Biomarker Directed Treatment in Metastatic Colorectal Cancer

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

Study Description

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

Study Design

• 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

Arms and Interventions

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

Outcome Measures

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 ]

Eligibility Criteria

• 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.

Contacts and Locations

Locations

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

• Principal Investigator: Thomas Winder, MD; LKH Feldkirch, Interne E

More Information

• 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
• 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:

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