PMID- 36335783 OWN - NLM STAT- MEDLINE DCOM- 20221130 LR - 20230105 IS - 1879-0852 (Electronic) IS - 0959-8049 (Linking) VI - 177 DP - 2022 Dec TI - A randomised phase 2 study comparing different dose approaches of induction treatment of regorafenib in previously treated metastatic colorectal cancer patients (REARRANGE trial). PG - 154-163 LID - S0959-8049(22)00780-8 [pii] LID - 10.1016/j.ejca.2022.09.037 [doi] AB - PURPOSE: The purpose of this article is to evaluate the safety of two regorafenib dose-escalation approaches in refractory metastatic colorectal cancer (mCRC) patients. PATIENTS AND METHODS: Patients with mCRC and progression during or within 3 months following their last standard chemotherapy regimen were randomised to receive the approved dose of regorafenib of 160 mg QD (arm A) or 120 mg QD (arm B) administered as 3 weeks of treatment followed by 1 week off, or 160 mg QD 1 week on/1 week off (arm C). The primary end-point was the percentage of patients with G3/G4 treatment-related adverse events (AEs) in each arm. RESULTS: There were 299 patients randomly assigned to arm A (n = 101), arm B (n = 99), or arm C (n = 99); 297 initiated treatments (arm A n = 100, arm B n = 98, arm C n = 99: population for safety analyses). G3/4 treatment-related AEs occurred in 60%, 55%, and 54% of patients in arms A, B, and C, respectively. The most common G3/4 AEs were hypertension (19, 12, and 20 patients), fatigue (20, 14, and 15 patients), hypokalemia (11, 7, and 10 patients), and hand-foot skin reaction (8, 7, and 3 patients). Median overall survival was 7.4 (IQR 4.0-13.7) months in arm A, 8.6 (IQR 3.8-13.4) in arm B, and 7.1 (IQR 4.4-12.4) in arm C. CONCLUSIONS: The alternative regorafenib dosing schedules were feasible and safe in patients with mCRC who had been previously treated with standard therapy. There was a higher numerical improvement on the most clinically relevant AEs in the intermittent dosing arm, particularly during the relevant first two cycles. GOV IDENTIFIER: NCT02835924. CI - Copyright (c) 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved. FAU - Argiles, Guillem AU - Argiles G AD - Vall d'Hebron University Hospital and Institute of Oncology (VHIO), CIBERONC, Barcelona, Spain; Universitat Autonoma de Barcelona, Barcelona, Spain; Memorial Sloan Kettering Cancer Center, New York, USA. Electronic address: argilesg@mskcc.org. FAU - Mulet, Nuria AU - Mulet N AD - Vall d'Hebron University Hospital and Institute of Oncology (VHIO), CIBERONC, Barcelona, Spain. FAU - Valladares-Ayerbes, Manuel AU - Valladares-Ayerbes M AD - Virgen del Rocio University Hospital and Institute of Biomedicine (IBIS), Sevilla, Spain. FAU - Vieitez, Jose M AU - Vieitez JM AD - Hospital Universitario Central de Asturias, Oviedo, Spain. FAU - Gravalos, Cristina AU - Gravalos C AD - Universitary Hospital 12 de Octubre, Madrid, Spain. FAU - Garcia-Alfonso, Pilar AU - Garcia-Alfonso P AD - Gregorio Maranon Hospital, Madrid, Spain. FAU - Santos, Cristina AU - Santos C AD - Institute Catala d'Oncologia (ICO), Duran i Reynals Hospital - ONCOBELL, CIBERONC, Barcelona, Spain. FAU - Tobena, Maria AU - Tobena M AD - Santa Creu i Sant Pau Hospital, Barcelona, Spain. FAU - Garcia-Paredes, Beatriz AU - Garcia-Paredes B AD - Clinico San Carlos Hospital, Instituto