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NCT04737187 · CITED IN SOURCE DOCUMENTS

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

An NCI or FDA source cites this study. A citation does not establish that it applies to an individual diagnosis.

Phase
PHASE3
Status at capture
COMPLETED
Registry last update
2024-09-24

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.

Open the original ClinicalTrials.gov record → · Download preserved record

What did the study report?

Outcomes, safety and baseline populations are separate source sections. Quality-of-life measures appear under their original outcome titles.

flow

Participant flow

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baseline

Baseline characteristics

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outcome · POSTED

Overall Survival (OS)

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outcome · POSTED

Survival Probability at 6 Months

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outcome · POSTED

Survival Probability at 12 Months

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outcome · POSTED

Survival Probability at 18 Months

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outcome · POSTED

Progression Free Survival (PFS)

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outcome · POSTED

Probability of Participants With Progression Free Survival at 3, 6, 9 and 12 Months

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outcome · POSTED

Overall Response Rate (ORR)

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outcome · POSTED

Percentage of Participants With Disease Control

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outcome · POSTED

Number of Participants With Treatment-emergent Adverse Events (TEAE) and Treatment-emergent Serious Adverse Events (TESAEs)

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outcome · POSTED

European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30): Time to Definitive Deterioration of >=10 Points in Sub-scale Scores - Kaplan-Meier Analysis

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outcome · POSTED

European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30): Time to Definitive Deterioration of >=10 Points in the Global Health Status Score - Kaplan-Meier Analysis

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outcome · POSTED

Change From Baseline in European Quality of Life Group Questionnaire With 5 Dimensions and 5 Levels Per Dimension (EQ-5D-5L): Health State Utility Index Value at Specified Timepoints

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outcome · POSTED

Change From Baseline in European Quality of Life Working Group Health Status Measure 5 Dimensions, 5 Levels (EQ-5D-5L) Score: Visual Analogic Scale (VAS) at Specified Timepoints

