Digestive and Liver Disease 47 (2015) 271–272

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Ongoing Clinical Trials

FOLFIRI+bevacizumab induction chemotherapy followed by bevacizumab or observation in metastatic colorectal cancer, a phase III trial (PRODIGE 9 – FFCD 0802) Thomas Aparicio a,∗ , Benjamin Linot b , Karine Le Malicot c , Olivier Bouché d , Valérie Boige e , Eric Franc¸ois f , Francois Ghiringhelli g , Jean-Louis Legoux h , Meher Ben Abdelghani i , Jean-Marc Phelip j , Roger Faroux k , Laetitia Dahan l , Julien Taieb m , Laurent Bedenne n a

Department of Gastroenterology, Avicenne Hospital, Bobigny, France

1. Rationale and aims During the last 15 years, treatment of patients with metastatic colorectal cancer (mCRC) has undergone major improvements. First-line treatment combination regimen with 5-fluorouracil and irinotecan (FOLFIRI) was associated with a significant increase in overall survival [1]. The addition of biological agents to chemotherapy, such as the anti-vascular endothelial growth factor and anti-epidermal growth factor receptor monoclonal antibodies bevacizumab and cetuximab [2,3] increased survival compared to chemotherapy alone. The duration of first-line combination chemotherapy has been questioned because of toxicities during long treatments, with a negative impact on patient quality of life. Three phase III studies evaluating sequential chemotherapy (firstline fluoropyrimidine monotherapy followed by second-line dual chemotherapy in case of progressive disease) revealed no survival advantage compared to first-line combination [4–6]. Therefore, a “step-up” strategy became an option in mCRC but has never been evaluated with regimens including biological agents. To avoid toxicities, the concept of chemotherapy-free intervals (CFIs) as a “top-down” strategy was proposed in different studies [7,8]. In the study by Labianca et al., the experimental arm was the repetition of sequences consisting of 2 months with FOLFIRI followed by 2 months without chemotherapy, even in the absence of tumour progression [8]: overall survival was the same compared to the arm with continuous chemotherapy. In the OPTIMOX II study, chemotherapy was re-introduced only in case of progression based on baseline status, and this strategy was less efficient than continuous chemotherapy [7]. Further to these two trials, an alternative therapy is the re-introduction of chemotherapy as soon as progression is detected, i.e. based on last tumour assessment during chemotherapy; this could increase survival and allow longer

∗ Corresponding author at: Service de Gastroentérologie et Cancérologie Digestive, Hôpital Avicenne, 125 rue de Stalingrad, 93009 Bobigny, France. Tel.: +33 1 48 95 54 31; fax: +33 1 48 95 54 39. E-mail address: [email protected] (T. Aparicio).

CFIs. The two previously cited studies were performed without anti-angiogenic treatment. Bevacizumab alone is a well-tolerated drug, and maintenance with bevacizumab during CFIs may allow to extend CFIs without tumour progression. The reintroduction of FOLFIRI after each CFI during a therapeutic sequence could result in longer disease control duration in first-line chemotherapy, resulting in the premise of the ongoing phase III study PRODIGE 9.

2. Study design PRODIGE 9 is a cooperative multicentre randomized phase III study for mCRC patients comparing disease control duration with or without bevacizumab maintenance during CFI. The main objective is to compare disease control duration between the two treatment arms: Arm A contains FOLFIRI+bevacizumab with bevacizumab maintenance during CFI, and Arm B contains FOLFIRI+bevacizumab without bevacizumab during CFI. The study is planned over a period of 7 years. Eligible patients are over 18 years of age with histologically proven metastatic colorectal adenocarcinoma and no possibility of surgical cure, with WHO status ≤2 and a life-expectancy ≥3 months. Patients should be naïve to chemotherapy or antiangiogenic therapy for metastatic disease. Previous adjuvant chemotherapy after primary tumour resection is allowed but must have been completed at least 6 months prior to enrolment. At least one measurable target according to RECIST criteria is mandatory, as well as written informed consent. Exclusion criteria include: potentially resectable colorectal cancer metastasis, active gastric or duodenal ulcer, comorbid conditions representing treatment contraindications, neutrophil count 5× ULN if hepatic metastases are present), creatinine >1.5× ULN, proteinuria >1 g/d, previous treatment with irinotecan, bevacizumab or any other anti-angiogenic drug, surgery within 4 weeks of treatment.

http://dx.doi.org/10.1016/j.dld.2015.01.146 1590-8658/© 2015 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

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T. Aparicio et al. / Digestive and Liver Disease 47 (2015) 271–272

Standard clinical and laboratory testing is performed within 14 days of randomization; a baseline tumour assessment (thoracoabdominal computed tomography scan or thoracic computed tomography scan plus abdominal magnetic resonance imaging) with identification and measurement of tumour targets is performed within 21 days of the first cycle. Patients are randomized in a 1:1 ratio and stratified according to centre, previous primary tumour resection, and Köhne scoring (low versus intermediate versus high). Treatment is begun from 72 hours to a maximum of 2 weeks after randomization. Patients will receive a first sequence of 12 cycles of FOLFIRI+bevacizumab; in case of disease control after these 12 cycles, a CFI with (arm A) or without (arm B) bevacizumab will follow. In case of progression according to RECIST criteria during this CFI, a sequence of 8 cycles of FOLFIRI+bevacizumab will be reintroduced, followed by another CFI in case of subsequent disease control after these 8 cycles; these sequences are repeated until progression under chemotherapy occurs. During the entire treatment, including chemotherapy sequence and CFI, clinical and radiological assessment is performed every 8 weeks. Safety is evaluated with laboratory and clinical testing before each cycle and during CFIs. After treatment termination, patients will be followed every 3 months in case of chemotherapy failure, or every 8 weeks until progression or death in case of premature treatment interruption (adverse events, non-compliance).

