• Proportion of patients treated with irinotecan hydrochloride (Ir) alone vs Ir and cyclosporine (IrC) who are progression-free at 12 weeks [ Designated as safety issue: No ]
  
• Overall survival of patients treated with Ir vs Ir and panitumumab (IrP) and no prior cetuximab [ Designated as safety issue: No ]
  

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

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.

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