Alternate Title
Basic Trial Information
Objectives
Entry Criteria
Expected Enrollment
Outcomes
Outline
Trial Contact Information
Registry Information

Alternate Title

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

Basic Trial Information

Phase	Type	Status	Age	Sponsor	Protocol IDs
Phase III	Treatment	Active	18 and over	Other, Pharmaceutical / Industry	CTRU-PICCOLO-MO-05-7289 EUDRACT-2005-003492-20, CTAAC-CTRU-PICCOLO-MO-05-7289, AMGEN-CTRU-PICCOLO-MO-05-7289, EU-20647, NCT00389870

Objectives

Primary

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

Secondary

1. Correlate the toxicity of Ir and/or IrC with genetic variability in the enzymes involved in irinotecan hydrochloride’s disposition pathway.
2. Compare IrC to Ir and its metabolites (SN38; SN38G), in terms of pharmacokinetic profile.
3. Correlate the benefit of IrP with tumor expression of epidermal growth factor receptor (EGFR) or its known down-stream molecules as a predictive measure.
4. 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.

Entry 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

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

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

Expected Enrollment

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

Outcomes

Proportion of patients treated with irinotecan hydrochloride (Ir) alone vs Ir and cyclosporine (IrC) who are progression-free at 12 weeks
Overall survival of patients treated with Ir vs Ir and panitumumab (IrP) and no prior cetuximab

Proportion of patients free from treatment failure at 12 weeks in patients treated with Ir vs IrC
Overall survival in patients treated with Ir vs IrC
Nurse-assessed toxicity (all-cause mortality, diarrhea ≥ grade 3 at 12 weeks) in patients treated with Ir vs IrC
Progression-free at 12 weeks in patients treated with Ir vs IrP and no prior cetuximab
Nurse assessed toxicity (all-cause mortality) in patients treated with Ir vs IrP and no prior cetuximab
Progression-free survival in patients treated with Ir vs IrP and prior cetuximab
Best response at 1 year in patients treated with Ir vs IrP and prior cetuximab
Patient-assessed symptom/quality of life/acceptability scores at 12 and 24 weeks in patients treated with Ir vs IrP and prior cetuximab

