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Efficacy and safety of chronomodulated irinotecan, oxaliplatin, 5‐fluorouracil and leucovorin combination as first‐ or second‐line treatment against metastatic colorectal cancer: Results from the International EORTC 05011 Trial

Abstract The triplet combination of irinotecan, oxaliplatin and fluorouracil is an active frontline regimen in metastatic colorectal cancer, but scarce data exist on its use as salvage treatment. We aimed at assessing its safety and efficacy profiles with its circadian‐based administration (chronoIFLO5) as either first‐ or second‐line treatment, within the time‐finding EORTC 05011 trial. Five‐day chronoIFLO5 was administered every 3 weeks in patients with PS 0, 1 or 2. It consisted of chronomodulated irinotecan (180 mg/sqm), oxaliplatin (80 mg/sqm) and fluorouracil‐leucovorin (2800 and 1200 mg/sqm, respectively). For our study, toxicity and antitumour activity were evaluated separately in first‐ and second‐line settings. Primary endpoints included Grade 3‐4 toxicity rates, best objective response rate (ORR), progression‐free survival (PFS) and overall survival (OS). One‐hundred forty‐nine and 44 patients were treated in first‐line and second‐line settings, respectively, with a total of 1138 cycles with median relative dose intensities of about 90%. Demographics were comparable in the two groups. Thirty‐six (24.7%) and 10 (22.2%) patients experienced at least one episode of severe toxicity in first line and second line, respectively. Frontline chronoIFLO5 yielded an ORR of 62.3% [95% CI: 54.2‐70.4] and resulted in median PFS and OS of 8.7 months [7.5‐9.9] and 19.9 months [15.4‐24.5]. Corresponding figures in second line were 37.5% [22.5‐52.5], 6.7 months [4.8‐8.9] and 16.3 months [11.8‐20.8]. International and prospective evaluation revealed the favourable safety and efficacy profiles of chronoIFLO5, both as frontline and as salvage treatment against metastatic colorectal cancer. In particular, encouraging activity in second line was observed, with limited haematological toxicity.

1200 mg/sqm, respectively). For our study, toxicity and antitumour activity were evaluated separately in first-and second-line settings. Primary endpoints included Grade 3-4 toxicity rates, best objective response rate (ORR), progression-free survival (PFS) and overall survival (OS). One-hundred forty-nine and 44 patients were treated in first-line and second-line settings, respectively, with a total of 1138 cycles with median relative dose intensities of about 90%. Demographics were comparable in the two groups. Thirty-six (24.7%) and 10

| BACKGROUND
Colorectal cancer is the second most common neoplastic disease across Europe in terms of both incidence and mortality. 1 Systemic chemotherapy is the principal therapeutic option for metastatic disease, and it is best tailored to patient's and disease's features within a multidisciplinary oncosurgical strategy. 2 One such approach is to intensify chemotherapy with the aim of obtaining substantial downsizing to allow conversion from nonresectable to resectable disease. 3 The combination of the three main cytotoxic drugs active against colorectal cancer, 5-fluorouracil, oxaliplatin and irinotecan, constitutes the chemotherapy backbone, which has achieved the best outcomes in the metastatic setting. 4,5 Nonetheless, the triplet regimen has also been associated with worse toxicity in comparison with doublets. 6 Hence, better patient outcomes could be expected with the improved tolerability of the triplet regimen.
The administration of each chemotherapy drug at a defined time based on its circadian tolerability constitutes the rationale of chronotherapy. [7][8][9] Indeed, the chronomodulated triplet has demonstrated satisfactory safety and efficacy in monocentric studies in patients with metastatic colorectal cancer. [10][11][12][13] Based on this evidence, we conducted an international time-finding study (EORTC 05011) to identify the least toxic administration time of Irinotecan, combined with chronomodulated oxaliplatin and 5-fluorouracil + leucovorin. 14 This trial failed to meet its primary endpoint of determining the time of irinotecan delivery causing the lowest toxicity in the whole population. 14 Nevertheless, in accordance with recent evidence of the impact of gender in outcomes of chemotherapy against colorectal cancer, we found a lag in the least toxic time of irinotecan administration according to gender. Thus, lower toxicity of irinotecan was highlighted following dosing in the early morning for men and in the afternoon for women. 14 Here, we performed a final update of the EORTC 05011 trial data, which complements overall safety and efficacy of chronomodulated triplet both in the first-line setting, comparatively to existing data with conventional administration, and as a second-line regimen, for which scant prospective multicentric data exist.

