Dataset Information

Safety and efficacy of regorafenib in patients with treatment-refractory metastatic colorectal cancer in Turkey: the single-arm, open-label REGARD study.

ABSTRACT: OBJECTIVES:Regorafenib improved overall survival in patients with metastatic colorectal cancer (mCRC) refractory to standard therapies in two randomised, phase III trials, but has not been evaluated in Turkey. REGARD evaluated the safety and efficacy of regorafenib in Turkish patients with treatment-refractory mCRC. DESIGN:Open-label, single-arm, phase IIIb study conducted between July 2013 and April 2015. SETTING:11 tertiary centres in Turkey. PARTICIPANTS:Eligible patients were adults with mCRC who had disease progression within 3 months after receiving their last dose of approved standard therapies and who had an Eastern Cooperative Oncology Group performance status ?1. Patients were excluded if they had previously received regorafenib. Of 139 patients screened, 100 were treated and completed the study, and all 100 were analysed. Fifty-eight per cent were male. INTERVENTIONS:Patients received oral regorafenib, 160?mg once daily, for the first 3 weeks of each 4-week cycle until disease progression, death or unacceptable toxicity. PRIMARY AND SECONDARY OUTCOME MEASURES:The primary endpoint was safety, assessed by incidence of treatment-emergent adverse events (TEAEs). Progression-free survival (PFS) per investigator was the primary efficacy endpoint. There were no secondary endpoints. RESULTS:The median treatment duration was 2.5 months (range 0.1 to 20.6). Ninety-six per cent of patients had at least one TEAE and 77% had a grade ?3?TEAE. The most common grade ?3 regorafenib-related TEAEs were hypophosphataemia (11%), fatigue (8%), hyperbilirubinaemia (6%), hand-foot skin reaction (5%), hypertension (5%), anorexia (5%) and increased alanine aminotransferase (5%). TEAEs led to dose reduction in 30% of patients. Regorafenib-related TEAEs led to treatment discontinuation in 17% of patients. Median PFS was 3.1 months (95% CI 2.9 to 3.8). CONCLUSION:The regorafenib safety profile and PFS in REGARD were consistent with the results of previous trials of regorafenib in mCRC. Regorafenib is an option for patients in Turkey with treatment-refractory mCRC. TRIAL REGISTRATION NUMBER:NCT01853319, ClinicalTrials.gov.

SUBMITTER: Dane F

PROVIDER: S-EPMC7170555 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Safety and efficacy of regorafenib in patients with treatment-refractory metastatic colorectal cancer in Turkey: the single-arm, open-label REGARD study.

Dane Faysal F Ozgurdal Kirhan K Yalçın Şuayib Ş Benekli Mustafa M Aykan Nuri Faruk NF Yücel İdris İ Özkan Metin M Evrensel Turkkan T Sevinç Alper A Coskun Hasan Şenol HŞ Sanli Ulus Ali UA Kara Ismail Oguz IO Yumuk Perran Fulden PF

BMJ open 20200326 3

<h4>Objectives</h4>Regorafenib improved overall survival in patients with metastatic colorectal cancer (mCRC) refractory to standard therapies in two randomised, phase III trials, but has not been evaluated in Turkey. REGARD evaluated the safety and efficacy of regorafenib in Turkish patients with treatment-refractory mCRC.<h4>Design</h4>Open-label, single-arm, phase IIIb study conducted between July 2013 and April 2015.<h4>Setting</h4>11 tertiary centres in Turkey.<h4>Participants</h4>Eligible ...[more]

PMID: 32220908

Similar Datasets

Project description:BackgroundRegorafenib 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.MethodsIn 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.FindingsBetween 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).InterpretationThe 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.FundingBayer HealthCare Pharmaceuticals.