de Investigacion Hospital Clinico San Carlos (IdISSC) CIBERONC, Madrid, Spain. FAU - Benavides, Manuel AU - Benavides M AD - Regional University Hospital, Malaga, Spain. FAU - Cano, Maria T AU - Cano MT AD - IMIBIC, Reina Sofia Hospital, University of Cordoba, CIBERONC, Instituto de Salud Carlos III, Spain. FAU - Loupakis, Fotios AU - Loupakis F AD - Istituto oncologico Veneto, Italy. FAU - Rodriguez-Garrote, Mercedes AU - Rodriguez-Garrote M AD - Ramon y Cajal University Hospital-IRYCIS, CIBERONC, Alcala University, Madrid, Spain. FAU - Rivera, Fernando AU - Rivera F AD - University Hospital Marques de Valdecilla (IDIVAL) Santander, Spain. FAU - Goldberg, Richard M AU - Goldberg RM AD - West Virgina University Cancer Institute, Morgantown, USA. FAU - Cremolini, Chiara AU - Cremolini C AD - Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy. FAU - Bennouna, Jaafar AU - Bennouna J AD - University Hospital of Nantes, Digestive Oncology, Nantes, France. FAU - Ciardiello, Fortunato AU - Ciardiello F AD - Universita della Campania L. Vanvitelli, Italy. FAU - Tabernero, Josep M AU - Tabernero JM AD - Vall d'Hebron University Hospital and Institute of Oncology (VHIO), CIBERONC, Barcelona, Spain. FAU - Aranda, Enrique AU - Aranda E AD - Regional University Hospital, Malaga, Spain. CN - Spanish Cooperative Group for the Treatment of Digestive Tumors (TTD) and UNICANCER GI CN - The, REARRANGE investigators CN - Principal investigator FAU - Argiles, Guillem AU - Argiles G AD - Vall d'Hebron University Hospital and Institute of Oncology (VHIO), CIBERONC, Barcelona, Spain. FAU - Tabernero, Josep AU - Tabernero J AD - Vall d'Hebron University Hospital and Institute of Oncology (VHIO), CIBERONC, Barcelona, Spain. CN - Steering Committee CN - Investigators LA - eng SI - ClinicalTrials.gov/NCT02835924 PT - Clinical Trial, Phase II PT - Journal Article PT - Randomized Controlled Trial PT - Research Support, Non-U.S. Gov't DEP - 20221014 PL - England TA - Eur J Cancer JT - European journal of cancer (Oxford, England : 1990) JID - 9005373 RN - 24T2A1DOYB (regorafenib) RN - 0 (Phenylurea Compounds) RN - 0 (Pyridines) SB - IM MH - Humans MH - Phenylurea Compounds MH - Pyridines MH - *Colorectal Neoplasms/pathology MH - *Colonic Neoplasms/drug therapy MH - *Rectal Neoplasms/drug therapy OTO - NOTNLM OT - Colorectal cancer OT - Drug administration schedule OT - Metastasis OT - Regorafenib COIS- Conflict of interest statement The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: G. Argiles received advisory honoraria, from Gadetta BV. Amgen, Bayer and Servier; M. Valladares-Ayerbes received honoraria, travel grants, and research grants from Hoffman La Roche, Bristol-Myers Squibb, Bayer, Servier, Amgen, Merck Serono and Sanofi. N. Mulet received grants and non-financial support from Merck Serono, Amgen and Roche, outside the submitted work; M. Tobena received personal fees from Amgen, Kyowa Kirin and Grunenthal, non-financial support from Merck, Roche and Rovi, outside the submitted work; B. Garcia received personal fees from Advanced Accelerator Applications (a Novartis company), Amgen, Bayer Hispania, Eisai, Lilly, MSD and Roche Farma, personal fees and non-financial support from Ipsen, Merck, Novartis, Sanofi-Aventis and Servier, outside the