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

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ClinicalTrials.gov Identifier: NCT04737187
Recruitment Status : Completed
First Posted : February 3, 2021
Results First Posted : December 26, 2023
Last Update Posted : December 26, 2023
Sponsor:
Collaborator:
Institut de Recherches Internationales Servier
Information provided by (Responsible Party):
Taiho Oncology, Inc.

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition Refractory Metastatic Colorectal Cancer
Interventions Drug: Trifluridine/Tipiracil
Drug: Bevacizumab
Enrollment 492
Recruitment Details The study was conducted at 99 active sites in 13 countries. A total of 659 participants were screened, of which 492 participants were randomized and treated.
Pre-assignment Details Participants were randomized to 2 treatment arms in 1:1 ratio by interactive web response system stratified by geographic region (North America, European Union, Rest of the World), time since first metastasis diagnosis (less than [<] 18 months, greater than or equal to [>=] 18 months) and rat sarcoma virus (RAS) status (wild-type, mutant). Data reported based on primary completion date, i.e., 19 July 2022.
Arm/Group Title Trifluridine/Tipiracil + Bevacizumab Trifluridine/Tipiracil
Hide Arm/Group Description 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 and 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. 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.
Period Title: Overall Study
Started 246 246
Completed 0 0
Not Completed 246 246
Reason Not Completed
Continuing the study on treatment             32             4
Radiological Progressive Disease             145             146
Clinical Progressive Disease             20             20
Radiological And Clinical Progressive Disease             26             52
Adverse Event             16             16
Physician Decision             2             0
Withdrawal by Subject             5             8
Arm/Group Title Trifluridine/Tipiracil + Bevacizumab Trifluridine/Tipiracil Total
Hide Arm/Group Description Participants were administered 35 mg/m²/dose 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; with bevacizumab 5 mg/kg, IV infusion administered every 2 weeks (Day 1 and Day 15). This treatment cycle was repeated every 4 weeks. 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. Total of all reporting groups
Overall Number of Baseline Participants 246 246 492
Hide Baseline Analysis Population Description
Full Analysis Set (FAS): all participants to whom a therapeutic unit was randomly assigned using Interactive Web Response System (IWRS). Participants were analyzed in the arm they were assigned by randomization.
Age, Continuous  
Median (Full Range)
Unit of measure:  Years
Number Analyzed 246 participants 246 participants 492 participants
62.00
(20.0 to 84.0)
64.00
(24.0 to 90.0)
63.00
(20.0 to 90.0)
Age, Customized  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 246 participants 246 participants 492 participants
Adults (18-64 years)
146
  59.3%
129
  52.4%
275
  55.9%
From 65-84 years
100
  40.7%
116
  47.2%
216
  43.9%
85 years and over
0
   0.0%
1
   0.4%
1
   0.2%
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 246 participants 246 participants 492 participants
Female
124
  50.4%
112
  45.5%
236
  48.0%
Male
122
  49.6%
134
  54.5%
256
  52.0%
Race (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 246 participants 246 participants 492 participants
American Indian or Alaska Native
1
   0.4%
0
   0.0%
1
   0.2%
Asian
0
   0.0%
1
   0.4%
1
   0.2%
Native Hawaiian or Other Pacific Islander
0
   0.0%
0
   0.0%
0
   0.0%
Black or African American
4
   1.6%
3
   1.2%
7
   1.4%
White
215
  87.4%
220
  89.4%
435
  88.4%
More than one race
0
   0.0%
0
   0.0%
0
   0.0%
Unknown or Not Reported
26
  10.6%
22
   8.9%
48
   9.8%
1.Primary Outcome
Title Overall Survival (OS)
Hide Description 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.
Time Frame From date of randomization to the death due to any cause or cut-ff date, whichever comes first (maximum duration: up to 20 months)
Hide Outcome Measure Data
Hide Analysis Population Description
Analysis was performed on FAS population.
