TY - JOUR
T1 - Regorafenib dose-optimisation in patients with refractory metastatic colorectal cancer (ReDOS)
T2 - a randomised, multicentre, open-label, phase 2 study
AU - Bekaii-Saab, Tanios S.
AU - Ou, Fang Shu
AU - Ahn, Daniel H.
AU - Boland, Patrick M.
AU - Ciombor, Kristen K.
AU - Heying, Erica N.
AU - Dockter, Travis J.
AU - Jacobs, Nisha L.
AU - Pasche, Boris C.
AU - Cleary, James M.
AU - Meyers, Jeffrey P.
AU - Desnoyers, Rodwige J.
AU - McCune, Jeannine S.
AU - Pedersen, Katrina
AU - Barzi, Afsaneh
AU - Chiorean, E. Gabriela
AU - Sloan, Jeffrey
AU - Lacouture, Mario E.
AU - Lenz, Heinz Josef
AU - Grothey, Axel
N1 - Funding Information:
Funding for the study was received from Bayer HealthCare Pharmaceuticals. We would like to acknowledge Alicia Elsing from Academic and Community Cancer Research United (ACCRU) for her role as the lead research protocol specialist on the study. Editorial and medical writing assistance was provided by Joanne Franklin and Sandra Mendes from Aptitude Health (The Hague, the Netherlands) and funded by ACCRU.
Funding Information:
TSB-S received travel expenses from Bayer to attend advisory board meetings; served as a paid consultant for AbbVie, Immunneering, Imugene, and Glenmark; and served on the data and safety monitoring boards of Exelixis, Silajen, and Armo during the conduct of the study. His institution has received honoraria from Bayer, Pfizer, Celgene, Ipsen, Amgen, Array, Bristol-Myers Squibb, and Incyte for consultant services, outside of the submitted work. DHA served as a consultant for Eisai and Astellas during the conduct of the study. PMB has received research funding from Merck, Boehringer Ingelheim, Ipsen, Merrimack, Advaxis, Theradiag, Athenex, Boston Biomedical, MedImmune, Bristol-Myers Squibb, Novartis, Incyte, Amgen, Sanofi, Array Biopharma, Daiichi Sankyo, and Nucano; and honoraria from Sirtex and Boston Biomedical, outside of the submitted work. KKC has been a consultant for Bayer, Foundation Medicine, Research to Practice and Taiho; she has received research funding to her institution from Incyte, Pfizer, Boston Biomedical, MedImmune, Onyx, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Merck, Novartis, Amgen, Sanofi, Array, Daiichi Sankyo, and Nucana, outside of the submitted work. JMC has received research funding from Merck and Tesaro; has been a consultant for Bristol-Myers Squibb; and has received travel expenses from Bristol-Myers Squibb, Roche and Agios, outside of the submitted work RJD is currently an employee of Bristol-Myers Squibb. KP reports personal fees from Bayer during the conduct of the study; and travel expenses from Beigene and Array Pharmaceuticals and grants from Mayo Foundation for Medical Education and Research and BiolineRx, outside of the submitted work. EGC has received research funding from Boehringer Ingelheim, Celgene, Stemline, Ignyta, Incyte, Eli Lilly, and Merck; and has received honoraria from Halozyme, Vicus, Ipsen, Five Prime, Exelixis, AstraZeneca, and Seattle Genetics, outside of the submitted work. She received research funding from Boehringer Ingelheim, Celgene, Stemline, Ignyta, Incyte, Eli Lilly; and honoraria from Halozyme, Vicus, Ipsen and Five Prime during the conduct of the study. MEL has received royalties from Legacy Healthcare Services, Adgero Bio Pharmaceuticals, Amryt Pharmaceuticals, Celldex Therapeutics, Debiopharm, Galderma Research and Development, Johnson and Johnson, Novocure, Lindi, Merck Sharp & Dohme, Helsinn Healthcare, Janssen Research & Development, Menlo Therapeutics, Novartis, F Hoffman-La Roche, AbbVie, Boehringer Ingelheim, Allergen, Amgen, ER Squibb & Sons, EMD Serono, AstraZeneca, Genentech, Leo Pharma, Seattle Genetics, Bayer, Manner, Lutris, Pierre Fabre, Paxman Coolers, Adjucare, Dignitana, Biotechspert, Teva Mexico, Parexel, OnQuality Pharmaceuticals, and Our Brain Bank; and has received research funding from Veloce, US Biotest, Berg, Bristol-Myers Squibb, Lutris, Paxman, and Novocure, outside of the submitted work. H-JL received honoraria from Bristol-Myers Squibb, Bayer, Merck, Isofol, and Genentech; and travel expenses from Merck KGA and Bayer during the conduct of the study. He also has a patent pending. AG received travel expenses from Bayer to attend advisory board meetings during the conduct of the study. His previous institution received honoraria from Genentech, Merck, Boston Biomedicals, Taiho, and Array for consulting activities outside of the submitted work. F-SO, ENH, TJD, NLJ, BCP, JPM, JSM, AB, and JS declare no competing interests.
