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Irinotecan Hydrochloride, Fluorouracil, and Leucovorin Calcium With or Without Zibotentan in Treating Patients With Metastatic Colorectal Cancer (FOLFERA)

This study has been completed.
Information provided by (Responsible Party):
Dr Anne Thomas, Cardiff University Identifier:
First received: September 17, 2010
Last updated: July 7, 2014
Last verified: July 2014

RATIONALE: Drugs used in chemotherapy, such as irinotecan hydrochloride, fluorouracil, and leucovorin calcium, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Zibotentan may be effective in treating metastatic colorectal cancer that has not responded to oxaliplatin. It is not yet known whether combination chemotherapy is more effective when given with or without zibotentan in treating metastatic colorectal cancer.

PURPOSE: This randomized phase II trial is studying giving irinotecan hydrochloride together with fluorouracil and leucovorin calcium to see how well it works when given with or without zibotentan in treating patients with metastatic colorectal cancer.

Condition Intervention Phase
Colorectal Cancer
Drug: FOLFIRI regimen
Drug: fluorouracil
Drug: irinotecan hydrochloride
Drug: leucovorin calcium
Drug: zibotentan
Other: laboratory biomarker analysis
Other: pharmacogenomic studies
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double-Blind
Primary Purpose: Treatment
Official Title: A Randomized Phase II Study of Irinotecan, 5-Fluorouracil and Folinic Acid (FOLFIRI) With or Without the Addition of an Endothelin Receptor Antagonist in Patients With Metastatic Colorectal Cancer After Failure of Oxaliplatin-Containing Chemotherapy

Resource links provided by NLM:

Further study details as provided by Cardiff University:

Primary Outcome Measures:
  • Progression-free survival

Secondary Outcome Measures:
  • Tolerability (side effects) and feasibility of use (number of participants requiring dose delays or reductions and/or treatment withdrawal)
  • Objective response rate as assessed by RECIST criteria
  • Overall survival

Enrollment: 111
Study Start Date: April 2010
Study Completion Date: September 2012
Primary Completion Date: July 2011 (Final data collection date for primary outcome measure)
Detailed Description:



  • To establish the anti-tumor activity of the combination of irinotecan hydrochloride, fluorouracil, and leucovorin calcium (FOLFIRI) with zibotentan (FOLFERA) as measured by progression-free survival (time-to-event) in patients with metastatic colorectal cancer after failure of oxaliplatin-containing chemotherapy.


  • To determine the toxicity profile of FOLFERA and of maintenance zibotentan in these patients.
  • To determine the feasibility of use of this regimen in these patients.
  • To collect tumor and blood samples for future translational work, including investigating endothelian A receptor (ETAR) expression, k-RAS/b-RAF status and alterations in relevant pathways such as Akt, MAPK/ERK.

OUTLINE: This is a multicenter study. Patients are stratified according to study site. Patients are randomized to 1 of 2 treatment arms.

  • Arm A: Patients receive irinotecan hydrochloride IV over 1 hour and leucovorin calcium IV over 2 hours on day 1; fluorouracil IV over 46 hours beginning on day 1; and an oral placebo tablet once daily on days 1-14. Treatment repeats every 14 days for 12 courses in the absence of disease progression or unacceptable toxicity. Patients achieving at least stable disease then receive oral placebo alone once daily in the absence of disease progression or unacceptable toxicity.
  • Arm B: Patients receive irinotecan hydrochloride IV over 2 hours, leucovorin calcium IV over 2 hours on day 1; fluorouracil IV over 46 hours beginning on day 1; and oral zibotentan once daily on days 1-14. Treatment repeats every 14 days for 12 courses in the absence of disease progression or unacceptable toxicity. Patients achieving at least stable disease then receive oral zibotentan alone once daily in the absence of disease progression or unacceptable toxicity.

Blood and tissue samples are collected periodically for pharmacogenetic, translational, and biomarker correlative studies.

After completion of study therapy, patients are followed up at 30 days and then every 12 weeks for up to 1 year.

