Trial design
This is a multicenter, randomized in a 2:1 ratio, controlled clinical trial with two parallel arms summarized in Fig 1. Neither the investigators nor the patients are masked to treatment allocation. In order to compare the efficacy and safety of regorafenib plus FOLFIRI with irinotecan dose adjusted based on UGT1A1 genotype (study group) and regorafenib monotherapy (control group), a total of 153 mCRCs that were previously treated with fluoropyrimidines, irinotecan, oxaliplatin, and monoclonal antibodies targeting VEGF; and monoclonal antibodies targeting EGFR for those with KRAS wild-type tumors will be recruited, of which 102 participants will be assigned to the study group and 51 participants will be assigned to the control group in a 2:1 ratio.
Study setting
The study will be conducted in 4 hospital centers in Taiwan.
Study participants
Participants will be recruited from Kaohsiung medical university hospital, Cathay General Hospital, Taichung Veterans General Hospital and Taipei Veterans General Hospital by the colorectal surgeons. The planned recruitment period is 24 months and informed consent will be obtained from all participants before randomization.
Eligibility criteria
Inclusion criteria
- Cyto-/histological confirmed mCRC
- Patients who have been previously treated with, or are not considered candidates for, other locally approved standard treatment(s) and for whom the decision has been made per investigator’s routine treatment practice to prescribe regorafenib as 3rd line (RAS mutant) or 4th line (RAS wildtype) therapy
- Aged no less than 20 years, at the time of acquisition of informed consent
- Eastern Cooperative Oncology Group (ECOG) performance score of 0-1
- Patients with measurable or non measurable disease in the colon or rectum, according to RECIST criteria version 1.1
- Life expectancy more than 12 weeks
- Women with childbearing potential must agree to perform adequate contraception measures since informed consent till a least 12 weeks after the last study drug administration. The investigators or designee are requested to advise the patient to achieve adequate birth control.
- Adequate organ and bone marrow function as defined below:
- Total bilirubin £5 x upper limit of normal (ULN)
- Alanine amino-transferase (ALT) and aspartate amino-transferase (AST) £5x ULN (£ 5x ULN for patients with liver metastases)
- Alkaline phosphatase (ALP) £5x ULN (£ 5x ULN for patients with liver metastases)
- Amylase and lipase £5 x ULN
- Serum creatinine £5 x ULN
- Glomerular filtration rate (GFR) ³ 30 ml/min/1.73 m2, according to the modified diet in renal disease (MDRD) abbreviated formula
- International normalized ratio (INR)/partial thromboplastin time (PTT) £5 x ULN
- Platelet count ³ 100000 /mm3
- Hemoglobin level ³ 9 g/dL
- Absolute neutrophil count ³ 1500/mm3
- Ability to understand and willingness to sign written Informed Consent Form
Exclusion criteria
- Treatment with any other investigational agents within 28 days prior to enrollment in this study
- Patients who have previously received FOFIRI with irinotecan dose escalation
- Other concurrent cancer or prior treatment for other carcinomas within the last five years, except curatively treated non-melanoma skin cancer, superficial bladder tumors, and cervical cancer in-situ
- Extended field radiotherapy within 28 days or limited radiotherapy within 14 days prior to randomization
- Major surgery within 28 days prior to start of study treatment (diagnostic biopsy, laparotomy, line placement is not considered as major surgery)
- Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, myocardial infarction in the past 12 months, active gastrointestinal bleeding, central nervous system disorders or psychiatric illness/social situation that would limit compliance with study requirements or judged to be ineligible for the study by the investigator
- History of myocardial infarction, deep venous or arterial thrombosis, CVA during the last 6 months
- Uncontrolled cardiac arrhythmias, unstable angina, or newly-onset angina within 3 months prior to study entry
- Uncontrolled hypertension despite optimal management (systolic blood pressure >150 mmHg or diastolic pressure >90 mmHg)
- Patients with known CNS metastases
- Having received any investigational agents or participated in any investigational drug study within 4 weeks prior to study enrollment
- Pregnant or breast-feeding female (a pregnancy test must be performed on all female patients who are of child-bearing potential within 7 days of treatment initiation, and the result must be negative)
- Inability to take oral medication
- Poor compliance as judged by the investigator.
Genotyping
DNA is extracted from 4 mL of patients’ peripheral blood with a PUREGENE® DNA isolation kit (Gentra Systems, Inc., Minneapolis, MN, USA). Then the genomic DNA extracted is analyzed using direct sequencing to determine the UGT1A1 promoter genotype. The primers are designed by primer 3 free software (http://primer3.wi.mit.edu), and the sequence of the forward is 5-AGT-CACGTGACACAGTCAAACA-3 and the reverse primer is 5-CTTTGCTCCTGCCAGAGGTT-3. The polymerase chain reaction (PCR) volume is 40 µL and the PCR conditions for the UGT1A1 are as follows: 94.0 oC for 5 minutes; annealing for 20 seconds at 67.5 oC; primer extension for 20 seconds at 72.0 oC; and final extension for 10 minutes at 72.0 oC. A fragment analysis of the PCR products is conducted to verify the genotypes by using the automated capillary electrophoresis on the ABI PRISM 310 Genetic Analyzer (Applied Biosystems, Foster City, CA, USA), and the genotypes are analyzed using GeneScan and Genotyper software (Applied Biosystems, Foster City, CA, USA) [10].
