Metastatic Colorectal Cancer
Conditions
Keywords
Futuximab/modotuximab, Trifluridine/tipiracil, Phase III, Safety Lead-In part, S95026, Sym004, Adult, Metastatic, Colorectal, Colorectal Cancer, EGFR
Brief summary
This is a randomized phase III study with a safety lead-in part in patients with KRAS/ NRAS and BRAF Wild Type metastatic colorectal cancer who have previously received treatment with oxaliplatin, irinotecan, fluoropyrimidines, anti-VEGF agents and anti-EGFR antibodies. The main objective of the safety lead-in part is to assess safety and tolerability of futuximab/modotuximab in combination with trifluridine/tipiracil. The primary objective of the phase III part is to compare Overall Survival of futuximab/modotuximab in combination with trifluridine/tipiracil vs trifluridine/tipiracil monotherapy in patients with tumours that are KRAS/NRAS and BRAF wild-type (WT).
Interventions
BIOLOGICALFutuximab/modotuximab
Concentrate for solution for infusion, futuximab/modotuximab will be administered via IV route, once weekly of each cycle at 9 mg/kg/dose at Cycle 1 Day 1 and then at 6 mg/kg/dose. Each cycle is up to 28 days.
DRUGTrifluridine/Tipiracil
Film-coated tablets of trifluridine/tipiracil (35 mg/m²/dose) will be administered orally before futuximab/ modotuximab administration, twice a day (BID) within 1 hour after completion of morning and evening meals, 5 days on/2 days off, over 14 days, followed by a 14-day rest. This treatment cycle will be repeated every 28 days.
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
* Histologically or cytologically confirmed adenocarcinoma of metastatic colorectal cancer (mCRC), not amenable to surgical intervention due to either medical contraindications or non-resectability of the tumour without RAS (KRAS and NRAS) and BRAF V600E mutations based on Circulating tumour DNA (ctDNA) screening blood test analysis * Participants with measurable or non-measurable lesion * Participants must have received at least 2 prior regimens of standard chemotherapy for mCRC and had demonstrated progressive disease or intolerance to their last regimen * Participants should have received previous treatment with commercially available anti-EGFR mAbs for ≥ 4 months * Estimated life expectancy ≥ 12 weeks * Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 * Adequate haematological, renal and hepatic function
Exclusion criteria
* Pregnancy, possibility of becoming pregnant during the study, breastfeeding woman * Patients currently receiving or having received anticancer therapies within 4 weeks prior to the inclusion visit (Safety Lead-in part) or randomization visit (Phase 3 part). * Major surgery within 4 weeks prior to the inclusion visit (Safety Lead-in part) or randomization visit (Phase 3 part) or participants who have not recovered from side effects of the surgery * Participants with serious/active/uncontrolled infection * Known clinically significant cardiovascular disease or condition * Significant gastrointestinal abnormality * Skin rash of Grade \> 1 from prior anti-EGFR at the time of inclusion (Safety Lead-in part) or randomization (Phase 3 part), or any other skin toxicity precluding participation in the study according to investigator's discretion. * Treatment with systemic immunosuppressive therapy within 4 weeks prior to inclusion (Safety Lead-in part) or randomization (Phase 3 part) * Prior radiotherapy if completed less than 4 weeks before the inclusion visit (Safety Lead-in part) or randomization visit (Phase 3 part) * Patients with other malignancies
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of Dose-limiting Toxicities (DLTs) (Safety Lead-In Part) | End of cycle 1 (Each cycle is up to 28 days) | DLTs observed during a 28-day period. A DLT is defined as the following: A clinically significant AE graded according to the NCI-CTCAE version 5.0, observed during the initial 28- day treatment period following the first IMP administration. Assessed as unrelated to underlying disease, disease progression, intercurrent illness, or concomitant medications. At least possibly related to the IMPs (futuximab/modotuximab or trifluridine/tipiracil or both) by the investigator and meeting criteria as outlined in the protocol. |
| Overall Survival (OS) (In Double Negative, KRAS/NRAS and BRAF Wild Type Patients) (Phase III Part) | up to 4 years 9 months | Time elapsed from date of randomization until the date of death from any cause |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (Safety Lead-In Part) | up to 24 months | Time elapsed from the first IMP intake to death |
| Overall Survival (In Triple Negative) (Phase III Part) | up to 4 years 9 months | Time elapsed from the date of randomization into the study to disease progression/death |
| Progression Free Survival (Phase III Part) | up to 4 years 9 months | Time elapsed from the date of randomization into the study to disease progression/death |
| Adverse Events (Phase III Part) | Through study completion, up to 4 years 9 months | Incidence, severity, and relationship of treatment emergent adverse event and treatment emergent serious adverse event |
Countries
Belgium, Denmark, Finland, Hungary, Japan, United States
Participant flow
Pre-assignment details
Sponsor decided to discontinue the study during the Lead-In part and the Phase III (randomized) part was not started due to strategic reasons.
Participants by arm
| Arm | Count |
|---|---|
| Futuximab/Modotuximab Combined With Trifluridine/Tipiracil (Safety Lead-In and Phase III Parts) Futuximab/modotuximab: Concentrate for solution for infusion, futuximab/modotuximab was administered via IV route, once weekly of each cycle at 9 mg/kg/dose at Cycle 1 Day 1 and then at 6 mg/kg/dose. Each cycle is up to 28 days.
Trifluridine/Tipiracil: Film-coated tablets of trifluridine/tipiracil (35 mg/m²/dose) was administered orally before futuximab/ modotuximab administration, twice a day (BID) within 1 hour after completion of morning and evening meals, 5 days on/2 days off, over 14 days, followed by a 14-day rest. This treatment cycle was repeated every 28 days. | 7 |
| Total | 7 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Protocol Violation | 1 |
| Overall Study | Study termination | 6 |
Baseline characteristics
| Characteristic | Futuximab/Modotuximab Combined With Trifluridine/Tipiracil (Safety Lead-In and Phase III Parts) |
|---|---|
| Age, Continuous | 67.3 years STANDARD_DEVIATION 3.7 |
| Disease duration (years) | 4.062 years STANDARD_DEVIATION 2.63 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 7 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Primary tumour site Rectosigmoid segment | 2 Participants |
| Primary tumour site Rectum | 4 Participants |
| Primary tumour site Sigmoid colon | 1 Participants |
| Race/Ethnicity, Customized Race Asian | 1 Participants |
| Race/Ethnicity, Customized Race White | 6 Participants |
| Sex: Female, Male Female | 2 Participants |
| Sex: Female, Male Male | 5 Participants |
| Site of metastasis Bone | 1 Participants |
| Site of metastasis Distant lymph node | 3 Participants |
| Site of metastasis Liver | 5 Participants |
| Site of metastasis Lung | 6 Participants |
| Site of metastasis Other | 2 Participants |
| Time from first metastasis diagnosis to inclusion (months) | 37.784 months STANDARD_DEVIATION 22.556 |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 1 / 7 |
| other Total, other adverse events | 7 / 7 |
| serious Total, serious adverse events | 3 / 7 |
Outcome results
Primary
Incidence of Dose-limiting Toxicities (DLTs) (Safety Lead-In Part)
DLTs observed during a 28-day period. A DLT is defined as the following: A clinically significant AE graded according to the NCI-CTCAE version 5.0, observed during the initial 28- day treatment period following the first IMP administration. Assessed as unrelated to underlying disease, disease progression, intercurrent illness, or concomitant medications. At least possibly related to the IMPs (futuximab/modotuximab or trifluridine/tipiracil or both) by the investigator and meeting criteria as outlined in the protocol.
Time frame: End of cycle 1 (Each cycle is up to 28 days)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Futuximab/Modotuximab Combined With Trifluridine/Tipiracil (Safety Lead-In and Phase III Parts) | Incidence of Dose-limiting Toxicities (DLTs) (Safety Lead-In Part) | 0 dose-limiting toxicities (DLTs) |
Primary
Overall Survival (OS) (In Double Negative, KRAS/NRAS and BRAF Wild Type Patients) (Phase III Part)
Time elapsed from date of randomization until the date of death from any cause
Time frame: up to 4 years 9 months
Population: Sponsor decided to discontinue the study during the Lead-In part and the Phase III part was not started due to strategic reasons. Therefore, outcome measure data is not available
Secondary
Adverse Events (Phase III Part)
Incidence, severity, and relationship of treatment emergent adverse event and treatment emergent serious adverse event
Time frame: Through study completion, up to 4 years 9 months
Population: Sponsor decided to discontinue the study during the Lead-In part and the Phase III part was not started due to strategic reasons. Therefore, outcome measure data is not available
Secondary
Overall Survival (In Triple Negative) (Phase III Part)
Time elapsed from the date of randomization into the study to disease progression/death
Time frame: up to 4 years 9 months
Population: Sponsor decided to discontinue the study during the Lead-In part and the Phase III part was not started due to strategic reasons. Therefore, outcome measure data is not available
Secondary
Overall Survival (Safety Lead-In Part)
Time elapsed from the first IMP intake to death
Time frame: up to 24 months
Population: No analysis done for this outcome measure as data was not collected.
Secondary
Progression Free Survival (Phase III Part)
Time elapsed from the date of randomization into the study to disease progression/death
Time frame: up to 4 years 9 months
Population: Sponsor decided to discontinue the study during the Lead-In part and the Phase III part was not started due to strategic reasons. Therefore, outcome measure data is not available