Clinical Trials /

Biomarker Directed Treatment in Metastatic Colorectal Cancer

NCT01703390

Description:

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.

Related Conditions:
  • Colorectal Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Biomarker Directed Treatment in Metastatic Colorectal Cancer
  • Official Title: Pilot Study: Biomarker Directed Treatment in Metastatic Colorectal Cancer

Clinical Trial IDs

  • ORG STUDY ID: AGMT_ERCC1
  • SECONDARY ID: 2011-003217-41
  • NCT ID: NCT01703390

Conditions

  • Metastatic Colorectal Cancer

Interventions

DrugSynonymsArms
FOLFIRI + CetuximabERCC-1 high
modifiedFOLFOX6 + CetuximabERCC-1 low

Purpose

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.

Trial Arms

NameTypeDescriptionInterventions
ERCC-1 lowExperimentalmodifiedFOLFOX6 + 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
  • modifiedFOLFOX6 + Cetuximab
ERCC-1 highExperimentalFOLFIRI + 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
  • FOLFIRI + Cetuximab

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

Primary Outcome Measures

Measure:Response
Time Frame:5 years
Safety Issue:
Description:Treatment response according to Response Evaluation Criteria In Solid Tumors [RECIST]

Secondary Outcome Measures

Measure:Progression free survival (PFS)
Time Frame:5 years
Safety Issue:
Description:
Measure:Response rate
Time Frame:5 years
Safety Issue:
Description:Description of group differences between ERCC-1 low and ERCC-1 high patients with respect to response rate, PFS and OS
Measure:Patient characteristics
Time Frame:5 years
Safety Issue:
Description:Description of group differences between ERCC-1 low and ERCC-1 high patients with respect to KRAS status
Measure:Secondary resection rate
Time Frame:5 years
Safety Issue:
Description:
Measure:Molecular markers for toxicity
Time Frame:5 years
Safety Issue:
Description:
Measure:Number of adverse events during study treatment
Time Frame:5 years
Safety Issue:
Description:

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Arbeitsgemeinschaft medikamentoese Tumortherapie

Trial Keywords

  • metastatic colorectal cancer
  • mCRC
  • ERCC-1
  • ERCC1
  • AGMT

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