Interventions
Control group
The treatment for the control group will be oral regorafenib monotherapy in the dosing schedule of 120 mg once daily for the first 3 weeks of each 4 week cycle, without UGT1A1 genotyping. If any regorafenib related AEs greater than grade 3 develops, regorafenib will be stopped until encountered AEs recover and dose of regorafenib will be reduced by 40 mg daily.
Study group
The treatment for the study group will be composed of oral regorafenib 120 mg once daily for the first 3 weeks of each 4 week cycle as described above and additional infusion of FOLFIRI regimen. If any regorafenib related AEs greater than grade 3 develops, regorafenib will be stopped until encountered AEs recover and dose of regorafenib will be reduced by 40 mg daily. According to the UGT1A1 genotypes, the study group is further divided into three subgroups:
Subgroup 1: UGT1A1*1/*1 genotype
Oral regorafenib will be administered in a dose of 120 mg once daily for the first 3 weeks of each 4 week cycle. FOLFIRI regimen will be initiated at a dose of 180 mg/m2 irinotecan and 200 mg/ m2 LV intravenously (IV) infused over 2 hours followed by 5-FU (2800 mg/ m2 as an IV infusion over a 46-hour period). If no greater than grade 3 FOLFIRI related AEs is observed after two cycles of each dose of irinotecan, the dose of irinotecan will be escalated in steps of 30 mg/ m2. If any FOLFIRI related AEs greater than grade 3 are encountered, the dose of irinotecan will be reduced by 30 mg/ m2 or back to the previous dose and be withheld at that dose at the next cycle. The maximal dose of irinotecan for subgroup 1 is 260 mg/ m2.
Subgroup 2: UGT1A1*1/*28 genotype
Oral regorafenib will be administered in a dose of 120 mg once daily for the first 3 weeks of each 4 week cycle. FOLFIRI regimen will be initiated at a dose of 180 mg/m2 irinotecan and 200 mg/ m2 LV intravenously (IV) infused over 2 hours followed by 5-FU (2800 mg/ m2 as an IV infusion over a 46-hour period). If no greater than grade 3 FOLFIRI related AEs is observed after two cycles of each dose of irinotecan, the dose of irinotecan will be escalated in steps of 30 mg/ m2. If any FOLFIRI related AEs greater than grade 3 are encountered, the dose of irinotecan will be reduced by 30 mg/ m2 or back to the previous dose and be withheld at that dose at the next cycle. The maximal dose of irinotecan for subgroup 2 is 240 mg/ m2.
Subgroup 3: UGT1A1*28/*28 genotype
Oral regorafenib will be administered in a dose of 120 mg once daily for the first 3 weeks of each 4 week cycle. FOLFIRI regimen will be initiated at a dose of 120 mg/m2 irinotecan and 200 mg/ m2 LV intravenously (IV) infused over 2 hours followed by 5-FU (2800 mg/ m2 as an IV infusion over a 46-hour period). If no greater than grade 3 FOLFIRI related AEs is observed after two cycles of each dose of irinotecan, the dose of irinotecan will be escalated in steps of 30 mg/ m2. If any FOLFIRI related AEs greater than grade 3 are encountered, the dose of irinotecan will be reduced by 30 mg/ m2 or back to the previous dose and be withheld at that dose at the next cycle. The maximal dose of irinotecan for subgroup 3 is 180 mg/ m2.
All the treatment will be stopped in the event of patient withdrawal, disease progression, or unacceptable AEs, which are defined as non-hemotological grade 4 AEs, no recovery from grade 3 AEs after two consecutive dose reductions or no recovery after a 2-week treatment delay.
Throughout the study period, participants should not receive other cytotoxic or biological treatments for mCRC. If concomitant treatments are considered necessary based on investigators’ discretion, product package insert should be referenced for contraindication and all concomitant treatments should be recorded on the relevant case report form (CRF) page.
Outcome measurements
Primary outcome
The treatment response will be radiologically assessed every 2 months through computed tomography, or magnetic resonance imaging. Objective responses were classified according to RECIST and optimal treatment responses will be recorded. The primary endpoint is PFS, which is defined as the time from initiation of study treatment to first radiological progression or tumor-related death, whichever comes first.
Secondary outcome
Secondary outcome will be as follows:
- OS is defined as the time from initiation of study treatment to death, due to any cause
- DCR is defined as percentage of patients, whose best response was not progressive disease [i.e. complete response (CR), partial response (PR) or stable disease (SD)]
- Time to progression (TTP) is defined as the time (days) from the start of study treatment to the first documented disease progression
- Duration of treatment (DoT) is defined as the time interval from the start of study treatment to the day of permanent discontinuation (including death); mean dose and reasons for treatment discontinuation or dose modification will be recorded
Safety assessment
The treatment-associated AEs will be assessed and recorded in each cycle using Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.
