Stein et al. BMC Cancer 2012, 12:356 http://www.biomedcentral.com/1471-2407/12/356 Page 4 of 10 bevacizumab [49]. Furthermore, early safety results of a phase III trial by the Italian group comparing FOLFIRI and bevacizumab with or without oxaliplatin revealed no unexpected toxicities in the first 100 randomized patients [54]. preoperative treatment (arm B), toxicity (according to NCI-CTCAE v 4.0), perioperative morbidity, quality of life (according to EORTC QLQ-C30 and module LMC21), and survival according to molecular or clinico- pathological factors. Methods/design Study design Both trials are multicentre, open labelled, prospective, randomized phase II studies. The study protocols were approved by the local ethics committees, and were also subject to authorization by the competent authority (BfArM for CHARTA and PEI for PERIMAX) as mandatory by federal law. All participants have to pro- vide written informed consent. The trials were assigned the EudraCT numbers 2010-022162-27 for CHARTA and 2010-023575-25 for PERIMAX and are registered at ClinicalTrials.gov (CHARTA: NCT01321957, PERIMAX: NCT01540435). Study objectives and endpoints The primary objective of the CHARTA study is to evaluate the efficacy of FOLFOXIRI and bevacizumab compared to FOLFOX and bevacizumab in patients with initially unresectable metastatic colorectal cancer. Secondary objectives are safety and tolerability of the treatment, efficacy in terms of secondary resectability, prognostic value of stratification into clinical groups, and validity of allocation to these groups and the exploratory question whether the addition of irinotecan might be more effective in terms of response and sur- vival in patient groups to be determined by angiogenic marker profiles, potentially indicating different sensi- tivity to bevacizumab. Primary endpoint is PFS rate at 9 months; secondary endpoints include PFS, OS, ORR (according to RECIST v1.1), secondary resection rate, toxicity (according to NCI-CTCAE v4.0) and quality of life (according to EORTC QLQ-C30 and modules CR29 and CIPN20) [55]. PFS is defined as time from randomization to date of first observed progression or death (without reintroduction). The primary objective of the PERIMAX study is to evaluate the efficacy of FOLFOX for 6 months post- operatively compared to FOLFOXIRI and bevacizumab for three months pre- and three months postoperatively for primarily resectable liver metastases from colorectal cancer. Secondary objectives are safety and tolerability of the treatment as well as efficacy in terms of survival. Primary endpoint is failure- free survival (FFS) rate at 18 months. Failure will be defined as macroscopically incomplete resection (R2), local or distant recurrence or death from any cause. Secondary endpoints are PFS, FFS, OS, achievability of macroscopically complete re- section (R0/1), ORR (according to RECIST v1.1) after Patient selection Patients with histologically confirmed diagnosis of mCRC can be included in the CHARTA-PERIMAX trials, independent of synchronous or metachronous me- tastases, although in case of synchronous disease in the PERIMAX trial the primary tumour needs to be asymp- tomatic and clearly R0 resectable. Inclusion into the PERIMAX trial is limited to patients with R0 resectable CLM as judged by the treating physician and thus excludes patients with extrahepatic disease. Measurable disease according to RECIST, adequate ECOG-PS (≤2 in CHARTA, although ECOG-PS 2, only if tumour related; ≤1 in PERIMAX), age≥18 (upper limit in the PERIMAX at 75 years of age), prior adjuvant treatment completed either at least 6 months before inclusion in the CHARTA, or at least 12 months for oxaliplatin-based treatment in the PERIMAX, are further selection cri- teria. Prerequisite laboratory values for both trials are absolute neutrophil counts ≥1.5 x 109/L, platelets ≥100 x109/L, haemoglobin ≥9 g/dl or 5.59 mmol/l, INR <1.5 and aPTT < 1.5 Upper Limit of Normal (ULN) for patients not receiving therapeutic anticoagulation (use of full dose anticoagulants is allowed as long as the INR or aPTT is within therapeutic limits and the pa- tient has been on a stable dose for anticoagulants for at least two weeks at the time of registration), serum transaminases (AST & ALT) ≤ 2.5 x ULN (in case of liver metastases < 5 x ULN), total bilirubin ≤ 1.5 x ULN, and creatinine ≤ 1.5 x ULN. Further selection cri- teria are based on current standard criteria (e.g. no preg- nancy or breast feeding, signed and dated consent form) and the contraindications of the used agents (e.g. severe thrombosis or bleeding, major surgery within 28 days, chronic diarrhoea or significant peripheral neuropathy). Treatment schedule Treatment schedules for CHARTA and PERIMAX are summarized in Figures 1 and 2, respectively. Patients will randomly be assigned in a 1:1 ratio stratified for the clinical groups one to three mentioned in Table 1 in the CHARTA trial and for number of CLM ≤3 vs >3 and Fong score <2 vs. ≥2 in the PERIMAX trial. CHARTA trial Induction chemotherapy with a modified FOLFOX with oxaliplatin at a dose of 85 mg/m2 iv over two hours (day 1), LV at a dose of 200 mg/m2 iv over two hours (day 1) and 5-FU at a dose of 3200 mg/m2 iv over