Biomodulation of irinotecan using ciclosporin: Results of PICCOLO, a randomized controlled trial in advanced colorectal cancer (aCRC).
Middleton GW., Gwyther SJ., Brown SR., Maughan T., Olivier C., Richman S., Maisey NR., Hill M., Gollins S., Myint S., Slater S., Wagstaff J., Bridgewater JA., Glynne-Jones R., Hemmings G., Marshall H., Blake D., Napp V., Quirke P., Seymour MT., UK NCRI Colorectal Clinical Studies Group None.
3566 Background: Phase I/II data showed that ciclosporin (Cs) profoundly reduces the hepatobiliary clearance of irinotecan (Ir), and suggested that 40% standard dose Ir with concurrent Cs (IrCs) may give equal efficacy to standard Ir, with less diarrhoea. PICCOLO is a multicentre randomized controlled trial in which patients (pts) with aCRC, progressing after prior therapy, were randomised to Ir or IrCs. It was designed to detect non-inferior efficacy with reduced toxicity. METHODS: Eligible pts had: measurable aCRC, progressive during/after ≥1 prior regimen with fluoropyrimidines ± other drugs; no prior Ir; WHO PS 0-2. Before summer 2008, pts were allocated 1:1:1 (without prospective KRAS analysis) to Ir, IrCs or Ir/panitumumab. Thereafter, KRAS was analysed prospectively and pts with mutated or undetermined KRAS were allocated 1:1 to Ir (irinotecan 350 mg/m(2) [300 mg/m(2) if ≥70 yrs or PS2], q3w), or IrCs (irinotecan 140 mg/m(2) [120 mg/m(2) if ≥70 yrs or PS2] d1, Cs 3 mg/kg tds d0-2, q3w). The primary efficacy endpoint was % pts alive and progression-free at 12 wks, with a lower non-inferiority boundary of -10.6% (80% power, 2.5% significance). Grade ≥3 diarrhoea within 12 wks was a key secondary endpoint. PFS, OS, RR, QoL and loperamide use were also assessed. Analysis was performed on both the ITT and per-protocol populations. RESULTS: 672 pts were randomised between Ir and IrCs. Median age was 64 yrs; 92% were PS0/1; 95% had received prior oxaliplatin; KRAS was mut in 60%, wt in 25%, unknown in 15%. ITT analysis showed 179/335 (53.4%) patients to be progression-free at 12 wks in the Ir arm, 159/337 (47.2%) in the IrCs arm. The difference was therefore -6.3% and the 95% CI crossed the prespecified non-inferiority margin (13.8%, +1.3%). Gr ≥3 diarrhoea was uncommon in both arms (Ir 12.2%; IrCs 10.1% pts), but fewer IrCs patients took loperamide within 12 wks (Ir 67.8%; IrCs 52.2%, p<0.001). CONCLUSIONS: As anticipated, IrCs was associated with less diarrhoea as assessed by loperamide use, but severe diarrhoea was uncommon in both arms. However, we failed to prove non-inferiority of IrCs compared with Ir, so cannot recommend it as a standard treatment option based on these data.