Project description:INTRODUCTION:Regorafenib was recently approved for patients with pretreated advanced colorectal cancer (aCRC), despite a moderate improvement of the patients' outcome, and significant toxicities. Based on previous studies showing that early fluorodeoxyglucose-positron emission tomography (FDG-PET)-based metabolic response assessment (MRA) might adequately select patients unlikely to benefit from treatment, the RegARd-C trial uses early MRA to identify likely non-responders to regorafenib in a population of patients with aCRC and guide a comprehensive evaluation of genomic and epigenetic determinants of resistance to treatment. METHODS AND ANALYSIS:RegARd-C is a multicentric prospective study. Its primary objective is to identify non-benefitters from regorafenib given at 160?mg/day, 3?weeks out of 4 in a population of patients with pretreated aCRC. Baseline PET is repeated at day 14 of the first treatment course. MRA is blinded for the investigators. Overall survival (OS) is the primary end point and will be correlated with metabolic parameters and (epi)genetic alterations assessed from tumour and serial blood samples. A target sample size of 105 evaluable patients (70 as derivation set and 35 as validation set), is considered as sufficient to validate an expected HR for OS of metabolic responders compared to metabolic non-responders significantly <1 (with 80% power and 1-sided 5% ? in case of a true HR?0.59 and a responders rate of 47%). ETHICS AND DISSEMINATION:The study was approved by the Institut Jules Bordet's competent ethics committee and complies with the Helsinki declaration or the Belgian laws and regulations, whichever provides the greatest protection for the patient, and follows the International Conference on Harmonisation E 6 (R1) Guideline for Good Clinical Practice, reference number CPMP/ICH/135/95. The protocol and the trials results, even inconclusive, will be presented at international oncology congresses, and published in peer-reviewed journals. Genomic and epigenetic data will be made available in public open data sets. TRIAL REGISTRATION NUMBERS:EudraCT number: 2012-005655-16; ClinicalTrials.gov number: NCT01929616.

Project description:BACKGROUND:In the phase III CORRECT trial, regorafenib significantly improved survival in treatment-refractory metastatic colorectal cancer (mCRC). The CONSIGN study was designed to further characterize regorafenib safety and allow patients access to regorafenib before market authorization. METHODS:This prospective, single-arm study enrolled patients in 25 countries at 186 sites. Patients with treatment-refractory mCRC and an Eastern Cooperative Oncology Group performance status (ECOG PS) ?1 received regorafenib 160 mg once daily for the first 3 weeks of each 4-week cycle. The primary endpoint was safety. Progression-free survival (PFS) per investigator assessment was the only efficacy evaluation. RESULTS:In total, 2,872 patients were assigned to treatment and 2,864 were treated. Median age was 62 years, ECOG PS 0/1 was 47%/53%, and 74% had received at least three prior regimens for metastatic disease. Median treatment duration was three cycles. Treatment-emergent adverse events (TEAEs) led to dose reduction in 46% of patients. Regorafenib-related TEAEs led to treatment discontinuation in 9%. Grade 5 regorafenib-related TEAEs occurred in <1%. The most common grade ?3 regorafenib-related TEAEs were hypertension (15%), hand-foot skin reaction (14%), fatigue (13%), diarrhea (5%), and hypophosphatemia (5%). Treatment-emergent grade 3-4 laboratory toxicities included alanine aminotransferase (6%), aspartate aminotransferase (7%), and bilirubin (13%). Ongoing monitoring identified one nonfatal case of regorafenib-related severe drug-induced liver injury per DILI Working Group criteria. Median PFS (95% confidence interval [CI]) was 2.7 months (2.6-2.7). CONCLUSION:In CONSIGN, the frequency and severity of TEAEs were consistent with the known safety profile of regorafenib. PFS was similar to reports of phase III trials. ClinicalTrials.gov: NCT01538680. IMPLICATIONS FOR PRACTICE:Patients with metastatic colorectal cancer (mCRC) who fail treatment with standard therapies, including chemotherapy and monoclonal antibodies targeting vascular endothelial growth factor or epidermal growth factor receptor, have few treatment options. The multikinase inhibitor regorafenib was shown to improve survival in patients with treatment-refractory mCRC in the phase III CORRECT (N = 760) and CONCUR (N = 204) trials. However, safety data on regorafenib for mCRC in a larger number of patients were not available. The CONSIGN trial, carried out prospectively in more than 2,800 patients across 25 countries, confirmed the safety profile of regorafenib from the phase III trials and reinforced the importance of using treatment modifications to manage adverse events.

