day 1 + 2400 mg/m2 46-hour infusion on days 1, 2 and 15, 16 and q d29 for 6 cycles or until unacceptable toxicity Cetuximab will be administered as a 120- minute intravenous infusion at 500 mg/m2 on day 1 then 500 mg/m2 bi-weekly
Drug: modifiedFOLFOX6 + Cetuximab
Experimental: ERCC-1 high
FOLFIRI + Cetuximab irinotecan 180 mg/m² on day 1, 15 q d29 for 6 cycles folinic acid (FA)400 mg/m2 on days 1 and 15 and q d29 for 6 cycles fluorouracil (5-FU) 400 mg/m2 bolus + 2400 mg/m2 46-hour infusion on days 1, 2 and 15, 16 and q d29 for 6 cycles or until unacceptable toxicity Cetuximab will be administered as a 120- minute intravenous infusion at 500 mg/m2 on day 1 then 500 mg/m2 bi-weekly
Drug: FOLFIRI + Cetuximab



Primary Outcome Measures :
  1. Response [ Time Frame: 5 years ]
    Treatment response according to Response Evaluation Criteria In Solid Tumors [RECIST]


Secondary Outcome Measures :
  1. Progression free survival (PFS) [ Time Frame: 5 years ]
  2. Response rate [ Time Frame: 5 years ]
    Description of group differences between ERCC-1 low and ERCC-1 high patients with respect to response rate, PFS and OS

  3. Patient characteristics [ Time Frame: 5 years ]
    Description of group differences between ERCC-1 low and ERCC-1 high patients with respect to KRAS status

  4. Secondary resection rate [ Time Frame: 5 years ]
  5. Molecular markers for toxicity [ Time Frame: 5 years ]
  6. Number of adverse events during study treatment [ Time Frame: 5 years ]


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

1.1 Inclusion criteria for pre-screening phase:

  • Untreated advanced metastatic colorectal cancer patients
  • Adequate tissue to evaluate for genotyping (10 x 10µm thick formalin fixed paraffin embedded tissue sections and one corresponding HE stained slide or a FFPE tumor block)

1.2 Inclusion criteria for treatment phase:

Patients must fulfill all criteria listed below prior to enrolment in the study:

  • Untreated wild-type KRAS metastatic colorectal cancer
  • Previous adjuvant therapy must have been completed > 6 months before therapy initiation on this study
  • Age >18 years
  • Measureable disease with CT or MRI
  • ECOG performance status of 0-2
  • Adequate organ function

    • Hematologic:

      • Absolute neutrophil count > 1,500/µL
      • Hemoglobin >9 mg/dl
      • Platelet count >100,000 /µl
    • Renal:

      • Serum creatinine <1.5 x Upper limit of normal (UPN) or estimated clearance > 30 ml/min
    • Hepatic:

      • Serum bilirubin < 1.5 mg/dl

Exclusion Criteria:

  • Creatinine clearance below 30 ml/min
  • Patients with a history of other malignancies within 2 years prior to study entry, except for adequately treated carcinoma in situ of the cervix; basal or squamous cell skin cancer; low grade, early stage localized prostate cancer treated surgically with curative intent; good prognosis DCIS of the breast treated with lumpectomy alone with curative intent.
  • Patients with a history of severe cardiac disease; e.g. NYHA Functional Class III or IV heart failure, myocardial infarction within 6 months, ventricular tachyarrhythmias requiring ongoing treatment, or unstable angina.
  • Other known co-morbidity with the potential to dominate survival
  • Hypersensitivity with anaphylactic reaction to humanized monoclonal antibodies or any of the applied drugs
  • Pregnant or breast feeding women
  • Any co-existing medical or psychological condition that would preclude participation in the study or compromise ability to give informed consent.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01703390


Locations
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Austria
KUK Linz - Med Campus III.: Univ.-Klinik für Hämatologie und Internistische Onkologie
Linz, Oberösterreich, Austria, 4021
A.ö. Bezirkskrankenhaus Kufstein, Innere Medizin / Hämatologie / Onkologie
Kufstein, Tirol, Austria, 6330
LKH Feldkirch, Interne E
Feldkirch, Vorarlberg, Austria, 6807
LKH Bludenz Innere Medizin
Bludenz, Austria, 6700
LKH Bregenz
Bregenz, Austria, 6900
KH Dornbirn, Innere Medizin
Dornbirn, Austria, 6850
Universitätsklinikum Graz
Graz, Austria, 8036
LKH Hohenems, Interne Intensivmedizin
Hohenems, Austria, 6845
Krankenhaus d. Barmherzigen Schwestern Linz
Linz, Austria, A-4010
Universitätsklinik für Innere Medizin III mit Hämatologie, internistischer Onkologie, Infektologie, Rheumatologie und Onkologisches Zentrum
Salzburg, Austria, 5020
Medizinische Universität Wien, Univ.Klinik für Innere Medizin I, Abteilung für Onkologie
Vienna, Austria, 1090
Sponsors and Collaborators
Arbeitsgemeinschaft medikamentoese Tumortherapie
Merck Sharp & Dohme LLC
Investigators
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Principal Investigator: Thomas Winder, MD LKH Feldkirch, Interne E
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Responsible Party: Arbeitsgemeinschaft medikamentoese Tumortherapie
ClinicalTrials.gov Identifier: NCT01703390    
Other Study ID Numbers: AGMT_ERCC1
2011-003217-41 ( EudraCT Number )
First Posted: October 10, 2012    Key Record Dates
Last Update Posted: December 21, 2020
Last Verified: December 2020
Keywords provided by Arbeitsgemeinschaft medikamentoese Tumortherapie:
metastatic colorectal cancer
mCRC
ERCC-1
ERCC1
AGMT
Additional relevant MeSH terms:
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Colorectal Neoplasms
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Neoplasms
Digestive System Diseases
Gastrointestinal Diseases
Colonic Diseases
Intestinal Diseases
Rectal Diseases
Cetuximab
Antineoplastic Agents, Immunological
Antineoplastic Agents