Arm/Group Title Trifluridine/Tipiracil + Bevacizumab Trifluridine/Tipiracil
Hide Arm/Group Description:
Participants were administered 35 mg/m²/dose 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; with bevacizumab 5 mg/kg, IV infusion administered every 2 weeks (Day 1 and Day 15). This treatment cycle was repeated every 4 weeks.
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.
Overall Number of Participants Analyzed 246 246
Median (95% Confidence Interval)
Unit of Measure: months
10.78
(9.36 to 11.83)
7.46
(6.34 to 8.57)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Trifluridine/Tipiracil + Bevacizumab, Trifluridine/Tipiracil
Comments Overall Survival Median analysis: The primary estimand 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).
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value < 0.001
Comments Stratified log-rank test, with a target p-value < 0.025 for level of significance.
Method Stratified log-rank test
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.61
Confidence Interval (2-Sided) 95%
0.49 to 0.77
Estimation Comments Hazard ratio and 95% confidence interval was estimated with stratified Cox proportional hazard model.
2.Primary Outcome
Title Survival Probability at 6 Months
Hide Description 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.
Time Frame From date of randomization until 6 months post treatment
Hide Outcome Measure Data
Hide Analysis Population Description
Analysis was performed on FAS population.
Arm/Group Title Trifluridine/Tipiracil + Bevacizumab Trifluridine/Tipiracil
Hide Arm/Group Description:
Participants were administered 35 mg/m²/dose 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; with bevacizumab 5 mg/kg, IV infusion administered every 2 weeks (Day 1 and Day 15). This treatment cycle was repeated every 4 weeks.
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.
Overall Number of Participants Analyzed 246 246
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: probability of participants
0.77
(0.72 to 0.82)
0.61
(0.55 to 0.67)
3.Primary Outcome
Title Survival Probability at 12 Months
Hide Description 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.
Time Frame From date of randomization until 12 months post treatment
Hide Outcome Measure Data
Hide Analysis Population Description
Analysis was performed on FAS population.
Arm/Group Title Trifluridine/Tipiracil + Bevacizumab Trifluridine/Tipiracil
Hide Arm/Group Description:
Participants were administered 35 mg/m²/dose 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; with bevacizumab 5 mg/kg, IV infusion administered every 2 weeks (Day 1 and Day 15). This treatment cycle was repeated every 4 weeks.
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.
Overall Number of Participants Analyzed 246 246
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: probability of participants
0.43
(0.36 to 0.49)
0.30
(0.24 to 0.36)
4.Primary Outcome
Title Survival Probability at 18 Months
Hide Description 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.
Time Frame From date of randomization until 18 months post treatment
Hide Outcome Measure Data
Hide Analysis Population Description
Analysis was performed on FAS population.
Arm/Group Title Trifluridine/Tipiracil + Bevacizumab Trifluridine/Tipiracil
Hide Arm/Group Description:
Participants were administered 35 mg/m²/dose 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; with bevacizumab 5 mg/kg, IV infusion administered every 2 weeks (Day 1 and Day 15). This treatment cycle was repeated every 4 weeks.
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.
Overall Number of Participants Analyzed 246 246
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: probability of participants
0.28
(0.19 to 0.37)
0.15
(0.09 to 0.22)
5.Secondary Outcome
Title Progression Free Survival (PFS)
Hide Description 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.
Time Frame 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)
Hide Outcome Measure Data
Hide Analysis Population Description
Analysis was performed on FAS population.
Arm/Group Title Trifluridine/Tipiracil + Bevacizumab Trifluridine/Tipiracil
Hide Arm/Group Description:
Participants were administered 35 mg/m²/dose 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; with bevacizumab 5 mg/kg, IV infusion administered every 2 weeks (Day 1 and Day 15). This treatment cycle was repeated every 4 weeks.
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.
Overall Number of Participants Analyzed 246 246
Median (95% Confidence Interval)
Unit of Measure: months
5.55
(4.50 to 5.88)
2.40
(2.07 to 3.22)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Trifluridine/Tipiracil + Bevacizumab, Trifluridine/Tipiracil
Comments PFS Median analysis: A hierarchical testing method was used to control type I error and handle key secondary endpoint analysis. When the primary outcome measure significant testing was then performed sequentially on the key secondary outcome measure. statistically significant at 0.05 level.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value < 0.001
Comments Stratified log-rank test, with a target p-value < 0.025 for level of significance.