Project description:Lessons learnedPatient compliance with the oral dosage treatment was good, with no need for hospitalization. Patients with tracheal and esophageal fistulas can take crushed apatinib by nutrient tube, with the same bioavailability and efficacy. Apatinib may be an effective and safe second- or further-line treatment for advanced esophageal cancer.BackgroundApatinib is an inhibitor of vascular endothelial growth factor receptor-2 (VEGFR2), which is thought to play a role in esophageal cancer progression. Our goal was to evaluate the efficacy and safety of apatinib in patients with unresectable esophageal cancer and to examine whether VEGFR2 expression influenced the clinical response.MethodsThis single-arm, open-label, investigator-initiated phase II study enrolled patients with advanced squamous cell carcinoma (SCC) or adenocarcinoma of the esophagus or esophagogastric junction who were admitted to Tianjin Medical University Cancer Institute and Hospital between August 2017 and January 2019. Apatinib monotherapy (500 mg/day) was given orally or via an enteral tube until disease progression, unacceptable toxicity, withdrawal, or death. Patients were followed until treatment was discontinued or death. The main endpoints were tumor response, progression-free survival (PFS), overall survival (OS), and adverse events (AEs).ResultsAmong 32 patients screened for inclusion, 30 were included in the safety and survival analyses (i.e., received apatinib), and 26 were included in the efficacy analysis (at least one imaging follow-up). Median follow-up time and exposure to apatinib were 5.34 months and 72 days, respectively. Among 26 patients included in the efficacy analysis, 2 had a partial response (PR; 7.7%) and 14 had stable disease (SD; 53.8%). The overall response rate (ORR) was 7.7%, and the disease control rate (DCR) was 61.5%. Median PFS and OS were 4.63 months (95% confidence interval, 2.11-7.16 months) and 6.57 months (4.90 months to not estimable), respectively. Fifteen patients (50.0%) experienced treatment-related AEs, most commonly hypertension (26.7%), diarrhea (20.0%), and hand-foot-skin reaction (10.0%). No patients had grade ≥4 treatment-related AEs.ConclusionApatinib was effective as second- or further-line treatment for advanced esophageal cancer.

Project description:LESSONS LEARNED:Patients with metastatic colorectal cancer with good performance status or no liver metastasis could benefit from apatinib.Circulating tumor DNA abundance may be a predictor in serial monitoring of tumor load. BACKGROUND:Apatinib, an oral vascular endothelial growth factor (VEGF) receptor-2 inhibitor, has been approved as third-line treatment for metastatic gastric cancer in China. The aim of this study was to evaluate the efficacy and safety of apatinib, in the treatment of patients with refractory metastatic colorectal cancer after failure of two or more lines of chemotherapy. METHODS:In this open-label, single-arm, phase II study, patients with histological documentation of adenocarcinoma of the colon or rectum were eligible if they had received at least two prior regimens of standard therapies including fluoropyrimidine, oxaliplatin, and irinotecan. These patients were treated with apatinib in a daily dose of 500 mg, p.o., in the third-line or higher setting. Capture sequencing was dynamically performed to identify somatic variants in circulating tumor DNA (ctDNA) with a panel of 1,021 cancer-related genes. The primary endpoint was progression-free survival (PFS) and the tumor response was determined according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Interim analysis was applied as predefined. RESULTS:From June 1, 2016 to December 31, 2017, 26 patients were enrolled. The median PFS of the whole group was 3.9 months (95% confidence interval [CI]: 2.1-5.9). The median overall survival (OS) was 7.9 months (95% CI: 4.6-10.1+). Patients with performance status (PS) 0-1 had longer PFS than those with PS 2 (4.17 months vs. 1.93 months, p = .0014). Patients without liver metastasis also had longer PFS than those who had live metastasis (5.87 months vs. 3.33 months, p = .0274). The common side effects of apatinib were hypertension, hand-foot syndrome, proteinuria, and diarrhea. The incidence of grade 3-4 hypertension, hand-foot syndrome, proteinuria, and diarrhea was 76.92%, 11.54%, 73.08%, and 23.08%, respectively. All of the patients received dose reduction because of adverse effect. Results of capture sequencing showed APC, TP53, and KRAS were most frequently mutant genes. ctDNA abundance increased before the radiographic assessment in ten patients. CONCLUSION:Apatinib monotherapy showed promising efficiency for patients with refractory colorectal cancer, especially in patients with PS 0-1 or no liver metastasis. ctDNA abundance may be a predictor in serial monitoring of tumor load.