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

Trial Contact Information

Trial Lead Organizations

Clinical Trials and Research Unit of the University of Leeds

Matthew Seymour, MA, MD, FRCP, Protocol chair		Ph: 44-113-267-3411

United Kingdom
England
	Bournemouth
	Royal Bournemouth Hospital NHS Trust
		Tamas Hickish, MD	Ph:  44-120-230-3626
			Email: tamas.hickish@rbch.nhs.uk
	Brighton
	Sussex Cancer Centre at Royal Sussex County Hospital
		Andrew Webb, MD	Ph:  44-12-7369-6955
	Bristol
	Bristol Haematology and Oncology Centre
		Stephen Falk, MD	Ph:  44-117-928-2416
			Email: stephen.falk@ubht.nhs.uk
	Cambridge
	Addenbrooke's Hospital
		Charles Wilson, MD	Ph:  44-1223-217-110
			Email: charles.wilson@addenbrookes.nhs.uk
	Cheltenham
	Gloucestershire Oncology Centre at Cheltenham General Hospital
		Kim Benstead, MD	Ph:  44-845-422-2222
			Email: kim.benstead@egnhst.org.uk
	Eastbourne
	Eastbourne District General Hospital
		Fiona McKinna, MD	Ph:  44-132-341-7400
			Email: fiona.mckinna@bsuh.nhs.uk
	Guildford
	St. Luke's Cancer Centre at Royal Surrey County Hospital
		Gary Middleton	Ph:  44-148-357-1122
			Email: gmiddleton@royalsurrey.nhs.uk
	Huddersfield, West Yorks
	Huddersfield Royal Infirmary
		Jo Dent	Ph:  44-1484-342-000
	Huntingdon
	Hinchingbrooke Hospital
		Li Tee Tan, MD	Ph:  44-1480-416-416
	Keighley
	Airedale General Hospital
		S. Michael Crawford, MD	Ph:  44-1535-652-511
			Email: michael.crawford@anhst.nhs.uk
	Leeds
	Cookridge Hospital
		Matthew Seymour, MA, MD, FRCP	Ph:  44-113-267-3411
	Liverpool
	Royal Liverpool University Hospital
		David Smith, MD	Ph:  44-151-706-2000
	London
	Queen Elizabeth Hospital - Woolwich
		Nick Maisey	Ph:  44-208-836-6000
			Email: nick.maisey@kcl.ac.uk
	St. Mary's Hospital
		Susan Cleator, MD, PhD	Ph:  44-207-886-6666
			Email: s.cleator@imperial.ac.uk
	UCL Cancer Institute
		Astrid Mayer, MD	Ph:  44-207-794-0500
			Email: a.mayer@ucl.ac.uk
	Maidstone
	Mid Kent Oncology Centre at Maidstone Hospital
		Mark Hill, MD	Ph:  44-1622-729-000
	Merseyside
	Clatterbridge Centre for Oncology
		Sun Myint, MD, FRCP(Edin), DMRT, FFRCS, FRCP	Ph:  44-151-334-1155
			Email: sun.myint@ccotrust.nhs.uk
	Middlesbrough
	James Cook University Hospital
		N. Wadd, MD	Ph:  44-1642-850-850
	Northwood
	Mount Vernon Cancer Centre at Mount Vernon Hospital
		Robert Glynne-Jones, MD	Ph:  44-192-382-6111
			Email: robglynnejones@nhs.net
	Peterborough
	Peterborough Hospitals Trust
		Karen McAdam, MD	Ph:  44-173-387-4000
	Poole Dorset
	Dorset Cancer Centre
		Tamas Hickish, MD	Ph:  44-120-266-5511
	Portsmouth Hants
	Portsmouth Oncology Centre at Saint Mary's Hospital
		Ann O'Callaghan, MD	Ph:  44-23-9228-6000 ext. 2361
			Email: ann.o'callaghan@porthosp.nhs.uk
	Sheffield
	Cancer Research Centre at Weston Park Hospital
		Jonathan Wadsley	Ph:  44-114-226-5000
	South Shields
	South Tyneside District Hospital
		Ashraf Azzabi, MD	Ph:  44-191-202-4178
	Sutton
	Royal Marsden - Surrey
		Ian Chau, MD	Ph:  44-208-661-3582
	Swindon
	Great Western Hospital
		Claire Blesing	Ph:  44-1793-604-020
	Worthing
	Worthing Hospital
		Andrew Webb, MD	Ph:  44-1903-205-111
	Yeovil
	Yeovil District Hospital
		Stephen Falk, MD	Ph:  44-193-547-5122
			Email: stephen.falk@swest.uhs.uk
Scotland
	Edinburgh
	Edinburgh Cancer Centre at Western General Hospital
		Lesley Dawson	Ph:  44-131-537-1000
Wales
	Bangor
	Ysbyty Gwynedd
		Catherine Bale	Ph:  44-124-838-4384
	Cardiff
	Velindre Cancer Center at Velindre Hospital
		Timothy Maughan, MD	Ph:  44-29-2061-5888
	Rhyl, Denbighshire
	Glan Clwyd Hospital
		Simon Gollins, MD	Ph:  44-1745-583-910
			Email: simon.gollins@cd-tr.wales.nhs.uk
	Swansea
	South West Wales Cancer Institute
		John Wagstaff, MD, MB, ChB, FRCP	Ph:  44-179-220-2666
			Email: profwagstaff@netscape.net

Registry Information
Official Title		A Randomised Clinical Trial of Treatment for Fluorouracil-Resistant Advanced Colorectal Cancer Comparing Standard Single-Agent Irinotecan Versus Irinotecan Plus Panitumumab and Versus Irinotecan Plus Ciclosporin [Panitumumab, Irinotecan & Ciclosporin in COLOrectal Cancer Therapy (PICCOLO)]
Trial Start Date		2006-12-04
Trial Completion Date		2010-03-01 (estimated)
Registered in ClinicalTrials.gov		NCT00389870
Date Submitted to PDQ		2006-09-18
Information Last Verified		2007-07-17

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