Funding Information:
Funding for the study was received from Bayer HealthCare Pharmaceuticals. We would like to acknowledge Alicia Elsing from Academic and Community Cancer Research United (ACCRU) for her role as the lead research protocol specialist on the study. Editorial and medical writing assistance was provided by Joanne Franklin and Sandra Mendes from Aptitude Health (The Hague, the Netherlands) and funded by ACCRU.
Publisher Copyright:
© 2019 Elsevier Ltd
PY - 2019/8
Y1 - 2019/8
N2 - Background: Regorafenib confers an overall survival benefit in patients with refractory metastatic colorectal cancer; however, the adverse event profile of regorafenib has limited its use. Despite no supportive evidence, various dosing schedules are used clinically to alleviate toxicities. This study evaluated the safety and activity of two regorafenib dosing schedules. Methods: In this randomised, multicentre, open-label, phase 2 study done in 39 outpatient cancer centres in the USA, adults aged 18 years or older with histologically or cytologically confirmed advanced or metastatic adenocarcinoma of the colon or rectum that was refractory to previous standard therapy, including EGFR inhibitors if KRAS wild-type, were enrolled. Eligible patients had an Eastern Cooperative Oncology Group performance status of 0–1 and had no previous treatment with regorafenib. Patients were randomly assigned (1:1:1:1) into four groups with two distinct regorafenib dosing strategies and two clobetasol usage plans, stratified by hospital. Regorafenib dosing strategies were a dose-escalation strategy (starting dose 80 mg/day orally with weekly escalation, per 40 mg increment, to 160 mg/day regorafenib) if no significant drug-related adverse events occurred and a standard-dose strategy (160 mg/day orally) for 21 days of a 28-day cycle. Clobetasol usage plans (0·05% clobetasol cream twice daily applied to palms and soles) were either pre-emptive or reactive. After randomisation to the four preplanned groups, using the Pocock and Simon dynamic allocation procedures stratified by the treating hospitals, we formally tested the interaction between the two interventions, dosing strategy and clobetasol usage. Given the absence of a significant interaction (p=0·74), we decided to pool the data for the pre-emptive and reactive treatment with clobetasol and compared the two dosing strategies (dose escalation vs standard dose). The primary endpoint was the proportion of evaluable patients (defined as those who were eligible, consented, and received any protocol treatment) initiating cycle 3 and was analysed per protocol. Superiority for dose escalation was declared if the one-sided p value with Fisher's exact test was less than 0·2. This trial is registered with ClinicalTrials.gov, number NCT02368886. This study is fully accrued but remains active. Findings: Between June 2, 2015, and June 22, 2017, 123 patients were randomly assigned to treatment, of whom 116 (94%) were evaluable. The per-protocol population consisted of 54 patients in the dose-escalation group and 62 in the standard-dose group. At data cutoff on July 24, 2018, median follow-up was 1·18 years (IQR 0·98–1·57). The primary endpoint was met: 23 (43%, 95% CI 29–56) of 54 patients in the dose-escalation group initiated cycle 3 versus 16 (26%, 15–37) of 62 patients in the standard-dose group (one-sided p=0·043). The most common grade 3–4 adverse events were fatigue (seven [13%] patients in the dose-escalation group vs 11 [18%] in the standard-dose group), hand-foot skin reaction (eight [15%] patients vs ten [16%] patients), abdominal pain (nine [17%] patients vs four [6%] patients), and hypertension (four [7%] patients vs nine [15%] patients). 14 patients had at least one drug-related serious adverse event: six patients in the dose-escalation group and eight patients in the standard-dose group. There was one probable treatment-related death in the standard-dose group (myocardial infarction). Interpretation: The dose-escalation dosing strategy represents an alternative approach for optimising regorafenib dosing with comparable activity and lower incidence of adverse events and could be implemented in clinical practice on the basis of these data. Funding: Bayer HealthCare Pharmaceuticals.