Method Stratified log-rank test
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.44
Confidence Interval (2-Sided) 95%
0.36 to 0.54
Estimation Comments Hazard ratio and 95% confidence interval was estimated with stratified Cox proportional hazard model.
6.Secondary Outcome
Title Probability of Participants With Progression Free Survival at 3, 6, 9 and 12 Months
Hide Description 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.
Time Frame From randomization until 3, 6, 9, and 12 months post treatment
Hide Outcome Measure Data
Hide Analysis Population Description
Analysis was performed on FAS population.
Arm/Group Title Trifluridine/Tipiracil + Bevacizumab Trifluridine/Tipiracil
Hide Arm/Group Description:
Participants were administered 35 mg/m²/dose 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; with bevacizumab 5 mg/kg, IV infusion administered every 2 weeks (Day 1 and Day 15). This treatment cycle was repeated every 4 weeks.
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.
Overall Number of Participants Analyzed 246 246
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: probability of participants
At 3 Months
0.73
(0.67 to 0.78)
0.45
(0.39 to 0.51)
At 6 Months
0.43
(0.37 to 0.49)
0.16
(0.11 to 0.21)
At 9 Months
0.28
(0.22 to 0.34)
0.05
(0.03 to 0.09)
At 12 Months
0.16
(0.12 to 0.21)
0.01
(0.00 to 0.03)
7.Secondary Outcome
Title Overall Response Rate (ORR)
Hide Description 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.
Time Frame 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)
Hide Outcome Measure Data
Hide Analysis Population Description
Analysis was performed on FAS population.
Arm/Group Title Trifluridine/Tipiracil + Bevacizumab Trifluridine/Tipiracil
Hide Arm/Group Description:
Participants were administered 35 mg/m²/dose 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; with bevacizumab 5 mg/kg, IV infusion administered every 2 weeks (Day 1 and Day 15). This treatment cycle was repeated every 4 weeks.
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.
Overall Number of Participants Analyzed 246 246
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
6.10
(3.45 to 9.86)
1.22
(0.25 to 3.52)
8.Secondary Outcome
Title Percentage of Participants With Disease Control
Hide Description 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.
Time Frame 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)
Hide Outcome Measure Data
Hide Analysis Population Description
Analysis was performed on FAS population.
Arm/Group Title Trifluridine/Tipiracil + Bevacizumab Trifluridine/Tipiracil
Hide Arm/Group Description:
Participants were administered 35 mg/m²/dose 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; with bevacizumab 5 mg/kg, IV infusion administered every 2 weeks (Day 1 and Day 15). This treatment cycle was repeated every 4 weeks.
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.
Overall Number of Participants Analyzed 246 246
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
69.51
(63.35 to 75.2)
41.87
(35.63 to 48.31)
9.Secondary Outcome
Title Number of Participants With Treatment-emergent Adverse Events (TEAE) and Treatment-emergent Serious Adverse Events (TESAEs)
Hide Description 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.
Time Frame From Baseline up to 30 days after the last dose of study treatments (i.e., up to 19.5 months)
Hide Outcome Measure Data
Hide Analysis Population Description
Analysis was performed on safety set which included all participants who had taken at least one dose of investigational medicinal products and were analyzed according to the treatment they actually received.
Arm/Group Title Trifluridine/Tipiracil + Bevacizumab Trifluridine/Tipiracil
Hide Arm/Group Description:
Participants were administered 35 mg/m²/dose 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; with bevacizumab 5 mg/kg, IV infusion administered every 2 weeks (Day 1 and Day 15). This treatment cycle was repeated every 4 weeks.
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.
Overall Number of Participants Analyzed 246 246
Measure Type: Count of Participants
Unit of Measure: Participants
TEAE
241
  98.0%
241
  98.0%
TESAE
61
  24.8%
77
  31.3%
Time Frame From baseline up to the cut-off date (19 July 2022, i.e., up to 20 months)
Adverse Event Reporting Description Analysis was performed on safety set population which included all participants who took at least one dose of FTD/TPI and were analyzed according to the treatment actually received.
