Metastatic Colorectal Cancer
Conditions
Keywords
metastatic, colorectal, cancer, untreated, first-line, S95005 (Trifluridine/tipiracil), bevacizumab, capecitabine
Brief summary
The main purpose of this study is to evaluate the progression-free survival (PFS) in patients receiving S 95005 + bevacizumab (experimental arm) or capecitabine + bevacizumab (control arm) as first-line treatment for unresectable metastatic colorectal cancer in patients non-eligible for intensive therapy.
Interventions
Patients were treated withTrifluridine/tipiracil + bevacizumab regimen until they met a discontinuation criterion.
Patients were treated with capecitabine+ bevacizumab regimen until they met a discontinuation criterion.
Sponsors
ADIR, a Servier Group company
Institut de Recherches Internationales Servier
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Written informed consent obtained. * Has ECOG (Eastern Cooperative Oncology Group) performance status of 0, 1 or 2 at the time of the randomisation. * Has definitive histologically or cytologically confirmed adenocarcinoma of the colon or rectum. * RAS status must have been determined (mutant or wild). * Has at least one measurable metastatic lesion. * No previous systemic anticancer therapy for unresectable metastatic colorectal cancer. * Previous adjuvant (or neoadjuvant for patients with rectal cancer) chemotherapy is allowed only if if it has been completed more than 6 months before start of study treatment. * Patient is not a candidate for combination chemotherapy with irinotecan or oxaliplatin, or for curative resection of metastatic lesions. * Is able to take medication orally (i.e., no feeding tube). * Has adequate organ function. * Coagulation parameters in normal limit (or in therapeutic limit for patients treated with anticoagulant drugs). * Women of childbearing potential must have been tested negative in a serum pregnancy test. Female participants of childbearing potential and male participants with partners of childbearing potential must agree to use a highly effective method of birth control. Women and female partners using hormonal contraceptive must also use a barrier method.
Exclusion criteria
* Is a pregnant or lactating female. * Has certain serious illness or serious medical condition(s) as described in the protocol. * Has had certain other recent treatment e.g. major surgery, field radiation, received investigational agent, within the specified time frames prior to randomisation. * Has previously received Trifluridine/tipiracil or history of allergic reactions attributed to compounds of similar composition to Trifluridine/tipiracil or any of its excipients. * Has rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption. * Has contra-indication to bevacizumab or capecitabine.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival (PFS) | Baseline and every 8 weeks (maximum follow-up duration: 17.9 months) | The progression free survival (PFS), defined as the time from the date of randomisation until the date of the investigator-assessed radiological disease progression or death due to any cause according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Progressive disease (PD) was defined at least a 20% increase in the sum of diameters of target lesions (taking as reference the smallest sum on study) and an absolute increase of at least 5 mm in the sum of lesions or the appearance of new lesions. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response Rate (ORR) | Baseline and every 8 weeks (maximum follow-up duration: 17.9 months) | As per RECIST v1.1, Complete Response (CR) was disappearance of all target lesions; Partial Response (PR) was at least 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. The ORR was the proportion of patients who presented CR or PR with confirmation at subsequent time point or at least 4 weeks later. |
| Duration of Response (DR) | Baseline and every 8 weeks (maximum follow-up duration: 16.6 months) | The DR was calculated among patients with CR or PR as the time (months) from the first documentation of response to the first documentation of objective tumor progression or death due to any cause, whichever occurred first. |
| Disease Control Rate (DCR) | Baseline and every 8 weeks (maximum follow-up duration: 17.9 months) | DCR was the proportion of patients with confirmed CR, PR or stable disease (SD) as best overall response. SD defined as neither sufficient decrease to qualify for PR nor sufficient increase to qualify for PD. |
| Overall Survival (OS) | Baseline up to death or study cut-off (maximum follow-up duration: 19.9 months) | The OS was defined as the time from the date of randomisation to the date of death. If death was not confirmed, or patient was alive at study cut-off date, survival time was censored at the date of last follow-up or at the study cut-off date, whichever was earlier. |
Countries
Australia, Belgium, Brazil, Denmark, France, Germany, Italy, Netherlands, Poland, Russia, Spain, United Kingdom
Participant flow
Pre-assignment details
154 patients were randomized among whom one was deemed ineligible after randomization.
Participants by arm
| Arm | Count |
|---|---|
| Trifluridine/Tipiracil + Bevacizumab Trifluridine/tipiracil (S95005): film-coated tablets containing 15mg of trifluridine and 7.065mg of tipiracil hydrochloride, or 20mg of trifluridine and 9.42mg of tipiracil hydrochloride.
Bevacizumab: concentrate for solution for IV infusion containing 25mg/ml of bevacizumab.
Trifluridine/tipiracil was administered at 35 mg/m2/dose orally within 1 hour after completion of morning and evening meals, for 5 days on/2 days off, over 2 weeks, followed by a 14-day rest period, with bevacizumab administered intravenously at the dose of 5 mg/kg every 2 weeks at Day 1 and Day 15.This treatment cycle was repeated every 4 weeks.