AB - Background: Regorafenib confers an overall survival benefit in patients with refractory metastatic colorectal cancer; however, the adverse event profile of regorafenib has limited its use. Despite no supportive evidence, various dosing schedules are used clinically to alleviate toxicities. This study evaluated the safety and activity of two regorafenib dosing schedules. Methods: In this randomised, multicentre, open-label, phase 2 study done in 39 outpatient cancer centres in the USA, adults aged 18 years or older with histologically or cytologically confirmed advanced or metastatic adenocarcinoma of the colon or rectum that was refractory to previous standard therapy, including EGFR inhibitors if KRAS wild-type, were enrolled. Eligible patients had an Eastern Cooperative Oncology Group performance status of 0–1 and had no previous treatment with regorafenib. Patients were randomly assigned (1:1:1:1) into four groups with two distinct regorafenib dosing strategies and two clobetasol usage plans, stratified by hospital. Regorafenib dosing strategies were a dose-escalation strategy (starting dose 80 mg/day orally with weekly escalation, per 40 mg increment, to 160 mg/day regorafenib) if no significant drug-related adverse events occurred and a standard-dose strategy (160 mg/day orally) for 21 days of a 28-day cycle. Clobetasol usage plans (0·05% clobetasol cream twice daily applied to palms and soles) were either pre-emptive or reactive. After randomisation to the four preplanned groups, using the Pocock and Simon dynamic allocation procedures stratified by the treating hospitals, we formally tested the interaction between the two interventions, dosing strategy and clobetasol usage. Given the absence of a significant interaction (p=0·74), we decided to pool the data for the pre-emptive and reactive treatment with clobetasol and compared the two dosing strategies (dose escalation vs standard dose). The primary endpoint was the proportion of evaluable patients (defined as those who were eligible, consented, and received any protocol treatment) initiating cycle 3 and was analysed per protocol. Superiority for dose escalation was declared if the one-sided p value with Fisher's exact test was less than 0·2. This trial is registered with ClinicalTrials.gov, number NCT02368886. This study is fully accrued but remains active. Findings: Between June 2, 2015, and June 22, 2017, 123 patients were randomly assigned to treatment, of whom 116 (94%) were evaluable. The per-protocol population consisted of 54 patients in the dose-escalation group and 62 in the standard-dose group. At data cutoff on July 24, 2018, median follow-up was 1·18 years (IQR 0·98–1·57). The primary endpoint was met: 23 (43%, 95% CI 29–56) of 54 patients in the dose-escalation group initiated cycle 3 versus 16 (26%, 15–37) of 62 patients in the standard-dose group (one-sided p=0·043). The most common grade 3–4 adverse events were fatigue (seven [13%] patients in the dose-escalation group vs 11 [18%] in the standard-dose group), hand-foot skin reaction (eight [15%] patients vs ten [16%] patients), abdominal pain (nine [17%] patients vs four [6%] patients), and hypertension (four [7%] patients vs nine [15%] patients). 14 patients had at least one drug-related serious adverse event: six patients in the dose-escalation group and eight patients in the standard-dose group. There was one probable treatment-related death in the standard-dose group (myocardial infarction). Interpretation: The dose-escalation dosing strategy represents an alternative approach for optimising regorafenib dosing with comparable activity and lower incidence of adverse events and could be implemented in clinical practice on the basis of these data. Funding: Bayer HealthCare Pharmaceuticals.
UR - http://www.scopus.com/inward/record.url?scp=85069809384&partnerID=8YFLogxK
U2 - 10.1016/S1470-2045(19)30272-4
DO - 10.1016/S1470-2045(19)30272-4
M3 - Article
C2 - 31262657
AN - SCOPUS:85069809384
VL - 20
SP - 1070
EP - 1082
JO - The Lancet Oncology
JF - The Lancet Oncology
SN - 1470-2045
IS - 8
ER -