 
Arm/Group Title Trifluridine/Tipiracil + Bevacizumab Trifluridine/Tipiracil
Hide Arm/Group Description Participants were administered 35 mg/m²/dose 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; with bevacizumab 5 mg/kg, IV infusion administered every 2 weeks (Day 1 and Day 15). This treatment cycle was repeated every 4 weeks. 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.
All-Cause Mortality
Trifluridine/Tipiracil + Bevacizumab Trifluridine/Tipiracil
Affected / at Risk (%) Affected / at Risk (%)
Total   148/246 (60.16%)   183/246 (74.39%) 
Hide Serious Adverse Events
Trifluridine/Tipiracil + Bevacizumab Trifluridine/Tipiracil
Affected / at Risk (%) Affected / at Risk (%)
Total   61/246 (24.80%)   77/246 (31.30%) 
Blood and lymphatic system disorders     
Neutropenia  1  2/246 (0.81%)  1/246 (0.41%) 
Anaemia  1  1/246 (0.41%)  8/246 (3.25%) 
Febrile neutropenia  1  1/246 (0.41%)  6/246 (2.44%) 
Iron deficiency anaemia  1  1/246 (0.41%)  0/246 (0.00%) 
Abdominal lymphadenopathy  1  0/246 (0.00%)  1/246 (0.41%) 
Cardiac disorders     
Angina pectoris  1  1/246 (0.41%)  1/246 (0.41%) 
Atrial fibrillation  1  1/246 (0.41%)  1/246 (0.41%) 
Cardiac failure  1  1/246 (0.41%)  1/246 (0.41%) 
Cardiac failure congestive  1  1/246 (0.41%)  0/246 (0.00%) 
Pericardial effusion  1  1/246 (0.41%)  0/246 (0.00%) 
Pericarditis  1  1/246 (0.41%)  0/246 (0.00%) 
Cardiac failure acute  1  0/246 (0.00%)  1/246 (0.41%) 
Congenital, familial and genetic disorders     
Phimosis  1  1/246 (0.41%)  0/246 (0.00%) 
Eye disorders     
Glaucoma  1  1/246 (0.41%)  0/246 (0.00%) 
Gastrointestinal disorders     
Intestinal obstruction  1  7/246 (2.85%)  5/246 (2.03%) 
Vomiting  1  2/246 (0.81%)  2/246 (0.81%) 
Abdominal pain  1  2/246 (0.81%)  1/246 (0.41%) 
Large intestinal obstruction  1  2/246 (0.81%)  0/246 (0.00%) 
Nausea  1  2/246 (0.81%)  0/246 (0.00%) 
Abdominal pain upper  1  1/246 (0.41%)  2/246 (0.81%) 
Ascites  1  1/246 (0.41%)  2/246 (0.81%) 
Ileus  1  1/246 (0.41%)  1/246 (0.41%) 
Subileus  1  0/246 (0.00%)  1/246 (0.41%) 
Abdominal hernia  1  1/246 (0.41%)  0/246 (0.00%) 
Anal fistula  1  1/246 (0.41%)  0/246 (0.00%) 
Abdominal tenderness  1  1/246 (0.41%)  0/246 (0.00%) 
Colitis  1  1/246 (0.41%)  0/246 (0.00%) 
Gastrointestinal fistula  1  1/246 (0.41%)  0/246 (0.00%) 
Gastrointestinal perforation  1  1/246 (0.41%)  0/246 (0.00%) 
Intestinal perforation  1  1/246 (0.41%)  0/246 (0.00%) 
Large intestinal stenosis  1  1/246 (0.41%)  0/246 (0.00%) 
Diarrhoea  1  0/246 (0.00%)  3/246 (1.22%) 
Constipation  1  0/246 (0.00%)  2/246 (0.81%) 
Gastritis haemorrhagic  1  0/246 (0.00%)  1/246 (0.41%) 
Gastrointestinal haemorrhage  1  0/246 (0.00%)  1/246 (0.41%) 
Gastrointestinal ischaemia  1  0/246 (0.00%)  1/246 (0.41%) 
Small intestinal stenosis  1  0/246 (0.00%)  1/246 (0.41%) 
Neutropenic colitis  1  1/246 (0.41%)  0/246 (0.00%) 
General disorders     
Asthenia  1  1/246 (0.41%)  0/246 (0.00%) 
Pain  1  1/246 (0.41%)  0/246 (0.00%) 
Fatigue  1  0/246 (0.00%)  3/246 (1.22%) 
Multiple organ dysfunction syndrome  1  0/246 (0.00%)  2/246 (0.81%) 
Pyrexia  1  0/246 (0.00%)  2/246 (0.81%) 
Death  1  0/246 (0.00%)  1/246 (0.41%) 
General physical health deterioration  1  0/246 (0.00%)  1/246 (0.41%) 
Malaise  1  0/246 (0.00%)  1/246 (0.41%) 
Hepatobiliary disorders     
Jaundice cholestatic  1  3/246 (1.22%)  0/246 (0.00%) 
Jaundice  1  2/246 (0.81%)  5/246 (2.03%) 
Cholangitis  1  2/246 (0.81%)  1/246 (0.41%) 
Bile duct stenosis  1  2/246 (0.81%)  0/246 (0.00%) 
Biliary dilatation  1  2/246 (0.81%)  0/246 (0.00%) 
Hyperbilirubinaemia  1  2/246 (0.81%)  0/246 (0.00%) 
Bile duct stone  1  1/246 (0.41%)  0/246 (0.00%) 
Cholecystitis acute  1  1/246 (0.41%)  0/246 (0.00%) 
Hepatic failure  1  0/246 (0.00%)  5/246 (2.03%) 
Cholestasis  1  0/246 (0.00%)  1/246 (0.41%) 
Hepatomegaly  1  0/246 (0.00%)  1/246 (0.41%) 
Immune system disorders     
Anaphylactic reaction  1  1/246 (0.41%)  0/246 (0.00%) 
Infections and infestations     
COVID-19  1  5/246 (2.03%)  6/246 (2.44%) 
Septic shock  1  2/246 (0.81%)  0/246 (0.00%) 
Pneumonia  1  1/246 (0.41%)  2/246 (0.81%) 
Urinary tract infection pseudomonal  1  1/246 (0.41%)  0/246 (0.00%) 
Vascular device infection  1  1/246 (0.41%)  1/246 (0.41%) 
Abdominal sepsis  1  1/246 (0.41%)  0/246 (0.00%) 
COVID-19 pneumonia  1  1/246 (0.41%)  0/246 (0.00%) 
Intestinal sepsis  1  1/246 (0.41%)  0/246 (0.00%) 
Paracancerous pneumonia  1  1/246 (0.41%)  0/246 (0.00%) 
Peritonitis  1  1/246 (0.41%)  0/246 (0.00%) 
Pneumonia streptococcal  1  1/246 (0.41%)  0/246 (0.00%) 
Postoperative abscess  1  1/246 (0.41%)  0/246 (0.00%) 
Pyelonephritis  1  1/246 (0.41%)  0/246 (0.00%) 
Staphylococcal sepsis  1  1/246 (0.41%)  0/246 (0.00%) 
Urinary tract infection bacterial  1  1/246 (0.41%)  0/246 (0.00%) 
Bacterial pyelonephritis  1  0/246 (0.00%)  2/246 (0.81%) 
Infection  1  0/246 (0.00%)  2/246 (0.81%) 
Abdominal infection  1  0/246 (0.00%)  1/246 (0.41%) 
Bacterial prostatitis  1  0/246 (0.00%)  1/246 (0.41%) 
Bronchitis  1  0/246 (0.00%)  1/246 (0.41%) 
Klebsiella sepsis  1  0/246 (0.00%)  1/246 (0.41%) 
Nasopharyngitis  1  0/246 (0.00%)  1/246 (0.41%) 
Pelvic abscess  1  0/246 (0.00%)  1/246 (0.41%) 
Sepsis  1  0/246 (0.00%)  1/246 (0.41%) 
Urinary tract infection  1  0/246 (0.00%)  1/246 (0.41%) 
Urosepsis  1  0/246 (0.00%)  1/246 (0.41%) 
Injury, poisoning and procedural complications     
Stoma site haemorrhage  1  2/246 (0.81%)  0/246 (0.00%) 
Spinal compression fracture  1  1/246 (0.41%)  1/246 (0.41%) 
