Phase 3 Study of Futuximab/Modotuximab in Combination With Trifluridine/Tipiracil Versus Trifluridine/Tipiracil Single Agent in Participants With Previously Treated Metastatic Colorectal Cancer

Study Overview
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Brief Summary
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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) (Double negative [DN].

Official Title
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A Randomised, Open-label, Multi-centre, Two-arm Phase 3 Study Comparing Futuximab/Modotuximab in Combination With Trifluridine/Tipiracil to Trifluridine/Tipiracil Single Agent With a Safety Lead-In Part in Participants With KRAS/NRAS and BRAF Wild Type Metastatic Colorectal Cancer Previously Treated With Standard Treatment and Anti-EGFR Therapy

Conditions
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Metastatic Colorectal Cancer

Intervention / Treatment
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* Biological: Futuximab/modotuximab
* Drug: Trifluridine/Tipiracil
* Drug: Trifluridine/Tipiracil


Participation Criteria
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Eligibility Criteria
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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

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: Futuximab/modotuximab combined with trifluridine/tipiracil (Safety Lead-In and Phase III parts)<br> | Biological: Futuximab/modotuximab<br>* 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.<br>Drug: Trifluridine/Tipiracil<br>* 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.<br>|
| Active Comparator: Trifluridine/tipiracil (Phase III part)<br> | Drug: Trifluridine/Tipiracil<br>* Film-coated tablets of trifluridine/tipiracil (35 mg/m²/dose) will be administered orally 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of dose-limiting toxicities (DLTs) (Safety Lead-In part) | DLTs observed during a 28-day period | End of cycle 1 (Each cycle is up to 28 days) | 
| 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 | up to 4 years 9 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival (Safety Lead-In part) | Time elapsed from the first IMP intake to death | up to 24 months | 
| Overall survival (In triple negative) (Phase III part) | Time elapsed from the date of randomization into the study to disease progression/death | up to 4 years 9 months | 
| Progression Free Survival (Phase III part) | Time elapsed from the date of randomization into the study to disease progression/death | up to 4 years 9 months | 
| Adverse Events (Phase III part) | Incidence, severity, and relationship of treatment emergent adverse event and treatment emergent serious adverse event | Through study completion, up to 4 years 9 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Futuximab/modotuximab, Trifluridine/tipiracil, Phase III, Safety Lead-In part, S95026, Sym004, Adult, Metastatic, Colorectal, Colorectal Cancer, EGFR