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adverse events

Adverse events

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more info

Limitations, agreements, and source contact

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Who could take part
eligibility Criteria
Inclusion Criteria: 1. Has histologically confirmed unresectable adenocarcinoma of the colon or rectum (all other histological types are excluded). 2. RAS status must have been previously determined (mutant or wild-type) based on local assessment of tumor biopsy. 3. 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. 4. Has measurable or non-measurable disease as defined by RECIST version 1.1 5. Is able to swallow oral tablets. 6. Estimated life expectancy ≥12 weeks. 7. Eastern Cooperative Oncology Group performance status (ECOG PS) 0 or 1 Exclusion Criteria: 1. More than 2 prior chemotherapy regimens for the treatment of advanced colorectal cancer. 2. Pregnancy, lactating female or possibility of becoming pregnant during the study. 3. Patients currently receiving or having received anticancer therapies within 4 weeks prior to randomization. 4. Has not recovered from clinically relevant non-hematologic CTCAE grade ≥ 3 toxicity of previous anticancer therapy prior to randomization (excluding alopecia, and skin pigmentation). 5. Has symptomatic central nervous system metastases that are neurologically unstable or requiring increasing doses of steroids to control CNS disease. 6. Has severe or uncontrolled active acute or chronic infection. 7. Has active or history of interstitial lung disease and/or pneumonitis, or pulmonary hypertension. 8. Known Hepatitis B or Hepatitis C Virus infection. 9. Known carriers of HIV antibodies. 10. 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. 11. Deep arterial thromboembolic events including cerebrovascular accident or myocardial infarction within the last 6 months prior to randomization. 12. 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 13. Other clinically significant medical conditions. 14. Other malignancies.
healthy Volunteers
false
minimum Age
18 Years
sex
ALL
std Ages
  1. ADULT
  2. OLDER_ADULT
Treatment arms and interventions
arm Groups
  1. 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 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.
    intervention Names
    1. Drug: Trifluridine/Tipiracil
    2. Drug: Bevacizumab
    label
    Trifluridine/Tipiracil + Bevacizumab
    type
    EXPERIMENTAL
  2. description
    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.
    intervention Names
    1. Drug: Trifluridine/Tipiracil
    label
    Trifluridine/Tipiracil
    type
    ACTIVE_COMPARATOR
interventions
  1. arm Group Labels
    1. Trifluridine/Tipiracil
    2. Trifluridine/Tipiracil + Bevacizumab
    description
    Taken by mouth two times a day, 5 days on/2 days off, over 2 weeks, followed by a 14-day rest
    name
    Trifluridine/Tipiracil
    other Names
    1. TAS102
    2. S 95005
    3. Lonsurf
    type
    DRUG
  2. arm Group Labels
    1. Trifluridine/Tipiracil + Bevacizumab
    description
    administered every 2 weeks (Day 1 and Day 15)
    name
    Bevacizumab
    other Names
    1. Avastin
    type
    DRUG
Study design
allocation
RANDOMIZED
intervention Model
PARALLEL
masking Info
masking
NONE
primary Purpose
TREATMENT
Enrollment
count
492
type
ACTUAL
Registered outcome plans (not posted results)
primary Outcomes
  1. 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.
    measure
    Overall Survival (OS)
    time Frame
    From date of randomization to the death due to any cause or cut-off date, whichever comes first (maximum duration: up to 20 months)
  2. 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.
    measure
    Survival Probability at 6 Months
    time Frame
    From date of randomization until 6 months post treatment
  3. 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.
    measure
    Survival Probability at 12 Months
    time Frame
    From date of randomization until 12 months post treatment
  4. 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.
    measure
    Survival Probability at 18 Months
    time Frame
    From date of randomization until 18 months post treatment
secondary Outcomes
  1. 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.
    measure
    Progression Free Survival (PFS)
    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)
  2. 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.
    measure
    Probability of Participants With Progression Free Survival at 3, 6, 9 and 12 Months
    time Frame
    From randomization until 3, 6, 9, and 12 months post treatment
  3. 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.
    measure
    Overall Response Rate (ORR)
    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)
  4. 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.
    measure
    Percentage of Participants With Disease Control
    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)
  5. 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.
    measure
    Number of Participants With Treatment-emergent Adverse Events (TEAE) and Treatment-emergent Serious Adverse Events (TESAEs)
    time Frame
    From baseline (Cycle 1 Day 1) up to 30 days after the last dose of study drug (i.e., up to 30.7 months)
  6. description