Humerus fracture  1  1/246 (0.41%)  0/246 (0.00%) 
Gastrointestinal stoma complication  1  0/246 (0.00%)  1/246 (0.41%) 
Investigations     
Blood bilirubin increased  1  2/246 (0.81%)  0/246 (0.00%) 
Blood alkaline phosphatase increased  1  1/246 (0.41%)  0/246 (0.00%) 
C-reactive protein increased  1  0/246 (0.00%)  1/246 (0.41%) 
Gastrointestinal stoma output decreased  1  0/246 (0.00%)  1/246 (0.41%) 
Neutrophil count increased  1  0/246 (0.00%)  1/246 (0.41%) 
Metabolism and nutrition disorders     
Dehydration  1  1/246 (0.41%)  2/246 (0.81%) 
Hypernatraemia  1  1/246 (0.41%)  0/246 (0.00%) 
Cachexia  1  0/246 (0.00%)  2/246 (0.81%) 
Hyponatraemia  1  0/246 (0.00%)  1/246 (0.41%) 
Musculoskeletal and connective tissue disorders     
Muscular weakness  1  1/246 (0.41%)  0/246 (0.00%) 
Arthralgia  1  0/246 (0.00%)  1/246 (0.41%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)     
Malignant neoplasm progression  1  6/246 (2.44%)  11/246 (4.47%) 
Metastases to meninges  1  2/246 (0.81%)  0/246 (0.00%) 
Metastases to spine  1  1/246 (0.41%)  0/246 (0.00%) 
Tumour pain  1  1/246 (0.41%)  0/246 (0.00%) 
Metastases to central nervous system  1  0/246 (0.00%)  4/246 (1.63%) 
Cancer pain  1  0/246 (0.00%)  1/246 (0.41%) 
Malignant pleural effusion  1  0/246 (0.00%)  1/246 (0.41%) 
Metastases to ovary  1  0/246 (0.00%)  1/246 (0.41%) 
Nervous system disorders     
Balance disorder  1  1/246 (0.41%)  0/246 (0.00%) 
Dizziness  1  1/246 (0.41%)  0/246 (0.00%) 
Haemorrhagic stroke  1  1/246 (0.41%)  0/246 (0.00%) 
Headache  1  1/246 (0.41%)  0/246 (0.00%) 
Hypoaesthesia  1  1/246 (0.41%)  0/246 (0.00%) 
Cerebrovascular accident  1  0/246 (0.00%)  1/246 (0.41%) 
Diplegia  1  0/246 (0.00%)  1/246 (0.41%) 
Hepatic encephalopathy  1  0/246 (0.00%)  1/246 (0.41%) 
Psychiatric disorders     
Confusional state  1  0/246 (0.00%)  1/246 (0.41%) 
Psychomotor retardation  1  0/246 (0.00%)  1/246 (0.41%) 
Renal and urinary disorders     
Acute kidney injury  1  2/246 (0.81%)  2/246 (0.81%) 
Pyelocaliectasis  1  1/246 (0.41%)  0/246 (0.00%) 
Urinary incontinence  1  1/246 (0.41%)  0/246 (0.00%) 
Haematuria  1  0/246 (0.00%)  1/246 (0.41%) 
Prerenal failure  1  0/246 (0.00%)  1/246 (0.41%) 
Reproductive system and breast disorders     
Prostatitis  1  1/246 (0.41%)  0/246 (0.00%) 
Respiratory, thoracic and mediastinal disorders     
Pulmonary embolism  1  1/246 (0.41%)  4/246 (1.63%) 
Dyspnoea  1  1/246 (0.41%)  0/246 (0.00%) 
Epistaxis  1  1/246 (0.41%)  0/246 (0.00%) 
Acute respiratory failure  1  0/246 (0.00%)  1/246 (0.41%) 
Dyspnoea at rest  1  0/246 (0.00%)  1/246 (0.41%) 
Pleural effusion  1  0/246 (0.00%)  1/246 (0.41%) 
Respiratory failure  1  0/246 (0.00%)  1/246 (0.41%) 
Vascular disorders     
