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A Randomized, Double-Blind Placebo-Controlled, Phase 3 Study of Debio 1143 in Combination With Platinum-Based Chemotherapy and Standard Fractionation Intensity-Modulated Radiotherapy in Patients With Locally Advanced Squamous Cell Carcinoma of the Head and Neck, Suitable for Definitive Chemoradiotherapy (TrilynX)

A randomized, double-blind placebo-controlled, Phase 3 study of Debio 1143 in combination with platinum-based chemotherapy and radiotherapy in patients with locally advanced squamous cell carcinoma of the head and neck (TrilynX)

730

Overall Number of Baseline Participants - Debio 1143 + CRT: 364 Participants - Placebo + CRT: 366 Participants - Total: 730 (calculated) Number Analyzed: - Debio 1143 + CRT: 364 Participants - Placebo + CRT: 366 Participants - Total: 730 (calculated) Participants Age Continuous - Units: Years, Parameter type: Mean, Dispersion type: Standard Deviation - Debio 1143 + CRT: 60(8.01) - Placebo + CRT: 60(8.53) - Total: 60(8.27) Race/Ethnicity, Customized - Units: Participants, Parameter type: Number, Dispersion type: Not Applicable Ethnicity-Hispanic or Latino - Debio 1143 + CRT: 41 - Placebo + CRT: 46 - Total: 87 (calculated) Ethnicity-Not Hispanic or Latino - Debio 1143 + CRT: 264 - Placebo + CRT: 273 - Total: 537 (calculated) Ethnicity-Unknown or Not Reported - Debio 1143 + CRT: 59 - Placebo + CRT: 47 - Total: 106 (calculated) Race-Asian - Debio 1143 + CRT: 59 - Placebo + CRT: 60 - Total: 119 (calculated) Race-Black or African American - Debio 1143 + CRT: 5 - Placebo + CRT: 6 - Total: 11 (calculated) Race- Other - Debio 1143 + CRT: 5 - Placebo + CRT: 9 - Total: 14 (calculated) Race-Unknown or Not Reported - Debio 1143 + CRT: 42 - Placebo + CRT: 35 - Total: 77 (calculated) Race-White - Debio 1143 + CRT: 253 - Placebo + CRT: 256 - Total: 509 (calculated) Sex: Female, Male - Units: Participants, Parameter type: Count of Participants, Dispersion type: Not Applicable Female - Debio 1143 + CRT: 64 - Placebo + CRT: 57 - Total: 121 (calculated) Male - Debio 1143 + CRT: 300 - Placebo + CRT: 309 - Total: 609 (calculated)

Started - Debio 1143 + CRT: 364 Participants - Placebo + CRT: 366 Participants - Total: 730 (calculated) Completed - Debio 1143 + CRT: 0 Participants - Placebo + CRT: 0 Participants - Total: 0 (calculated) Not Completed: (=Started - Completed) - Debio 1143 + CRT: 364 Participants - Placebo + CRT:366 Participants - Total: 730 (calculated) Reason for Not Completed Total: (=sum per column) - Debio 1143 + CRT: 364 (calculated) - Placebo + CRT: 366 (calculated) - Total: 730 (calculated) Adverse event - Debio 1143 + CRT: 3 - Placebo + CRT: 3 - Total: 6 (calculated) Death - Debio 1143 + CRT: 111 - Placebo + CRT: 93 - Total: 204 (calculated) Lost to Follow-up - Debio 1143 + CRT: 10 - Placebo + CRT: 9 - Total: 19 (calculated) Other, Other Reasons - Debio 1143 + CRT: 4 - Placebo + CRT: 5 - Total: 9 (calculated) Other, Protocol deviation - Debio 1143 + CRT: 0 - Placebo + CRT: 1 - Total: 1 (calculated) Other, Randomized by mistake - Debio 1143 + CRT: 0 - Placebo + CRT: 1 - Total: 1 (calculated) Other, Study terminated by sponsor - Debio 1143 + CRT: 214 - Placebo + CRT: 232 - Total: 446 (calculated) Withdrawal by Subject - Debio 1143 + CRT: 22 - Placebo + CRT: 22 - Total: 44 (calculated)

Refer to the attached "20250806_MS202359_0006 TrilynX_Adverse Events_EN.pdf".