| Study population
The EORTC 05011 trial involved 18 institutions in Europe, which enrolled a total of 199 adult patients with histologically proven, measurable and unresectable advanced colorectal cancer and good

What's new?
Triple chemotherapy of irinotecan, oxaliplatin and fluorouracil-leucovorin achieves the best survival against metastatic colorectal cancer (CRC) but has worse toxicity than doublet therapy. Chronomodulation is a strategy to reduced toxicity by coordinating drug administration with the patient's circadian rhythm. Here, the authors evaluated the safety and efficacy of chronomodulated triple therapy given over a 5-day period every 3 weeks. 149 patients received the treatment as a first-line regimen, while 44 received it as salvage therapy. In both settings, the safety and efficacy of chronomodulated triple therapy were validated, although the optimal timing of irinotecan for minimizing toxicity remains to be determined. issues representing a potential risk for study compliance and for patient's safety were excluded. The main endpoint of the study was to identify the least toxic time of administration of irinotecan, and patients were randomised to one of six possible times; details on the sample size calculation and allocation to the six treatment arms are provided elsewhere. 14 Specifically, 193 patients out of the 199 randomised ones (97%) were considered eligible for tolerability and efficacy evaluation: 149 patients were treated in the first-line setting and 44 in the second-line one ( Figure 1). The trial was approved by the respective ethics review boards at each centre and/or country. It was conducted in accordance with the Declaration of Helsinki guidelines for experimentation on humans. 15 Signed informed consent was obtained from every participating patient.

| Chemotherapy schedule
Chrono-IFLO5 consisted of the association of irinotecan, administered as a 6-hour chronomodulated infusion with peak delivery times sched- Irinotecan was administered at only one of the six time points in each patient days ( Figure 2). Respective starting doses were 180 mg/sqm for irinotecan, 700 mg/sqm/day for 5-fluorouracil, 300 mg/sqm/day for leucovorin and 20 mg/sqm/day for oxaliplatin. 14 The treatments were administered on a full outpatient basis through an ambulatory infusion pump allowing in time programming and delivery of all the medications while the patient was at her/his home (Melodie, Aguettant, France). 16 Treatment courses were repeated every 3 weeks, that is, after a 16-day chemotherapy-free interval. No primary or secondary G-CSF prophylaxis was allowed.

| Outcomes
Efficacy outcome measures included objective response rate, which was calculated using the RECIST v1.1 criteria, 14 and time-