Project description:BackgroundPatients with microsatellite stable (MSS) colorectal carcinoma (CRC) do not respond to immune checkpoint inhibitors. Preclinical models suggested synergistic anti-tumour activity combining CXD101 and anti-programmed cell death protein 1 treatment; therefore, we assessed the clinical combination of CXD101 and nivolumab in heavily pre-treated patients with MSS metastatic CRC (mCRC).Patients and methodsThis single-arm, open-label study enrolled patients aged 18 years or older with biopsy-confirmed MSS CRC; at least two lines of systemic anticancer therapies (including oxaliplatin and irinotecan); at least one measurable lesion; Eastern Cooperative Oncology Group performance status of 0, 1 or 2; predicted life expectancy above 3 months; and adequate organ and bone marrow function. Nine patients were enrolled in a safety run-in study to define a tolerable combination schedule of CXD101 and nivolumab, followed by 46 patients in the efficacy assessment phase. Patients in the efficacy assessment cohort were treated orally with 20 mg CXD101 twice daily for 5 consecutive days every 3 weeks, and intravenously with 240 mg nivolumab every 2 weeks. The primary endpoint was immune disease control rate (iDCR).ResultsBetween 2018 and 2020, 55 patients were treated with CXD101 and nivolumab. The combination therapy was well tolerated with the most frequent grade 3 or 4 adverse events being neutropenia (18%) and anaemia (7%). Immune-related adverse reactions commonly ascribed to checkpoint inhibitors were surprisingly rare although we did see single cases of pneumonitis, hypothyroidism and hypopituitarism. There were no treatment-related deaths. Of 46 patients assessable for efficacy, 4 (9%) achieved partial response and 18 (39%) achieved stable disease, translating to an immune disease control rate of 48%. The median overall survival (OS) was 7.0 months (95% confidence interval 5.13-10.22 months).ConclusionsThe primary endpoint was met in this phase II study, which showed that the combination of CXD101 and nivolumab, at full individual doses in the treatment of advanced or metastatic MSS CRC, was both well tolerated and efficacious.

Project description:Regorafenib is an orally administered multikinase inhibitor that has been approved for patients with chemotherapy-refractory metastatic colorectal cancer (mCRC). Even though regorafenib significantly improved survival in two international phase 3 trials (CORRECT and CONCUR), a high rate of treatment-related toxic effects and dose modifications were observed with a modest benefit. The aim of this study was to provide information concerning the efficacy, safety, and cost of regorafenib in patients with mCRC in clinical practice.We retrospectively reviewed patients treated with regorafenib monotherapy for unresectable mCRC in five Franche-Comté cancer hospitals (France). The primary end point was overall survival. Secondary end points were safety and descriptive cost analyses of patients treated with regorafenib in clinical practice. Another aim of this study was to assess the impact of regorafenib prescription on the risk of hospitalization in real-life practice.From January 2014 to August 2014, 29 consecutive patients were enrolled. Patients were heavily pretreated and were refractory to standard chemotherapies. The primary tumor sites were the colon and the rectum for 55% and 45% of patients, respectively. Fifteen patients (51%) harbored an RAS mutation. Eastern Cooperative Oncology Group - Performance Status (PS) was 0-1 for 86% of patients and 2 for 14% of patients. Nineteen patients (66%) initially received reduced doses of 120 or 80 mg/day. The median duration of treatment was 2.5 months (range, 0.13-11.4 months). Treatment-related adverse events occurred in 86% of patients. The most frequent adverse events of any grade were fatigue (35%), diarrhea (20%), and hand-foot skin reaction (20%). Grade 3 or 4 treatment-related adverse events occurred in 10 patients (35%). Three patients (10%) were admitted to hospital due to drug-related severe adverse events. The mean cost of patient management with regorafenib for the duration of treatment was 9908 ± 8191€, and median cost was 7917€ (Interquartile range (IQR) 4469-13,042). The median overall survival was six months (95% confidence interval, five to eight months).The safety and efficacy of regorafenib in heavily pretreated mCRC patients was comparable, in our study, to prospective and retrospective trials. Toxic effects were mostly manageable in an outpatient setting. Regorafenib itself represented the most important (93%) part of supported costs. Even though most side effects were manageable in an outpatient setting, severe adverse events occurred from hospitalization in 10% of patients. These data should be confirmed in a larger real-life-based cohort. Identification of predictive biomarkers is needed for mCRC patient selection for regorafenib treatment.

Dataset Information

Safety and efficacy of regorafenib in patients with treatment-refractory metastatic colorectal cancer in Turkey: the single-arm, open-label REGARD study.

Publications

Safety and efficacy of regorafenib in patients with treatment-refractory metastatic colorectal cancer in Turkey: the single-arm, open-label REGARD study.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets