Phase III Study of Trifluridine/Tipiracil With and Without Bevacizumab in Refractory Metastatic Colorectal Cancer Patients

Study Overview
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Brief Summary
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This study is designed as an international, open-label, controlled two-arm, randomized phase III comparison study evaluating the efficacy and safety of trifluridine/tipiracil in combination with bevacizumab versus trifluridine/tipiracil monotherapy in patients with refractory mCRC.

Detailed Description
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This is an international, open-label, controlled two-arm, randomised phase III study evaluating the efficacy and safety of trifluridine/tipiracil in combination with bevacizumab versus trifluridine/tipiracil monotherapy in patients with refractory mCRC. The analysis will be done after 331 events are reported. In order to observe this number of events, 490 patients will be randomised (1:1) to receive trifluridine/tipiracil in combination with bevacizumab (experimental arm) or trifluridine/tipiracil monotherapy (control arm).

Official Title
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An Open-label, Randomized, Phase III Study Comparing Trifluridine/Tipiracil in Combination With Bevacizumab to Trifluridine/Tipiracil Monotherapy in Patients With Refractory Metastatic Colorectal Cancer (SUNLIGHT Study)

Conditions
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Refractory Metastatic Colorectal Cancer

Intervention / Treatment
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* Drug: Trifluridine/Tipiracil
* Drug: Bevacizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Has histologically confirmed unresectable adenocarcinoma of the colon or rectum (all other histological types are excluded). RAS status must have been previously determined (mutant or wild-type) based on local assessment of tumor biopsy. Has received a maximum of 2 prior chemotherapy regimens for the treatment of advanced colorectal cancer and had demonstrated progressive disease or intolerance to their last regimen. Has measurable or non-measurable disease as defined by RECIST version 1.1 Is able to swallow oral tablets. Estimated life expectancy ≥12 weeks. Eastern Cooperative Oncology Group performance status (ECOG PS) 0 or 1 Exclusion Criteria: More than 2 prior chemotherapy regimens for the treatment of advanced colorectal cancer. Pregnancy, lactating female or possibility of becoming pregnant during the study. Patients currently receiving or having received anticancer therapies within 4 weeks prior to randomization. Has not recovered from clinically relevant non-hematologic CTCAE grade ≥ 3 toxicity of previous anticancer therapy prior to randomization (excluding alopecia, and skin pigmentation). Has symptomatic central nervous system metastases that are neurologically unstable or requiring increasing doses of steroids to control CNS disease. Has severe or uncontrolled active acute or chronic infection. Has active or history of interstitial lung disease and/or pneumonitis, or pulmonary hypertension. Known Hepatitis B or Hepatitis C Virus infection. Known carriers of HIV antibodies. Confirmed uncontrolled arterial hypertension (defined as systolic blood pressure ≥ 150 mm Hg and/or diastolic blood pressure ≥ 100 mm Hg) or uncontrolled or symptomatic arrhythmia. Deep arterial thromboembolic events including cerebrovascular accident or myocardial infarction within the last 6 months prior to randomization. Treatment with any of the following within the specified time frame prior to randomization: major surgery within 4 weeks prior to randomisation (the surgical incision should be fully healed prior to study drug administration), or has not recovered from side effects of previous surgery, or patient that may require major surgery during the study Prior radiotherapy if completed less than 4 weeks before randomisation, except if provided as a short course for symptoms palliation only. Drainage for ascites, pleural effusion or pericardial fluid within 4 weeks prior to randomization Other clinically significant medical conditions. Other malignancies.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Trifluridine/Tipiracil + Bevacizumab<br>Participants were administered 35 milligrams per square meter per dose (mg/m²/dose) trifluridine/tipiracil (FTD/TPI) orally twice a day (BID), within 1 hour after completion of morning and evening meals, 5 days on (Day 1 to 5 and Day 8 to 12) with 2 days off (Day 6 to 7 an Day 13 to 14), over 2 weeks, followed by a 14-day rest; with bevacizumab (5 milligrams per kilogram [mg/kg], intravenous [IV] infusion administered every 2 weeks (Day 1 and Day 15). This treatment cycle was repeated every 4 weeks. | Drug: Trifluridine/Tipiracil<br>* Taken by mouth two times a day, 5 days on/2 days off, over 2 weeks, followed by a 14-day rest<br>* Other names: Lonsurf;Drug: Bevacizumab<br>* administered every 2 weeks (Day 1 and Day 15)<br>* Other names: Avastin;|
| Active Comparator: Trifluridine/Tipiracil<br>Participants were administered 35 mg/m²/dose of FTD/TPI orally BID, within 1 hour after completion of morning and evening meals, 5 days on (Day 1 to 5 and Day 8 to 12) with 2 days off (Day 6 to 7 and Day 13 to 14), over 2 weeks, followed by a 14-day rest. This treatment cycle was repeated every 4 weeks. | Drug: Trifluridine/Tipiracil<br>* Taken by mouth two times a day, 5 days on/2 days off, over 2 weeks, followed by a 14-day rest<br>* Other names: Lonsurf;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) | Overall survival defined as the observed time elapsed between the date of randomization and the date of death due to any cause. The primary estimand of interest was defined to assess the effect of the randomized treatments on the survival duration in all participants regardless of whether or not intercurrent events had occurred (treatment policy strategy). Analysis was performed using Kaplan- Meier method. | From date of randomization to the death due to any cause or cut-ff date, whichever comes first (maximum duration: up to 20 months) | 
| Survival Probability at 6 Months | Overall survival defined as the observed time elapsed between the date of randomization and the date of death due to any cause. The primary estimand of interest was defined to assess the effect of the randomized treatments on the survival duration in all participants regardless of whether or not intercurrent events had occurred (treatment policy strategy). Analysis was performed using Kaplan- Meier method. In this outcome measure, data of survival probability at 6 months was reported. | From date of randomization until 6 months post treatment | 
| Survival Probability at 12 Months | Overall survival defined as the observed time elapsed between the date of randomization and the date of death due to any cause. The primary estimand of interest was defined to assess the effect of the randomized treatments on the survival duration in all participants regardless of whether or not intercurrent events had occurred (treatment policy strategy). Analysis was performed using Kaplan- Meier method. In this outcome measure, data of survival probability at 12 months was reported. | From date of randomization until 12 months post treatment | 
| Survival Probability at 18 Months | Overall survival defined as the observed time elapsed between the date of randomization and the date of death due to any cause. The primary estimand of interest was defined to assess the effect of the randomized treatments on the survival duration in all participants regardless of whether or not intercurrent events had occurred (treatment policy strategy). Analysis was performed using Kaplan- Meier method. In this outcome measure, data of survival probability at 18 months was reported. | From date of randomization until 18 months post treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival (PFS) | PFS was defined as the time elapsed between the date of randomisation and the date of radiological tumour progression as per Response Evaluation Criteria in Solid Tumors (RECIST v1.1) assessed by investigator, or death (from any cause), whichever comes first. Progressive Disease (PD) as per RECIST 1.1: at least a 20 percent (%) increase in sum of diameters of target lesions, unequivocal progression of existing non-target lesions. Analysis was performed by Kaplan-Meier method. | From randomization to the date of radiological tumour progression or death due to any cause or data cut-off date whichever comes first (i.e., up to 20 months) | 
| Probability of Participants With Progression Free Survival at 3, 6, 9 and 12 Months | PFS was defined as the time elapsed between the date of randomisation and the date of radiological tumour progression as per Response Evaluation Criteria in Solid Tumors (RECIST v1.1) assessed by investigator, or death (from any cause), whichever comes first. Progressive Disease (PD) as per RECIST 1.1: at least a 20 percent (%) increase in sum of diameters of target lesions, unequivocal progression of existing non-target lesions. Analysis was performed by Kaplan-Meier method. In this outcome measure, data of PFS at 3 months was reported. | From randomization until 3, 6, 9, and 12 months post treatment | 
| Overall Response Rate (ORR) | Objective response was defined as percentage of participants who achieved complete response (CR) or partial response (PR) according to the RECIST version 1.1 and using investigator's tumour assessment. As per RECIST 1.1, CR was defined as disappearance of all target and non-target lesions and normalization of tumor marker level. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to less than (<) 10 millimeters (mm). PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the Baseline sum diameters. | From the date of randomization to the date of documentation of progression or death due to any cause or data cut-off, whichever occurred first (i.e., up to 20 months) | 
| Percentage of Participants With Disease Control | Disease control is defined as percentage of participants who achieved CR or PR, or stable disease (SD) as per RECIST 1.1 and using investigator's tumour assessment from the date of randomization to until disease progression or death due to any cause. As per RECIST 1.1, CR: disappearance of all target and non-target lesions and normalization of tumor marker level. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. PR: at least a 30% decrease in sum of diameters of target lesions, taking as reference baseline sum diameters. SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease, taking as reference the smallest sum diameters. PD: at least 20% increase in sum of diameters of target lesions, unequivocal progression of existing non-target lesions. | From randomization to the date of first documented tumor progression, death due to any cause or data cut-off date whichever comes first (i.e., up to 20 months) | 
| Number of Participants With Treatment-emergent Adverse Events (TEAE) and Treatment-emergent Serious Adverse Events (TESAEs) | An AE was defined as any untoward medical occurrence in a participant who received study drug and did not necessarily have to have a causal relationship with the treatment. Serious adverse events (SAEs) was any untoward medical occurrence that at any dose: resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, was a congenital anomaly/birth defect, was a medically important event. TEAEs were defined as AEs that developed, worsened or became serious during the TEAE period (time from the first dose of study treatment up to 30 days after the last dose of study treatment). TEAEs included both SAEs and non-SAEs. | From Baseline up to 30 days after the last dose of study treatments (i.e., up to 19.5 months) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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trifluridine/tipiracil/lonsurf, TAS102, bevacizumab, avastin, RAS status (wild type, mutant)