Clinical trial NCT00389870: Irinotecan With or Without Panitumumab or Cyclosporine in Treating Patients With Advanced or Metastatic Colorectal Cancer That Did Not Respond to Fluorouracil
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)]
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Colorectal Cancer
Keywords: recurrent colon cancer
stage IV colon cancer
recurrent rectal cancer
stage IV rectal cancer
adenocarcinoma of the colon
adenocarcinoma of the rectum
Lead sponsor: University of Leeds
Sponsor class: OTHER
First posted: 2006-10-19
Enrollment: 1198
Sex: ALL
Minimum age (years): 18
Maximum age (years): 120
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Primary purpose: TREATMENT

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.

Eligibility 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

Primary outcomes:
measure: Proportion of patients treated with irinotecan hydrochloride (Ir) alone vs Ir and cyclosporine (IrC) who are progression-free at 12 weeks
measure: Overall survival of patients treated with Ir vs Ir and panitumumab (IrP) and no prior cetuximab
Secondary outcomes:
measure: Proportion of patients free from treatment failure at 12 weeks in patients treated with Ir vs IrC
measure: Overall survival in patients treated with Ir vs IrC
measure: Nurse-assessed toxicity (all-cause mortality, diarrhea ≥ grade 3 at 12 weeks) in patients treated with Ir vs IrC
measure: Progression-free at 12 weeks in patients treated with Ir vs IrP and no prior cetuximab
measure: Nurse assessed toxicity (all-cause mortality) in patients treated with Ir vs IrP and no prior cetuximab
measure: Progression-free survival in patients treated with Ir vs IrP and prior cetuximab
measure: Best response at 1 year in patients treated with Ir vs IrP and prior cetuximab
measure: Patient-assessed symptom/quality of life/acceptability scores at 12 and 24 weeks in patients treated with Ir vs IrP and prior cetuximab
Other outcomes:
Locations:
city: Bournemouth
country: United Kingdom
facility: Royal Bournemouth Hospital
state: England
city: Brighton
country: United Kingdom
facility: Sussex Cancer Centre at Royal Sussex County Hospital
state: England
city: Bristol
country: United Kingdom
facility: Bristol Haematology and Oncology Centre
state: England
city: Cambridge
country: United Kingdom
facility: Addenbrooke's Hospital
state: England
city: Cheltenham
country: United Kingdom
facility: Gloucestershire Oncology Centre at Cheltenham General Hospital
state: England
city: Eastbourne
country: United Kingdom
facility: Eastbourne District General Hospital
state: England
city: Guildford
country: United Kingdom
facility: St. Luke's Cancer Centre at Royal Surrey County Hospital
state: England
city: Huddersfield, West Yorks
country: United Kingdom
facility: Huddersfield Royal Infirmary
state: England
city: Huntingdon
country: United Kingdom
facility: Hinchingbrooke Hospital
state: England
city: Keighley
country: United Kingdom
facility: Airedale General Hospital
state: England
city: Leeds
country: United Kingdom
facility: Cookridge Hospital
state: England
city: Liverpool
country: United Kingdom
facility: Royal Liverpool University Hospital
state: England
city: London
country: United Kingdom
facility: UCL Cancer Institute
state: England
city: London
country: United Kingdom
facility: Queen Elizabeth Hospital - Woolwich
state: England
city: London
country: United Kingdom
facility: St. Mary's Hospital
state: England
city: Maidstone
country: United Kingdom
facility: Mid Kent Oncology Centre at Maidstone Hospital
state: England
city: Merseyside
country: United Kingdom
facility: Clatterbridge Centre for Oncology
state: England
city: Middlesbrough
country: United Kingdom
facility: James Cook University Hospital
state: England
city: Northwood
country: United Kingdom
facility: Mount Vernon Cancer Centre at Mount Vernon Hospital
state: England
city: Peterborough
country: United Kingdom
facility: Peterborough Hospitals Trust
state: England
city: Poole Dorset
country: United Kingdom
facility: Dorset Cancer Centre
state: England
city: Portsmouth Hants
country: United Kingdom
facility: Portsmouth Oncology Centre at Saint Mary's Hospital
state: England
city: Sheffield
country: United Kingdom
facility: Cancer Research Centre at Weston Park Hospital
state: England
city: South Shields
country: United Kingdom
facility: South Tyneside District Hospital
state: England
city: Sutton
country: United Kingdom
facility: Royal Marsden - Surrey
state: England
city: Swindon
country: United Kingdom
facility: Great Western Hospital
state: England
city: Worthing
country: United Kingdom
facility: Worthing Hospital
state: England
city: Yeovil
country: United Kingdom
facility: Yeovil District Hospital
state: England
city: Edinburgh
country: United Kingdom
facility: Edinburgh Cancer Centre at Western General Hospital
state: Scotland
city: Bangor
country: United Kingdom
facility: Ysbyty Gwynedd
state: Wales
city: Cardiff
country: United Kingdom
facility: Velindre Cancer Center at Velindre Hospital
state: Wales
city: Rhyl, Denbighshire
country: United Kingdom
facility: Glan Clwyd Hospital
state: Wales
city: Swansea
country: United Kingdom
facility: South West Wales Cancer Institute
state: Wales
Study officials:
affiliation: Cookridge Hospital
name: Matthew T. Seymour, MA, MD, FRCP
role: STUDY_CHAIR
References:
citation: 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.
citation: 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.
citation: 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.