submitted work; E. Aranda received honoraria for advisory role from Amgen, Bayer, Celgene, Merck, Roche and Sanofi; C. Cremolini received honoraria for Advisory Board/Speaker from Amgen, Bayer, Merck, MSD, Roche, Servier and Research, grants from Bayer, Roche and Servier. The other authors have stated that they have no conflicts of interest. FIR - Tabernero, Josep IR - Tabernero J FIR - Argiles, Guillem IR - Argiles G FIR - Falcone, Alfredo IR - Falcone A FIR - Ciardiello, Fortunato IR - Ciardiello F FIR - Goldberg, Richard IR - Goldberg R FIR - Bennouna, Jaafar IR - Bennouna J FIR - Argiles IR - Argiles IRAD- Memorial Sloan Kettering Cancer Center, New York, USA. FIR - Tabernero, J IR - Tabernero J IRAD- Memorial Sloan Kettering Cancer Center, New York, USA. FIR - Mulet, N IR - Mulet N IRAD- Memorial Sloan Kettering Cancer Center, New York, USA. FIR - Limon, M L IR - Limon ML IRAD- H. Virgen del Rocio, Sevilla, Spain. FIR - Valladares, M IR - Valladares M IRAD- H. Virgen del Rocio, Sevilla, Spain. FIR - Jimenez, P IR - Jimenez P IRAD- H. Universitario Central de Asturias, Spain. FIR - Vieitez, J Ma IR - Vieitez JM IRAD- H. Universitario Central de Asturias, Spain. FIR - Gravalos, C IR - Gravalos C IRAD- H. 12 de Octubre, Madrid, Spain. FIR - Garcia-Alfonso, P IR - Garcia-Alfonso P IRAD- H. Gregorio Maranon, Madrid, Spain. FIR - Santos, C IR - Santos C IRAD- ICO. H. Duran i Reynals, Barcelona, Spain. FIR - Paez, D IR - Paez D IRAD- H. Santa Creu i Sant Pau, Barcelona, Spain. FIR - Tobena, M IR - Tobena M IRAD- H. Santa Creu i Sant Pau, Barcelona, Spain. FIR - Sastre, J IR - Sastre J IRAD- H. Universitario Clinico San Carlos, Madrid, Spain. FIR - Garcia Paredes, B IR - Garcia Paredes B IRAD- H. Universitario Clinico San Carlos, Madrid, Spain. FIR - Benavides, M IR - Benavides M IRAD- Hospital Universitario Regional y Virgen de la Victoria, Malaga, Spain. FIR - Aranda, E IR - Aranda E IRAD- H. Universitario Reina Sofia, Cordoba, Spain. FIR - Cano, M T IR - Cano MT IRAD- H. Universitario Reina Sofia, Cordoba, Spain. FIR - Loupakis, F IR - Loupakis F IRAD- IOV (Istituto oncologico Veneto), Italy. FIR - Rguez Garrote, M IR - Rguez Garrote M IRAD- H. Ramon y Cajal, Madrid, Spain. FIR - Guillen, C IR - Guillen C IRAD- H. Ramon y Cajal, Madrid, Spain. FIR - Rivera, Ma F IR - Rivera MF IRAD- H. Marques de Valdecilla, Santander, Spain. FIR - Safont, J IR - Safont J IRAD- H. General Universitario, Valencia, Spain. FIR - Hiret, S IR - Hiret S IRAD- Institut de Cancerologie de l'Ouest, France. FIR - Bennouna, J IR - Bennouna J IRAD- CHU-Nante, France. FIR - Pannier, D IR - Pannier D IRAD- Centre Oscar Lambret, France. FIR - Malka, D IR - Malka D IRAD- Gustave Roussy, France. FIR - Falcone, A IR - Falcone A IRAD- Gustave Roussy, France. FIR - Cremolini, C IR - Cremolini C IRAD- A. O. Universitaria Pisana, Italy. EDAT- 2022/11/07 06:00 MHDA- 2022/12/01 06:00 CRDT- 2022/11/06 18:17 PHST- 2022/06/15 00:00 [received] PHST- 2022/09/28 00:00 [revised] PHST- 2022/09/30 00:00 [accepted] PHST- 2022/11/07 06:00 [pubmed] PHST- 2022/12/01 06:00 [medline] PHST- 2022/11/06 18:17 [entrez] AID - S0959-8049(22)00780-8 [pii] AID - 10.1016/j.ejca.2022.09.037 [doi] PST - ppublish SO - Eur J Cancer. 2022 Dec;177:154-163. doi: 10.1016/j.ejca.2022.09.037. Epub 2022 Oct 14.