Peer Reviewed and Funded or Endorsed by Cancer Research UK


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


  • Histologically or cytologically confirmed colorectal cancer

    • Metastatic disease with no bone metastases
  • Must have progressed within 6 months of adjuvant oxaliplatin-containing chemotherapy and have no significant ongoing toxicity (excluding grade 1 neurotoxicity)
  • Measurable disease by RECIST criteria
  • No known brain or leptomeningeal metastases

    • Stable disease following surgical resection or radiosurgery of oligometastases allowed


  • ECOG performance status 0-1
  • Life expectancy ≥ 12 weeks
  • Hemoglobin ≥ 9.0 g/dL (no prior transfusion) OR ≥ 10.0 g/dL (transfusion within past 4 weeks)
  • Absolute neutrophil count ≥ 1.5 times 10^9/L
  • Platelet count ≥ 100 times 10^9/L
  • Total bilirubin < 1.5 times upper limit of normal (ULN)
  • AST and ALT ≤ 2.5 times ULN (≤ 5 times ULN with liver metastases)
  • Creatinine clearance ≥ 50 mL/min
  • Negative pregnancy test
  • Not pregnant or nursing
  • Fertile patients must use effective double-method contraception during and for 3 months (female) or 2 months (male) after completion of study treatment
  • No active infection or serious concurrent medical condition
  • No significant cardiovascular disease including any of the following:

    • History of NYHA class II-IV congestive heart failure requiring therapy
    • History of unstable angina pectoris or myocardial infarction within the past 6 months
    • Severe valvular heart disease
    • Ventricular arrhythmia requiring treatment
    • Prolonged QTc interval > 470 msec
  • No concurrent medical condition, that in the investigator's judgement, will substantially increase the risk associated with the patient's participation in the study, or potentially hamper compliance with the study protocol and follow-up schedule
  • No psychiatric disorders or altered mental status precluding understanding of the informed consent process and/or compliance with the study protocol
  • No gastrointestinal disorders likely to interfere with absorption of the study drug (e.g., partial bowel obstruction or malabsorption)
  • No known serological positivity for hepatitis B or hepatitis C
  • No immunocompromised patients (e.g., no known serological positivity for HIV)
  • No other prior or current malignant disease likely to interfere with protocol treatment or comparisons


  • See Disease Characteristics
  • No prior zibotentan or irinotecan hydrochloride
  • More than 4 weeks since prior chemotherapy, radiotherapy (except for palliative reasons), endocrine therapy, or immunotherapy
  • No more than 1 prior course of chemotherapy for metastatic disease
  • No prior extensive radiotherapy (i.e., likely to deplete bone marrow reserve)
  • At least 4 weeks since prior major surgery and recovered
  • Concurrent corticosteroids allowed provided the dose is stable for 4 weeks and not altered during the first 15 days of this study
  • No concurrent warfarin

    • Low molecular weight heparin allowed
  Contacts and Locations
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Please refer to this study by its identifier: NCT01205711

United Kingdom
Leicester Royal Infirmary
Leicester, England, United Kingdom, LE1 5WW
Centre for Cancer Research and Cell Biology at Queen's University Belfast
Belfast, Northern Ireland, United Kingdom, BT9 7AB
Wales Cancer Trials Unit
Cardiff, Wales, United Kingdom, CF11 9LJ
Velindre Cancer Center at Velindre Hospital
Cardiff, Wales, United Kingdom, CF14 2TL
Sponsors and Collaborators
Cardiff University
Principal Investigator: Anne Thomas, MD University Hospitals, Leicester
  More Information

Responsible Party: Dr Anne Thomas, Dr, Cardiff University Identifier: NCT01205711     History of Changes
Other Study ID Numbers: CDR0000685062
Study First Received: September 17, 2010
Last Updated: July 7, 2014

Keywords provided by Cardiff University:
recurrent colon cancer
stage IV colon cancer
recurrent rectal cancer
stage IV rectal cancer

Additional relevant MeSH terms:
Colorectal Neoplasms
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Digestive System Diseases
Gastrointestinal Diseases
Colonic Diseases
Intestinal Diseases
Rectal Diseases
Calcium, Dietary
Endothelin Receptor Antagonists
Molecular Mechanisms of Pharmacological Action
Antimetabolites, Antineoplastic
Antineoplastic Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Bone Density Conservation Agents
Antineoplastic Agents, Phytogenic
Topoisomerase I Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors processed this record on May 25, 2017