Irinotecan With or Without Panitumumab or Cyclosporine in Treating Patients With Advanced or Metastatic Colorectal Cancer That Did Not Respond to Fluorouracil

NCT ID: NCT00389870

Last Updated: 2022-06-01

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 1198 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2006-12-31

Brief Summary

RATIONALE: Drugs used in chemotherapy, such as irinotecan, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Cyclosporine may help irinotecan work better by making tumor cells more sensitive to the drug. 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. Panitumumab may also stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. It is not yet known whether irinotecan is more effective when given with or without panitumumab or cyclosporine in treating colorectal cancer.

PURPOSE: This randomized phase III trial is studying irinotecan to compare how well it works when given with or without panitumumab or cyclosporine in treating patients with advanced or metastatic colorectal cancer that did not respond to fluorouracil.

Detailed Description

OBJECTIVES:

Primary

• Compare the efficacy and toxicity of single-agent irinotecan hydrochloride (Ir) vs Ir with cyclosporine (IrC) in patients with fluorouracil-resistant advanced colorectal cancer.
• Compare the efficacy of single-agent Ir vs Ir with panitumumab (IrP) in these patients.

Secondary

• Correlate the toxicity of Ir and/or IrC with genetic variability in the enzymes involved in irinotecan hydrochloride's disposition pathway.
• Compare IrC to Ir and its metabolites (SN38; SN38G), in terms of pharmacokinetic profile.
• Correlate the benefit of IrP with tumor expression of epidermal growth factor receptor (EGFR) or its known down-stream molecules as a predictive measure.
• Correlate IrP efficacy or toxicity (specifically the severity of skin rash) with somatic alterations in the EGFR gene and/or with germline variability in related genes.

OUTLINE: This is a randomized, open-label, controlled, multicenter study. Patients are stratified according to prior cetuximab (yes vs no). Patients are randomized to 1 of 3 treatment arms.

• Arm I: Patients receive irinotecan hydrochloride IV over 30-90 minutes on day 1.
• Arm II: Patients receive irinotecan hydrochloride IV over 15-40 minutes on day 1 and oral cyclosporine three times a day on days 1-3.
• Arm III: Patients receive panitumumab IV over 30-90 minutes followed by irinotecan hydrochloride IV over 30-90 minutes on day 1. Single-agent panitumumab may be continued during breaks in chemotherapy treatment.

In all arms, treatment repeats every 3 weeks for 4 courses in the absence of disease progression or unacceptable toxicity. Patients with responding or stable disease may continue treatment in the absence of disease progression or unacceptable toxicity.

Quality of life is assessed at baseline and at 12 and 24 weeks.

After completion of study treatment, patients are followed every 12 weeks for 1 year.

Peer Reviewed and Funded or Endorsed by Cancer Research UK

PROJECTED ACCRUAL: A total of 1,269 patients will be accrued for this study.

Conditions

Colorectal Cancer

Study Design

• Allocation Method: RANDOMIZED
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Interventions

panitumumab

Intervention Type: BIOLOGICAL

cyclosporine

Intervention Type: DRUG

irinotecan hydrochloride

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

DISEASE CHARACTERISTICS:

• Diagnosis of colorectal adenocarcinoma meeting 1 of the following criteria:

• Previous or current histologically confirmed primary adenocarcinoma of the colon or rectum and clinical/radiological evidence of advanced or metastatic disease
• Histologically or cytologically confirmed metastatic adenocarcinoma with clinical or radiological evidence of colorectal primary tumor
• Unidimensionally measurable disease
• Disease progression during or after prior fluorouracil with or without oxaliplatin therapy and/or with or without bevacizumab

• Adjuvant therapy and/or prior therapy for advanced disease allowed
• No clinical or radiological evidence of pleural effusion or ascites causing ≥ grade 2 dyspnea
• No clinical or radiological evidence of biliary obstruction
• No known CNS metastases or carcinomatous meningitis

PATIENT CHARACTERISTICS:

• WHO performance status 0-2
• Life expectancy ≥ 12 weeks
• Hemoglobin > 10.0 g/dL
• WBC > 3,000/mm³
• Platelet count > 100,000/mm³
• Glomerular filtration rate > 50 mL/min OR EDTA clearance > 60 mL/min
• Bilirubin < 1.46 mg/dL
• Alkaline phosphatase ≤ 5 times upper limit of normal (ULN)
• AST and ALT ≤ 2.5 times ULN
• No history of Gilbert's syndrome
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception during and for 6 months after completion of study treatment
• Capable of completing quality of life questionnaires
• No prior anaphylactic allergic reaction to cetuximab
• No other prior or concurrent cancer (excluding nonmelanomatous skin cancer)
• No unresolved bowel obstruction, uncontrolled gastrointestinal infection, chronic enteropathy (e.g., Crohn's disease or ulcerative colitis), or chronic diarrhea (≥ 4 stools per day) of any cause
• No recent history of seizures
• No clinical or radiological evidence of interstitial pneumonitis or pulmonary fibrosis,
• Capable of reliable oral self-medication
• No other condition that would make the patient unsuitable for participation in this study

PRIOR CONCURRENT THERAPY:

• See Disease Characteristics
• No major thoracic or abdominal surgery within the past 4 weeks
• No systemic anticancer therapy within the past 3 weeks
• No prior irinotecan hydrochloride
• No grapefruit juice within 3 days before and after each chemotherapy treatment
• No experimental drug therapy or antibody therapy, other than cetuximab, within the past 6 weeks
• No systemic chemotherapy and/or cetuximab within the past 3 weeks
• No antifungals or antibiotics within the past 5 days
• No ongoing requirement for cyclosporine or any other medication including, but not limited to, the following:

