Fluorouracil and Oxaliplatin With or Without Panitumumab In Treating Patients With High-Risk Colon Cancer That Can Be Removed by Surgery

Colorectal Cancer Clinical Trial

— FOxTROT  

Official title:

FOxTROT - Fluoropyrimidine, Oxaliplatin and Targeted Receptor Pre-Operative Therapy: a Controlled Trial in High-Risk Operable Colon Cancer

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT00647530
• Other study ID #: BCTU-FOXTROT-001
• Secondary ID: CDR0000590089ISC
• Status: Active, not recruiting
• Phase: Phase 2/Phase 3
• Start date: May 15, 2008
• Est. completion date: December 31, 2019

Study information

• Verified date: May 2019
• Source: University of Birmingham
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

RATIONALE: Drugs used in chemotherapy, such as fluorouracil and oxaliplatin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Monoclonal antibodies, such as panitumumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Giving chemotherapy before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed. Giving chemotherapy after surgery may kill any tumor cells that remain after surgery. It is not yet known whether chemotherapy is more effective with or without panitumumab in treating patients with colon cancer.

PURPOSE: This randomized phase III trial assessing whether preoperative chemotherapy and/or an anti-EGFR monoclonal antibody improve outcome in high risk operable colon cancer.

Description:

FOxTROT is a multi-centre randomised controlled trial (RCT) with the following objectives:

Primary objectives:

• To determine if neoadjuvant chemotherapy with or without panitumumab followed by deferred surgery and completion of chemotherapy postoperatively can reduce the 2-year recurrence as compared to surgery and postoperative chemotherapy with or without panitumumab.

• To determine if, in patients with RAS-wt tumours, adding panitumumab to neoadjuvant therapy increases anti-tumour activity as measured by tumour shrinkage.

Secondary

• To assess the accuracy of pre-treatment CT scan staging.

• To assess the tolerability of the neoadjuvant therapies.

• To assess the nature and frequency of surgical complications.

• To measure the impact of the treatments on quality of life and on resource usage.

• To assess whether adding panitumumab to neoadjuvant CT reduces 2-year recurrence

• To assess the prognostic and predictive value of tumour biomarkers

• To assess the influence of resectional quality on outcome

OUTLINE: This is a multicenter study. Patients are stratified according to age (< 50 year vs 50-59 years vs 60-69 years vs ≥ 70 years), radiological T-stage (T3 vs T4), radiological nodal status (Nx vs N0 vs N1 vs N2), site of primary tumor, proposed chemotherapy (OxMdG vs OxCap), and defunctioning colostomy (yes vs no). Planned chemo duration 12 or 24 weeks.

Patients receive 1 of the 2 following treatment regimens:

• OxMdG: Patients receive oxaliplatin IV and folinic acid IV over 2 hours followed by fluorouracil IV continuously over 46 hours on day 1 for 1 course.

• OxCap: Patients receive oxaliplatin IV over 2 hours on day 1 and oral capecitabine twice daily on days 1-15 for 1 course.

Patients are randomized to 1 of 2 treatment arms.

• Neoadjuvant therapy:

• Arm I: Patients receive 1 of the following chemotherapy regimens:

• OxMdG: Patients receive oxaliplatin IV over 2 hours and fluorouracil IV continuously over 46 hours on day 1. Treatment repeats every 2 weeks for 3 courses in the absence of disease progression or unacceptable toxicity.

• OxCap: Patients receive oxaliplatin IV over 2 hours on day 1 and oral capecitabine twice daily on days 1-15. Treatment repeats every 3 weeks for 2 courses in the absence of disease progression or unacceptable toxicity.

• Arm II: Patients receive the following regimen:

• OxMdG + panitumumab: Patients receive panitumumab IV over 60 minutes on day 1 followed by oxaliplatin IV over 2 hours and fluorouracil IV continuously over 46 hours on day 1. Treatment repeats every 2 weeks for 3 courses in the absence of disease progression or unacceptable toxicity.

Approximately 52 days after beginning chemotherapy, patients in both arms proceed to surgery.

• Surgery: Patients in both arms undergo surgical resection of the primary tumour.

• Adjuvant therapy: Beginning 4-8 weeks after completion of surgery, patients receive adjuvant treatment on the same arm for which they received neoadjuvant therapy.

• Patients receive either nine 2-week courses of OxMdG therapy or six 3-week courses of OxCap therapy.

Tumour tissue is collected during surgery and blood samples are collected periodically for biomarker studies. Samples are analyzed for the detection of KRAS and NRAS mutations; the detection of EGFR expression and/or functional genetic polymorphisms of the EGFR gene via PCR; the detection of copy number EGFR gene amplification via fluorescence in situ hybridization (FISH); the detection of EGFR activation via immunohistochemistry (IHC); the detection of EGFR by downstream parameters via western blotting and/or gene expression microarray techniques; for proteomics; and for epigenetics.

Patients complete quality of life questionnaires prior to surgery, before first course of postoperative chemotherapy, and at 1 year following randomization.

After completion of study treatment, patients are followed every 6 months for 3 years and then annually thereafter.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 1053
• Est. completion date: December 31, 2019
• Est. primary completion date: December 23, 2016
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

INCLUSION CRITERIA

• Histologically proven adenocarcinoma of the colon or high grade dysplasia on histology plus unequivocal radiological evidence of invasive cancer.

• A candidate for adjuvant oxaliplatin/ fluoropyrimidine chemotherapy based on:

• Either radiological high risk (rT4 or rT3 tumour with extramural extension = 5mm)

• Or radiological intermediate risk (rT3 tumour with <5mm extramural extension) and younger age/good general health

• Patients presenting with acute colonic obstruction may enter the trial only after obstruction is relieved by a successful defunctioning stoma, and when recovered to a fitness level consistent with the other eligibility criteria

• Adequate full blood count: WBC >3.0 x109/l; Plts >100 x109/l. Anaemia (Hb < 10.0 g/dl) is not an exclusion, but should be corrected by transfusion prior to surgery and chemotherapy. If Hb remains low despite transfusions, surgery and chemotherapy can be given at the decision of the surgical and oncology teams.

• Adequate renal biochemistry: GFR >50 ml/min calculated by the Wright or Cockroft formula or EDTA clearance >70 ml/min

• Adequate hepatobiliary function: bilirubin < 25 µmol/l (Patients with Gilbert's syndrome who have raised bilirubin but otherwise normal liver function tests are eligible for the study.)

• Aged 18 or over

• WHO performance status of 0, 1 or 2

• If female and of childbearing potential, must:

• Have a negative pregnancy test =72hours prior to initiating study treatment

• Agree to avoid pregnancy during and for 6 months after study treatment

• If male with a partner of childbearing potential, must:

• Agree to use adequate, medically approved, contraceptive precautions during and for 90 days after the last dose of study treatment

• Patient able and willing to provide written informed consent for the study

EXCLUSION CRITERIA

• Any patient for whom radiotherapy is advised by the MDT

• Strong evidence of distant metastases or peritoneal nodules (M1)

• Peritonitis (secondary to perforated tumour)

• Colonic obstruction that has not been defunctioned

• Serious medical comorbidity, eg uncontrolled inflammatory bowel disease, uncontrolled angina or recent (<6 months) MI

• Another serious medical condition judged to compromise ability to tolerate neoadjuvant therapy and/or surgery

• Any other malignant disease within the preceding 5 years with the exception of non-melanomatous skin cancer, carcinoma in situ and early stage disease with a recurrence risk <5%

ADDITIONAL EXCLUSION CRITERIA FOR PANITUMUMAB RANDOMISATION

• RAS-mutant or unknown RAS status tumours

• Allocated post-operative chemotherapy

• History of interstitial pneumonitis or pulmonary fibrosis

• History of severe or life-threatening hypersensitivity reactions

• Serum magnesium levels within the normal range at trial entry (which can include intravenous correction)

Related Conditions & MeSH terms

• Colonic Neoplasms
• Colorectal Cancer
• Colorectal Neoplasms

Intervention

Biological:
• panitumumab

Drug:
• capecitabine

• fluorouracil

• oxaliplatin

Locations

Country	Name	City	State
United Kingdom	Queen Elizabeth Hospital at University Hospital of Birmingham NHS Trust	Birmingham	England
United Kingdom	Birmingham Clinical Trials Unit	Birmingham,	England
United Kingdom	Queen Elizabeth Hospital	Gateshead	England
United Kingdom	Huddersfield Royal Infirmary	Huddersfield, West Yorks	England
United Kingdom	Royal Lancaster Infirmary	Lancaster	England
United Kingdom	Leeds Cancer Centre at St. James's University Hospital	Leeds	England
United Kingdom	Derriford Hospital	Plymouth	England
United Kingdom	Southport and Formby District General Hospital	Southport	England
United Kingdom	Sandwell General Hospital	West Bromwich	England
United Kingdom	Clatterbridge Centre for Oncology	Wirral	England

Sponsors (1)

Lead Sponsor	Collaborator
University of Birmingham

Country where clinical trial is conducted

United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Freedom from recurrence or persistent disease (including failure of macroscopic disease clearance at primary surgery) within the first two years following randomization		2 year post randomization
Primary	Pathological down-staging as measured by depth of extramural spread among patients allocated to preoperative chemotherapy with or without panitumumab		Time of surgery
Secondary	Death from colon cancer		2 years
Secondary	Overall survival		2 years
Secondary	Freedom from recurrence or persistent disease at 2 years (panitumumab comparison)		2 years
Secondary	Pathological assessment of downstaging (involvement of lymph nodes, serosa, and resection margin) and quality of resection specimen		at surgery
Secondary	Quality of resection specimen and distance to high-tie		post surgery
Secondary	Radiological assessment of response to neoadjuvant treatment		prior to surgery
Secondary	Quality of life by EORTC QLQ C-30 and EuroQol EQ-5D		before surgery, before 1st post-op chemo, 1 year post randomization
Secondary	Lenght of hospital stay		post surgery
Secondary	Surgical morbidity/mortality		30 days post surgery
Secondary	Chemotherapy toxicity		during chemotherapy administration
Secondary	Adverse events		throughout the trial, up to 2 years

External Links

•   Feasibility of preoperative chemotherapy for locally advanced, operable colon cancer: the pilot phase of a randomised controlled trial. Lancet Oncol. 2012 Nov;13(11):1152-60. doi: 10.1016/S1470-2045(12)70348-0. Epub 2012 Sep 25.
•   FOxTROT website