Safety stopping rules
Study will be stopped according to patients’ willing and patients’ conditions judged by investigators, or if any grade 4 AE develops.
Participant timeline
Study is planned to start in May 2018 and is expected to end in May 2020, last for 2 years including recruitment, follow-up, data collection and data analysis. The schedule of study visits and assessments is summarized in Table 1.
Sample size estimation
Using a per-protocol two-sided α of 0.025, a 2:1 randomization between regorafenib plus FOLFIRI dose escalation and regorafenib, and a median progression free survival of 3.2 months in the regorafenib group [9], the study would have 90% power to detect assumed median progression free survival 7.0 months with Regorafenib plus FOLFIRI [3]. The assumption of overall probability of events: 0.77 (10 progressions at the end of the study/ 13 in total) [9]. The calculated sample size is 121 patients. Considering 20% of drop rate, total of 153 patients would be enrolled into the study, assigned 102 in the study group (FOLFIRI plus regorafenib group) and 51 in the control group (regorafenib monotherapy group).
Recruitment
Participants will be enrolled from patients with mCRC, whose diseases are refractory to fluoropyrimidines, irinotecan, oxaliplatin, and monoclonal antibodies targeting vascular endothelial growth factor (VEGF); and monoclonal antibodies targeting epidermal growth factor receptor (EGFR) for those with KRAS wild-type cancers.
Assignment of interventions
Randomization and allocation
Before study initiation, a randomization sequence is computer generated (GraphPad statistical software, GraphPad, USA) and participants are allocated to either the study or the control group in 2:1 ratio in blocks of size 6 by an independent investigator.
Data collection, management, and analysis
Data collection methods
Table 1 shows details of data collection throughout the study period
Data management
An electronic CRF will be made available and for the assurance of the data accuracy, completeness, and reliability. The research staff will preserve documented data from all sources on CRF.
Statistical methods
Results would be compared using Mann-Whitney U test or Kruskal-Wallis test for categorical unpaired data. The Wilcoxon rank-sum test or the Friedman test was used to analyze paired data. The Fisher’s exact test was used to compare dichotomous variables. The Pearson chi-square test was used to analyze nominal variables. The McNemar test was used to analyze paired categorical data. The means were compared using the 2-sample test and using analysis of variance (ANOVA) or linear regression, as appropriate. However, for all aforementioned inferential analysis methods, the center effect was not considered when comparing one treatment with another. Therefore, ANOVA incorporating the center effect and Cochran–Mantel–Haenszel test stratified by the center effect were applied to replace the 2-sample t-test and the Fisher’s exact test. For efficacy analyses and part of the safety analyses (including laboratory data and vital sign data), considering the effect of baseline data on the endpoints, analysis of covariance (ANCOVA) was applied when comparing one treatment mean with another, with their respective baseline as covariates. Baseline data were defined as the data obtained before the first administration of treatment before surgery. Endpoints were defined as the net change of post-treatment data from baseline data. Statistical analyses were conducted using SPSS 20.0 (SPSS, Chicago, IL, USA). P values less than 0.05 were statistically significant.
Data monitoring
All aspect of the study will be conducted under international conference on harmonization (ICH), good clinical practice (GCP) guidelines, and government regulations. Monitoring (by phone, fax, or on site) will be done by a representative of the study monitor designated by the investigators. The monitor will check CRFs for completeness and clarify, and crosscheck them with source documents. Data safety monitoring committee (DSMC) organized by the Institutional Review Board of Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan also monitors patient safety and treatment efficacy data while the study is ongoing. The DSMC is composed of 2 oncologists, a physician, and a statistician and none of them is involved in the study.
The DSMC receives reports every 6 months to ensures that the investigation is conducted according to protocol design and regulatory requirements. The DSMC also monitors AEs/SAEs involves issue of the risk benefit to consider termination of the study.
Interim analysis
Early safety analysis will be performed 6 months after study is initiated.
Adverse events
All AEs including local and systemic reactions will be collected includes the event description, time of onset, clinicians’ assessment of severity, relation to study drugs and time of resolution or stabilization of the event. All AEs will be followed up until adequate resolution. Pre-existing conditions will be recorded as medical histories. If the pre-existing condition does not change, it will not be recorded as an AE. Instead, if it deteriorates at any time during the study, it will be recorded as an AE.
Auditing
Domestic authorities and the institutional reviewing board may request access to all source documents, CRFs, and other study documentation for on-site audit or inspection. The purpose of the audits is to evaluate study conduct and compliance with the protocol, standard operating procedures, GCP, and the applicable regulatory requirements. The observations and findings will be documented.
Consent
The patients’ free, informed and written consent will be collected by the investigator, or a doctor representing them prior to final inclusion in the study. A copy of the information and consent form signed by both parties will be given to the patient; the investigator will keep the original.
Confidentiality
Only the patient number will be recorded in the CRF. The investigators maintain a personal patient identification list (patient numbers with the corresponding patient names) to enable records to be identified.
Publication plan
The results of the trial will be published in international oncological, medical and scientific journals and presented at national and international congresses. The investigators will follow the rules and guidelines of the International Committee for Medical Journal Editors (ICMJE) for authorship.