    EORTC QLQ-C30: 30 item questionnaires with 5 multi-item functional subscales (physical, role, cognitive, emotional, social functioning), 3 multi-item symptom scales (fatigue, nausea/vomiting, and pain), global health/quality of life (QOL) subscale and 6 single items assessing other cancer related symptoms (dyspnea, sleep disturbance, appetite, diarrhea, constipation and financial impact of cancer). It employed twenty-eight 4-point Likert scales with responses from "not at all" to "very much" and GHS/QoL, scored on scale of 1 (very poor) to 7 (excellent). All scales are transformed from raw scores to linear scales ranging 0 to 100. Higher score for functional \& GHS/QoL = higher level of functioning, \& higher score for symptoms scales = higher symptom burden. Time to definitive \>=10 points deterioration: time from date of randomization to first deterioration in QoL score \>=10 points compared to baseline with no later improvement or death due to any cause. Kaplan-Meier method was used.
    measure
    European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30): Time to Definitive Deterioration of >=10 Points in Sub-scale Scores - Kaplan-Meier Analysis
    time Frame
    Date of randomization to first deterioration in QoL score >=10 points or death due to any cause, which ever occurred first (i.e., up to 20 months)
  7. description
    EORTC QLQ-C30: 30 item questionnaires composed of 5 multi-item functional subscales (physical, role, cognitive, emotional, social functioning), 3 multi-item symptom scales (fatigue, nausea/vomiting, and pain), global health/QOL subscale and 6 single items assessing other cancer related symptoms (dyspnea, sleep disturbance, appetite, diarrhea, constipation and financial impact of cancer). It employed twenty-eight 4-point Likert scales with responses from "not at all" to "very much" and GHS/QoL, scored on scale of 1 (very poor) to 7 (excellent). All scales are transformed from raw scores to linear scales ranging 0 to 100. Higher score for functional \& GHS/QoL = higher level of functioning, \& higher score for symptoms scales = higher symptom burden. Time to definitive \>=10 points deterioration: time from date of randomization to the first deterioration in QoL score \>=10 points compared to baseline with no later improvement or death due to any cause. Kaplan-Meier method was used.
    measure
    European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30): Time to Definitive Deterioration of >=10 Points in the Global Health Status Score - Kaplan-Meier Analysis
    time Frame
    Date of randomization to first deterioration in QoL score >=10 points or death due to any cause, which ever occurred first (i.e., up to 20 months)
  8. description
    The EQ-5D-5L is a standardized measure of health status that provides a general assessment of health utility and consist in 2 sections a descriptive system comprising 5 dimensions (mobility, self-care, usual activities, pain/discomfort and anxiety/depression) and Visual Analog Scale (VAS). Each dimension has a 5-level response: no problems, slight problems, moderate problems, severe problems, and extreme problems. Response options are measured with a 5-point Likert scale. The 5D-5L systems are converted into a single index utility score between 0 to 1, where higher score indicates a better health state and lower score indicate worse health state.
    measure
    Change From Baseline in European Quality of Life Group Questionnaire With 5 Dimensions and 5 Levels Per Dimension (EQ-5D-5L): Health State Utility Index Value at Specified Timepoints
    time Frame
    Baseline, Cycle 1, Cycle 2, Cycle 3, Cycle 4, Cycle 5, Cycle 6, Cycle 7, Cycle 8, Cycle 9, Cycle 10, Cycle 11, Cycle 12, Cycle 13 and Cycle 14
  9. description
    The EQ-5D-5L is a standardized measure of health status that provides a general assessment of health utility and consist of 2 sections; descriptive system comprises 5 dimensions (mobility, self-care, usual activities, pain/discomfort and anxiety/depression) and a VAS. The VAS records the respondent's self-rated health on a 20 centimeter (cm) vertical VAS; the scale went from 0 (worst imaginable health state) to 100 (best imaginable health state). This information can be used as a quantitative measure of health as judged by the individual respondents.
    measure
    Change From Baseline in European Quality of Life Working Group Health Status Measure 5 Dimensions, 5 Levels (EQ-5D-5L) Score: Visual Analogic Scale (VAS) at Specified Timepoints
    time Frame
    Baseline, Cycle 1, Cycle 2, Cycle 3, Cycle 4, Cycle 5, Cycle 6, Cycle 7, Cycle 8, Cycle 9, Cycle 10, Cycle 11, Cycle 12, Cycle 13 and Cycle 14
Full study description
brief Summary
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
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).
Source references
references
  1. citation
    Prager GW, Taieb J, Fakih M, Ciardiello F, Van Cutsem E, Elez E, Cruz FM, Wyrwicz L, Stroyakovskiy D, Papai Z, Poureau PG, Liposits G, Cremolini C, Bondarenko I, Modest DP, Benhadji KA, Amellal N, Leger C, Vidot L, Tabernero J; SUNLIGHT Investigators. Trifluridine-Tipiracil and Bevacizumab in Refractory Metastatic Colorectal Cancer. N Engl J Med. 2023 May 4;388(18):1657-1667. doi: 10.1056/NEJMoa2214963.
    pmid
    37133585
    type
    RESULT
  2. citation
    Prager GW, Taieb J, Fakih M, Ciardiello F, Van Cutsem E, Elez E, Wyrwicz L, Stroyakovskiy D, Liposits G, Bondarenko I, Modest DP, Amellal N, Tabernero J; SUNLIGHT Investigators. Plain language summary of SUNLIGHT: trifluridine/tipiracil and bevacizumab for refractory metastatic colorectal cancer. Future Oncol. 2024;20(36):2823-2832. doi: 10.1080/14796694.2024.2366100. Epub 2024 Jul 2.
    pmid
    38953855
    type
    DERIVED
Source notices and limitations
    Discovery and provenance
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    Preserved source evidence · Independent clinical review pending · Not medical advice