Biomarker Directed Treatment in Metastatic Colorectal Cancer

• Sponsor: Arbeitsgemeinschaft medikamentoese Tumortherapie
• Collaborator: Merck Sharp & Dohme Corp.
• 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)
• Estimated Enrollment: 30 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
• Study Start Date: August 2012
• Estimated Primary Completion Date: August 2019
• Estimated Study Completion Date: December 2019

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

Contacts

Contact: Richard Greil, MD; 004357255 ext 25801; r.greil@salk.at

Locations

Austria

AKH Linz, Innere Medizin 3, Zentrum für Hämatologie und medizinische Onkologie; Recruiting

Linz, Oberösterreich, Austria, 4021

Principal Investigator: Michael Fridrik, MD

A.ö. Bezirkskrankenhaus Kufstein, Innere Medizin / Hämatologie / Onkologie; Recruiting

Kufstein, Tirol, Austria, 6330

Principal Investigator: August Zabernigg, MD

LKH Feldkirch, Interne E; Recruiting

Feldkirch, Vorarlberg, Austria, 6807

Principal Investigator: Thomas Winder, MD

LKH Bludenz Innere Medizin; Recruiting

Bludenz, Austria, 6700

Principal Investigator: Othmar Thurnes, MD

LKH Bregenz; Recruiting

Bregenz, Austria, 6900

Principal Investigator: Franz X Schmid, Dr

KH Dornbirn, Innere Medizin; Recruiting

Dornbirn, Austria, 6850

Principal Investigator: Guntram Winder, MD

Universitätsklinikum Graz; Recruiting

Graz, Austria, 8036

Principal Investigator: Helmuth Samonigg, MD

LKH Hohenems, Interne Intensivmedizin; Recruiting

Hohenems, Austria, 6845

Principal Investigator: Günter Höfle, MD

Krankenhaus d. Barmherzigen Schwestern Linz; Recruiting

Linz, Austria, A-4010

Principal Investigator: Andreas Petzer, MD

Universitätsklinik für Innere Medizin III mit Hämatologie, internistischer Onkologie, Infektologie, Rheumatologie und Onkologisches Zentrum; Recruiting

Salzburg, Austria, 5020

Principal Investigator: Richard Greil, MD

Medizinische Universität Wien, Univ.Klinik für Innere Medizin I, Abteilung für Onkologie; Recruiting

Vienna, Austria, 1090

Principal Investigator: Gerald Prager, MD

Sponsors and Collaborators

Arbeitsgemeinschaft medikamentoese Tumortherapie

Merck Sharp & Dohme Corp.

Investigators

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

More Information

• Responsible Party: Arbeitsgemeinschaft medikamentoese Tumortherapie
• ClinicalTrials.gov Identifier: NCT01703390 History of Changes
• Other Study ID Numbers: AGMT_ERCC1; 2011-003217-41 ( EudraCT Number )
• First Posted: October 10, 2012
• Last Update Posted: January 14, 2019
• Last Verified: January 2019

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