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
18 Years
N/A
Both
Colorectal Cancer
Trial Information
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
OBJECTIVES:
Primary
- 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.
Secondary
- 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
Inclusion Criteria
DISEASE CHARACTERISTICS:
- 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
PATIENT CHARACTERISTICS:
- 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
PRIOR CONCURRENT THERAPY:
- 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
Type of Study:
Interventional
Study Design:
Allocation: Randomized, Masking: Double-Blind, Primary Purpose: Treatment
Outcome Measure:
Progression-free survival
Safety Issue:
No
Principal Investigator
Anne Thomas, MD
Investigator Role:
Principal Investigator
Investigator Affiliation:
University Hospitals, Leicester
Authority:
Unspecified
Study ID:
CDR0000685062
NCT ID:
NCT01205711
Start Date:
April 2010
Completion Date:
Related Keywords:
- Colorectal Cancer
- recurrent colon cancer
- stage IV colon cancer
- recurrent rectal cancer
- stage IV rectal cancer
- Colorectal Neoplasms
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