Toxicities will be described by treatment group based on NCICTC grade. Dose intensity will be calculated and reported for each treatment and by treatment group. Conflict of interest Benjamin Linot, Karine Le Malicot, Valérie Boige, Eric Franc¸ois, Francois Ghiringhelli, Jean-Louis Legoux, Meher Ben Abdelghani, Jean-Marc Phelip, Roger Faroux, Laetitia Dahan, have no conflict of interest to declare; Thomas Aparicio, Olivier Bouché, Julien Taieb have received honoraria for presentation from Roche; Laurent Bedenne has received grants for FFCD due to his position as president of FFCD. Funding FFCD is funded by the “Ligue Nationale Contre le Cancer”. A research grant was obtained from Roche Pharmaceuticals (Basel, Switzerland). Appendix A. Co-authors affiliation b Department

The primary endpoint is disease control duration, defined as the time elapsed between randomization (before chemotherapy) and tumour progression during a chemotherapy sequence (FOLFIRI+bevacizumab). Secondary endpoints are objective response rate (defined according to RECIST 1.1 criteria), toxicities (graded according to NCICTC 2.0), overall survival (defined as the time between randomization and death by any cause), total duration of CFIs, time to treatment failure (defined as the time between randomization and definitive suspension of first-line chemotherapy), progressionfree survival (defined as the time between randomization and first progression or death by any cause), and quality of life evaluations (QLQ-C30).

of Oncology, Institut de Cancérologie de l’Ouest Nantes-Angers, France c INSERM, Dijon, France d Department of Gastroenterology, CHU Reims, France e Department of Gastrointestinal Oncology, Gustave Roussy, Villejuif, France f Department of Gastroenterology, Centre Antoine Lacassagne, Nice, France g Department of Oncology, Centre George Francois Leclerc, Dijon, France h Department of Gastroenterology, CH Orléans, France i Department of Oncology, Centre Paul Strauss, Strasbourg, France j Department of Gastroenterology, CHU Bellevue Nord, Saint Etienne, France k Department of Gastroenterology, CH Les Oudaries, La Roche sur Yon, France l Department of Gastroenterology, CHU La Timone, Aix-Marseille University, Marseille, France m Department of Gastroenterology, Georges Pompidou Hospital, Paris, France n Department of Gastroenterology, CHU Le Bocage, Dijon, France.

2.2. Statistical methods

References

Study hypothesis is to extend median disease-control duration from 10 to 14 months with bevacizumab maintenance during CFI (HR = 0.714). With a two-sided ␣ risk of 5%, and a power of 90%, 396 events will be necessary. Taking into account an interim analysis at 50% of the events, an assumption of 10 inclusions per month and a 10% loss to follow-up, a sample size of 492 patients is required. The interim analysis is planned to prematurely stop trial accrual in case of futility or prematurely conclude based on efficacy of the bevacizumab maintenance arm. P-values will be calculated with an alpha-spending function method adapted to the exact number of events (O’Brien and Fleming function for the superiority test and Kim-DeMets function for the futility analysis). All efficacy analyses will be based on intent-to-treat (ITT), and a per-protocol analysis is also planned. The safety analysis will be performed on the ITT patients having received at least one dose of FOLFIRI+bevacizumab chemotherapy. Survival analyses will use the Kaplan–Meier method (stratified or not) and survival curves comparison will be use log-rank test. Survival time will be described using medians and their 95% confidence intervals. Hazards ratios will be estimated by Cox model and all hypotheses linked to this method will be graphically tested.

[1] Douillard JY, Cunningham D, Roth AD, et al. Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: a multicentre randomised trial. Lancet 2000;355:1041–7. [2] Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. New England Journal of Medicine 2004;350:2335–42. [3] Van Cutsem E, Kohne CH, Lang I, et al. Cetuximab plus irinotecan, fluorouracil, and leucovorin as first-line treatment for metastatic colorectal cancer: updated analysis of overall survival according to tumor KRAS and BRAF mutation status. Journal of Clinical Oncology 2011;29:2011–9. [4] Ducreux M, Malka D, Mendiboure J, et al. Sequential versus combination chemotherapy for the treatment of advanced colorectal cancer (FFCD 2000–05): an open-label, randomised, phase 3 trial. Lancet Oncology 2011;12:1032–44. [5] Koopman M, Antonini NF, Douma J, et al. Sequential versus combination chemotherapy with capecitabine, irinotecan, and oxaliplatin in advanced colorectal cancer (CAIRO): a phase III randomised controlled trial. Lancet 2007;370:135–42. [6] Seymour MT, Maughan TS, Ledermann JA, et al. Different strategies of sequential and combination chemotherapy for patients with poor prognosis advanced colorectal cancer (MRC FOCUS): a randomised controlled trial. Lancet 2007;370:143–52. [7] Chibaudel B, Maindrault-Goebel F, Lledo G, et al. Can chemotherapy be discontinued in unresectable metastatic colorectal cancer? The GERCOR OPTIMOX2 Study. Journal of Clinical Oncology 2009;27:5727–33. [8] Labianca R, Sobrero A, Isa L, et al. Intermittent versus continuous chemotherapy in advanced colorectal cancer: a randomised ‘GISCAD’ trial. Annals of Oncology 2011;22:1236–42.

2.1. Study endpoints

FOLFIRI+bevacizumab induction chemotherapy followed by bevacizumab or observation in metastatic colorectal cancer, a phase III trial (PRODIGE 9--FFCD 0802).

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