Deep vein thrombosis  1  1/246 (0.41%)  1/246 (0.41%) 
Hypertension  1  1/246 (0.41%)  0/246 (0.00%) 
1
Term from vocabulary, MedDRA (25.0)
Indicates events were collected by systematic assessment
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Trifluridine/Tipiracil + Bevacizumab Trifluridine/Tipiracil
Affected / at Risk (%) Affected / at Risk (%)
Total   238/246 (96.75%)   237/246 (96.34%) 
Blood and lymphatic system disorders     
Neutropenia  1  153/246 (62.20%)  126/246 (51.22%) 
Anaemia  1  70/246 (28.46%)  71/246 (28.86%) 
Thrombocytopenia  1  42/246 (17.07%)  28/246 (11.38%) 
Leukopenia  1  16/246 (6.50%)  21/246 (8.54%) 
Gastrointestinal disorders     
Nausea  1  90/246 (36.59%)  67/246 (27.24%) 
Diarrhoea  1  51/246 (20.73%)  46/246 (18.70%) 
Vomiting  1  45/246 (18.29%)  35/246 (14.23%) 
Abdominal pain  1  27/246 (10.98%)  26/246 (10.57%) 
Constipation  1  27/246 (10.98%)  27/246 (10.98%) 
Stomatitis  1  27/246 (10.98%)  9/246 (3.66%) 
Abdominal pain upper  1  21/246 (8.54%)  8/246 (3.25%) 
General disorders     
Asthenia  1  59/246 (23.98%)  55/246 (22.36%) 
Fatigue  1  53/246 (21.54%)  37/246 (15.04%) 
Pyrexia  1  12/246 (4.88%)  14/246 (5.69%) 
Investigations     
Neutrophil count decreased  1  34/246 (13.82%)  17/246 (6.91%) 
Platelet count decreased  1  22/246 (8.94%)  5/246 (2.03%) 
Alanine aminotransferase increased  1  21/246 (8.54%)  14/246 (5.69%) 
Aspartate aminotransferase increased  1  21/246 (8.54%)  14/246 (5.69%) 
Weight decreased  1  20/246 (8.13%)  12/246 (4.88%) 
Blood bilirubin increased  1  12/246 (4.88%)  14/246 (5.69%) 
Metabolism and nutrition disorders     
Decreased appetite  1  50/246 (20.33%)  38/246 (15.45%) 
Musculoskeletal and connective tissue disorders     
Arthralgia  1  17/246 (6.91%)  5/246 (2.03%) 
Back pain  1  16/246 (6.50%)  13/246 (5.28%) 
Nervous system disorders     
Headache  1  19/246 (7.72%)  9/246 (3.66%) 
Renal and urinary disorders     
Proteinuria  1  15/246 (6.10%)  3/246 (1.22%) 
Vascular disorders     
Hypertension  1  24/246 (9.76%)  5/246 (2.03%) 
1
Term from vocabulary, MedDRA (25.0)
Indicates events were collected by systematic assessment
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
 
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Taiho
Organization: Taiho Oncology, Inc.
Phone: 1-609-250-7336
EMail: clinicaltrialinfo@taihooncology.com
Layout table for additonal information
Responsible Party: Taiho Oncology, Inc.
ClinicalTrials.gov Identifier: NCT04737187    
Other Study ID Numbers: CL3-95005-007
2020-001976-14 ( EudraCT Number )
First Submitted: January 29, 2021
First Posted: February 3, 2021
Results First Submitted: October 17, 2023
Results First Posted: December 26, 2023
Last Update Posted: December 26, 2023