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

Sponsor

Cardiff University (Other)

Overall Status

Completed

CT.gov ID

NCT01205711

Collaborator

(none)

111

Enrollment

Locations

Duration (Months)

27.8

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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 or Disease	Intervention/Treatment	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

Detailed Description

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

Study Design

Study Type:

Interventional

Actual Enrollment :

111 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Double

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

Study Start Date :

Apr 1, 2010

Actual Primary Completion Date :

Jul 1, 2011

Actual Study Completion Date :

Sep 1, 2012

Outcome Measures

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 []

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Leicester Royal Infirmary	Leicester	England	United Kingdom	LE1 5WW
2	Centre for Cancer Research and Cell Biology at Queen's University Belfast	Belfast	Northern Ireland	United Kingdom	BT9 7AB
3	Wales Cancer Trials Unit	Cardiff	Wales	United Kingdom	CF11 9LJ
4	Velindre Cancer Center at Velindre Hospital	Cardiff	Wales	United Kingdom	CF14 2TL