Trifluridine/tipiracil + bevacizumab: Patients were treated withTrifluridine/tipiracil + bevacizumab regimen until they met a discontinuation criterion. | 77 |
| Capecitabine + Bevacizumab Capecitabine was administered at 1250 mg/m² orally BID on Days 1-14 of each cycle, with bevacizumab (7.5 mg/kg, IV) administered on Day 1 of each cycle. This treatment cycle was repeated every 3 weeks
Capecitabine + bevacizumab: Patients were treated with capecitabine+ bevacizumab regimen until they met a discontinuation criterion. | 77 |
| Total | 154 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 17 | 14 |
| Overall Study | non medical reason | 8 | 2 |
| Overall Study | Patient not eligible, not treated | 0 | 1 |
| Overall Study | Physician Decision | 2 | 5 |
| Overall Study | Progressive disease | 29 | 38 |
Baseline characteristics
| Characteristic | Trifluridine/Tipiracil + Bevacizumab | Capecitabine + Bevacizumab | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 57 Participants | 61 Participants | 118 Participants |
| Age, Categorical Between 18 and 65 years | 20 Participants | 16 Participants | 36 Participants |
| Age, Continuous | 69.8 years STANDARD_DEVIATION 10.2 | 72.8 years STANDARD_DEVIATION 11 | 71.3 years STANDARD_DEVIATION 10.7 |
| Race/Ethnicity, Customized Asian | 1 Participants | 2 Participants | 3 Participants |
| Race/Ethnicity, Customized Not collected | 2 Participants | 2 Participants | 4 Participants |
| Race/Ethnicity, Customized Other | 1 Participants | 1 Participants | 2 Participants |
| Race/Ethnicity, Customized White | 73 Participants | 72 Participants | 145 Participants |
| Sex: Female, Male Female | 37 Participants | 29 Participants | 66 Participants |
| Sex: Female, Male Male | 40 Participants | 48 Participants | 88 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 22 / 77 | 33 / 76 |
| other Total, other adverse events | 75 / 77 | 69 / 76 |
| serious Total, serious adverse events | 42 / 77 | 44 / 76 |
Outcome results
Primary
Progression Free Survival (PFS)
The progression free survival (PFS), defined as the time from the date of randomisation until the date of the investigator-assessed radiological disease progression or death due to any cause according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Progressive disease (PD) was defined at least a 20% increase in the sum of diameters of target lesions (taking as reference the smallest sum on study) and an absolute increase of at least 5 mm in the sum of lesions or the appearance of new lesions.
Time frame: Baseline and every 8 weeks (maximum follow-up duration: 17.9 months)
Population: Full Analysis Set (FAS): all randomised patients who have taken at least one dose of study treatment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Trifluridine/Tipiracil + Bevacizumab | Progression Free Survival (PFS) | 9.2 months |
| Capecitabine + Bevacizumab | Progression Free Survival (PFS) | 7.8 months |
p-value: 0.0995% CI: [0.48, 1.06]Cox proportional hazard model
Secondary
Disease Control Rate (DCR)
DCR was the proportion of patients with confirmed CR, PR or stable disease (SD) as best overall response. SD defined as neither sufficient decrease to qualify for PR nor sufficient increase to qualify for PD.
Time frame: Baseline and every 8 weeks (maximum follow-up duration: 17.9 months)
Population: FAS
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Trifluridine/Tipiracil + Bevacizumab | Disease Control Rate (DCR) | 66 Participants |
| Capecitabine + Bevacizumab | Disease Control Rate (DCR) | 59 Participants |
p-value: 0.22Fisher Exact
Secondary
Duration of Response (DR)
The DR was calculated among patients with CR or PR as the time (months) from the first documentation of response to the first documentation of objective tumor progression or death due to any cause, whichever occurred first.
Time frame: Baseline and every 8 weeks (maximum follow-up duration: 16.6 months)
Population: Tumour Response population: patients with measurable disease at baseline and with at least one tumour evaluation while on treatment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Trifluridine/Tipiracil + Bevacizumab | Duration of Response (DR) | 7.9 months |
| Capecitabine + Bevacizumab | Duration of Response (DR) | 9.9 months |
95% CI: [0.49, 2.74]
Secondary
Overall Response Rate (ORR)
As per RECIST v1.1, Complete Response (CR) was disappearance of all target lesions; Partial Response (PR) was at least 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. The ORR was the proportion of patients who presented CR or PR with confirmation at subsequent time point or at least 4 weeks later.
Time frame: Baseline and every 8 weeks (maximum follow-up duration: 17.9 months)
Population: FAS
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Trifluridine/Tipiracil + Bevacizumab | Overall Response Rate (ORR) | 26 Participants |
| Capecitabine + Bevacizumab | Overall Response Rate (ORR) | 23 Participants |
p-value: 0.73Fisher Exact
Secondary
Overall Survival (OS)
The OS was defined as the time from the date of randomisation to the date of death. If death was not confirmed, or patient was alive at study cut-off date, survival time was censored at the date of last follow-up or at the study cut-off date, whichever was earlier.
Time frame: Baseline up to death or study cut-off (maximum follow-up duration: 19.9 months)
Population: FAS
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Trifluridine/Tipiracil + Bevacizumab | Overall Survival (OS) | 18.0 months |
| Capecitabine + Bevacizumab | Overall Survival (OS) | 16.2 months |
p-value: 0.0495% CI: [0.32, 0.98]Cox proportional hazard model