• Ketoconazole, fluconazole, itraconazole
• Erythromycin, clarithromycin, norfloxacin
• Diltiazem hydrochloride, verapamil, amiodarone hydrochloride
• Fluvoxamine

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 120 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

University of Leeds

OTHER

Sponsor Role: lead

Principal Investigators

Matthew T. Seymour, MA, MD, FRCP

Role: STUDY_CHAIR

Cookridge Hospital

Locations

Royal Bournemouth Hospital

Bournemouth, England, United Kingdom

Sussex Cancer Centre at Royal Sussex County Hospital

Brighton, England, United Kingdom

Bristol Haematology and Oncology Centre

Bristol, England, United Kingdom

Addenbrooke's Hospital

Cambridge, England, United Kingdom

Gloucestershire Oncology Centre at Cheltenham General Hospital

Cheltenham, England, United Kingdom

Eastbourne District General Hospital

Eastbourne, England, United Kingdom

St. Luke's Cancer Centre at Royal Surrey County Hospital

Guildford, England, United Kingdom

Huddersfield Royal Infirmary

Huddersfield, West Yorks, England, United Kingdom

Hinchingbrooke Hospital

Huntingdon, England, United Kingdom

Airedale General Hospital

Keighley, England, United Kingdom

Cookridge Hospital

Leeds, England, United Kingdom

Royal Liverpool University Hospital

Liverpool, England, United Kingdom

UCL Cancer Institute

London, England, United Kingdom

Queen Elizabeth Hospital - Woolwich

London, England, United Kingdom

St. Mary's Hospital

London, England, United Kingdom

Mid Kent Oncology Centre at Maidstone Hospital

Maidstone, England, United Kingdom

Clatterbridge Centre for Oncology

Merseyside, England, United Kingdom

James Cook University Hospital

Middlesbrough, England, United Kingdom

Mount Vernon Cancer Centre at Mount Vernon Hospital

Northwood, England, United Kingdom

Peterborough Hospitals Trust

Peterborough, England, United Kingdom

Dorset Cancer Centre

Poole Dorset, England, United Kingdom

Portsmouth Oncology Centre at Saint Mary's Hospital

Portsmouth Hants, England, United Kingdom

Cancer Research Centre at Weston Park Hospital

Sheffield, England, United Kingdom

South Tyneside District Hospital

South Shields, England, United Kingdom

Royal Marsden - Surrey

Sutton, England, United Kingdom

Great Western Hospital

Swindon, England, United Kingdom

Worthing Hospital

Worthing, England, United Kingdom

Yeovil District Hospital

Yeovil, England, United Kingdom

Edinburgh Cancer Centre at Western General Hospital

Edinburgh, Scotland, United Kingdom

Ysbyty Gwynedd

Bangor, Wales, United Kingdom

Velindre Cancer Center at Velindre Hospital

Cardiff, Wales, United Kingdom

Glan Clwyd Hospital

Rhyl, Denbighshire, Wales, United Kingdom

South West Wales Cancer Institute

Swansea, Wales, United Kingdom

Countries

United Kingdom

References

Seymour MT, Brown SR, Middleton G, Maughan T, Richman S, Gwyther S, Lowe C, Seligmann JF, Wadsley J, Maisey N, Chau I, Hill M, Dawson L, Falk S, O'Callaghan A, Benstead K, Chambers P, Oliver A, Marshall H, Napp V, Quirke P. Panitumumab and irinotecan versus irinotecan alone for patients with KRAS wild-type, fluorouracil-resistant advanced colorectal cancer (PICCOLO): a prospectively stratified randomised trial. Lancet Oncol. 2013 Jul;14(8):749-59. doi: 10.1016/S1470-2045(13)70163-3. Epub 2013 May 29.

Reference Type: RESULT

PMID: 23725851 (View on PubMed)

Middleton G, Brown S, Lowe C, Maughan T, Gwyther S, Oliver A, Richman S, Blake D, Napp V, Marshall H, Wadsley J, Maisey N, Chau I, Hill M, Gollins S, Myint S, Slater S, Wagstaff J, Bridgewater J, Seymour M. A randomised phase III trial of the pharmacokinetic biomodulation of irinotecan using oral ciclosporin in advanced colorectal cancer: results of the Panitumumab, Irinotecan & Ciclosporin in COLOrectal cancer therapy trial (PICCOLO). Eur J Cancer. 2013 Nov;49(16):3507-16. doi: 10.1016/j.ejca.2013.06.017. Epub 2013 Aug 13.

Reference Type: RESULT

PMID: 23953030 (View on PubMed)

Seligmann JF, Elliott F, Richman SD, Jacobs B, Hemmings G, Brown S, Barrett JH, Tejpar S, Quirke P, Seymour MT. Combined Epiregulin and Amphiregulin Expression Levels as a Predictive Biomarker for Panitumumab Therapy Benefit or Lack of Benefit in Patients With RAS Wild-Type Advanced Colorectal Cancer. JAMA Oncol. 2016 May 1;2(5):633-642. doi: 10.1001/jamaoncol.2015.6065.

Reference Type: RESULT

PMID: 26867820 (View on PubMed)

Other Identifiers

CTRU-PICCOLO-MO-05-7289

Identifier Type: -

Identifier Source: secondary_id

EUDRACT-2005-003492-20

Identifier Type: -

Identifier Source: secondary_id

CTAAC-CTRU-PICCOLO-MO-05-7289

Identifier Type: -

Identifier Source: secondary_id

AMGEN-CTRU-PICCOLO-MO-05-7289

Identifier Type: -

Identifier Source: secondary_id

EU-20647

Identifier Type: -

Identifier Source: secondary_id

CDR0000510284

Identifier Type: -

Identifier Source: org_study_id