| Chemotherapy
The

| Subsequent treatments
After this triplet chronomodulated protocol, investigators had no restriction in the choice of subsequent chemotherapy drugs or regimens, if they felt further treatment was indicated. In both settings, half of the patients received relative dose intensities of the order of at least 90% ( Figure 3) and five or more cycles, assuring therefore satisfactory balance between adequate treatment intensity and duration for most patients. This converted consequently into promising objective response rate and progression-free survival outcomes ( Figure 4C-F).
In the first-line setting, these results compare favourably with literature reports in multicentre trials with conventional triplet regimens of the same drugs, FOLFIRINOX (irinotecan, fluorouracil, leucovorin, oxaliplatin) or FOLFOXIRI (folinic acid, 5-fluorouracil, oxaliplatin and irinotecan), [17][18][19] and even more so with less successful combination schedules. [20][21][22][23] Similarly favourable appears the overall tolerability of frontline chronoIFLO5 (Table 2) comparatively to literature data. [20][21][22][23] Moreover, although the current study was performed before molecular selection and targeted treatments became widely implemented, 24 the overall survival observed here ( Figure 4A) is of the same order of magnitude as that in the most recent studies conducted in metastatic colorectal cancer. 2 In the second-line setting, limited evidence currently exists for the triplet combination, beside small single-institution studies. 11,25,26 Although the various schedules were reported altogether to be feasible and active, chronoIFLO5 11 was the only one to be tested prospectively in an international setting as salvage regimen in pretreated patients with metastatic colorectal cancer, albeit as an exploratory outcome of a tolerance-based study. Indeed, there is concern about the risk of poor tolerance to the triplet regimen, even as frontline T A B L E 2 Incidence of main severe (Grades 3 and 4) toxicities per patient and per cycle, separately in first-and second-line settings treatment; hence, the scarce experience reported and the preference for doublet combination. 27 Nonetheless, the activity of second-line doublets after failure of the other appears substantially lower than that observed in our study 28,29 ( Figure 4B,D,F). However, targeted agents against EGFR or VEGF, in selected populations, meaningfully improved antitumour activity of the doublet combinations in this context. 29,30 Interestingly, monoclonal antibodies added to first-line triplet, chronomodulated or conventional, also displayed significantly better outcomes. 10,31,32 Second-line chronomodulated triplet could further be associated with the appropriate targeted agent thus enhancing efficacy in chemorefractory disease. 13,33 In case of contraindication to the use of anti-EGFR or anti-VEGF agents, second-line triplet combination could offer nonetheless arguably the highest salvage activity, especially in candidates for an onco-surgical strategy. 34 Although this was a time-finding study in a cohort of unselected  18 Our findings here support prior evidence of a much lower neutropenia incidence with chronomodulated chemotherapy in comparison with conventional administration. 35 Hence, chronoIFLO5 could be regarded as a possible fully-ambulatory administration schedule of the triplet in those patients with poor tolerance to conventional delivery, as well as in other clinical scenarios where the triplet administration is an available therapeutic option, such as pancreatic ductal adenocarcinoma, or even biliary tract and gastric adenocarcinomas. [36][37][38] There is evidence suggesting that circadian-based treatment administration of anticancer drugs could be further optimised to provide supplementary benefit when individual biological clock features are taken into account. 8 In particular, for this triplet combination, adaptation of the timing of administration of irinotecan differently in women (afternoon) and men (morning) could lead to an additional reduction in adverse events without impact on antitumour activity. 14 Interestingly, neutropenia and appetite loss are two of the toxicities most affected by genderspecific circadian refinement, 8,14 and also two surrogate adverse events of suboptimal chronotherapy delivery. 8 Moreover, chronomodulated chemotherapy delivered completely at the patient's home with dedicated infusional pumps can benefit from integrative solutions of digital multidimensional remote surveillance of physiology and behaviour, whose feasibility and clinical relevance has been demonstrated expressly with this triplet regimen. 39 This provides a novel opportunity of an adaptive closed-loop control of cytotoxic drug administration based on patientgenerated data, unique to the fully-ambulatory schedule. 16 We acknowledge the limitations of our study in the current era of precision oncology, since the recruitment and treatment occurred when molecular genotype and phenotype or sideness had not yet been identified as relevant factors for treatment selection. Moreover, the time-finding primary endpoint of the trial was toxicity based; hence, the efficacy outcomes presented here remain exploratory in nature.
Intriguingly, a lower incidence of severe diarrhoea appeared to occur with chronoIFLO5 in second-line compared to first-line treatment (Table 2), despite similar doses used regardless of the setting.
Although more careful patient selection could have accounted for this difference, a potential adaptation of the digestive mucosa or of the intestinal microbiota 40 to toxicity and/or of the patient's behaviour relatively to chemotherapy administration, diet and support medications could have also played a role.
In conclusion, although this international trial did not meet its