1. Primary: Event-Free Survival (EFS) as assessed by Blinded Independent Review Committee (BIRC) Number of Participants Analyzed (N): -Debio1143 + CRT: 364 -Placebo + CRT: 366 Number Analyzed (n): -Debio1143 + CRT: 364 Participants, Median: 19.4, 95% Confidence Interval (CI): 14.46 to NA -Placebo + CRT: 366 Participants, Median: 33.1, 95% CI: 20.99 to NA 2. Secondary: Overall Survival (OS) N: -Debio1143 + CRT: 364 -Placebo + CRT: 366 n (Units: months): -Debio1143 + CRT: 364 Participants, Median: NA, Full Range: 0.0 to 37.6 -Placebo + CRT: 366 Participants, Median: NA, Full Range: 0.0 to 39.4 3. Secondary: Progression Free Survival (PFS) According to RECIST v1.1 as Assessed by BIRC N: -Debio1143 + CRT: 364 -Placebo + CRT: 366 n (Units: months): -Debio1143 + CRT: 364 Participants, Median: 26.8, 95% CI: 15.93 to NA -Placebo + CRT: 366 Participants, Median: 33.1, 95% CI: 22.83 to NA 4. Secondary: Locoregional control (LRC) Time N: -Debio1143 + CRT: 364 -Placebo + CRT: 366 n (Units: months): -Debio1143 + CRT: 364 Participants, Median: NA, Full Range: 0.0 to 37.0 -Placebo + CRT: 366 Participants, Median: NA, Full Range: 0.0 to 38.2 5. Secondary: Objective Response Rate (ORR) as Assessed by BIRC N: -Debio1143 + CRT: 364 -Placebo + CRT: 366 n (Units: percentage of participants): [9 Months Post Randomization] -Debio1143 + CRT: 364 Participants, Number: 73.4 -Placebo + CRT: 366 Participants, Number: 77.3 [12 Months Post Randomization] -Debio1143 + CRT: 364 Participants, Number: 73.6 -Placebo + CRT: 366 Participants, Number: 77.9 6. Secondary: Complete Response Rate (CRR) N: -Debio1143 + CRT: 364 -Placebo + CRT: 366 n (Units: participants) [9 Months Post Randomization] -Debio1143 + CRT: 364 Participants, Count of Participants (#Participants): 187 (51.37%) -Placebo + CRT: 366 Participants, #Participants: 212 (57.92%) [12 Months Post Randomization] -Debio1143 + CRT: 364 Participants, #Participants: 194 (53.3%) -Placebo + CRT: 366 Participants, #Participants: 222 (60.66%) 7. Secondary: Duration of Response (DOR) N: -Debio1143 + CRT: 269 -Placebo + CRT: 287 n (Units: months): -Debio1143 + CRT: 269 Participants, Median: NA, Full Range: 0.0 to 33.5 -Placebo + CRT: 287 Participants, Median: NA, Full Range: 0.0 to 33.7 8. Secondary: Number of Participants with Radical Salvage Surgery N: -Debio1143 + CRT: 364 -Placebo + CRT: 366 n (Units: participants): [Months 9] -Debio1143 + CRT: 364 Participants, #Participants: 10 (2.75%) -Placebo + CRT: 366 Participants, #Participants: 3 (0.82%) [Months 12] -Debio1143 + CRT: 364 Participants, #Participants: 19 (5.22%) -Placebo + CRT: 366 Participants, #Participants: 5 (1.37%) [Months 24] -Debio1143 + CRT: 364 Participants, #Participants: 23 (6.32%) -Placebo + CRT: 366 Participants, #Participants: 9 (2.46%) [Months 36] -Debio1143 + CRT: 364 Participants, #Participants: 23 (6.32%) -Placebo + CRT: 366 Participants, #Participants: 9 (2.46%) 9. Secondary: Time to Subsequent Systemic Cancer Treatments N: -Debio1143 + CRT: 364 -Placebo + CRT: 366 n (Units: months): -Debio1143 + CRT: 364 Participants, Median: NA, Inter-Quartile Range: 0.0 to 37.6 -Placebo + CRT: 366 Participants, Median: NA, Inter-Quartile Range: 0.0 to 39.4 10. Secondary: Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs, AESI N: -Debio1143 + CRT: 364 -Placebo + CRT: 356 n (Units: participants): [TEAEs] -Debio1143 + CRT: 364 Participants, #Participants: 362 (99.45%) -Placebo + CRT: 356 Participants, #Participants: 351 (98.6%) [Serious TEAEs] -Debio1143 + CRT: 364 Participants, #Participants: 194 (53.3%) -Placebo + CRT: 356 Participants, #Participants: 129 (36.24%) [AESI] -Debio1143 + CRT: 364 Participants, #Participants: 357 (98.08%) -Placebo + CRT: 356 Participants, #Participants: 342 (96.07%) 11. Secondary: Number of Participants With Severity of Grade Greater or Equal to 3 TEAEs N: -Debio1143 + CRT: 364 -Placebo + CRT: 356 n (Units: participants): -Debio1143 + CRT: 364 Participants, #Participants: 320 (87.91%) -Placebo + CRT: 356 Participants, #Participants: 286 (80.34%) 12. Secondary: Change from Baseline in Laboratory Parameters: Basophils, Leukocytes, Lymphocytes, Monocytes, Neutrophils, Platelets N: -Debio1143 + CRT: 363 -Placebo + CRT: 352 n (Units: 1e9 per liter): [Basophils: Baseline] -Debio1143 + CRT: 363 Participants, Mean: 0.052, Standard Deviation (SD): 0.0343 -Placebo + CRT: 352 Participants, Mean: 0.054, SD: 0.0367 [Basophils: C3D1] -Debio1143 + CRT: 283 Participants, Mean: -0.032, SD: 0.0367 -Placebo + CRT: 288 Participants, Mean: -0.041, SD: 0.0362 [Basophils: EOT] -Debio1143 + CRT: 280 Participants, Mean: -0.021, SD: 0.0367 -Placebo + CRT: 287 Participants, Mean: -0.023, SD: 0.0312 [Basophil: Max on-treatment change] -Debio1143 + CRT: 357 Participants, Mean: -0.022, SD: 0.0673 -Placebo + CRT: 345 Participants, Mean: -0.031, SD: 0.0618 [Leukocytes: Baseline] -Debio1143 + CRT: 363 Participants, Mean: 8.175, SD: 2.9656 -Placebo + CRT: 352 Participants, Mean: 8.105, SD: 2.6725 [Leukocytes: C3D1] -Debio1143 + CRT: 288 Participants, Mean: -4.065, SD: 3.1244 -Placebo + CRT: 290 Participants, Mean: -4.597, SD: 2.9352 [Leukocytes: EOT] -Debio1143 + CRT: 282 Participants, Mean: -2.129, SD: 3.2074 -Placebo + CRT: 287 Participants, Mean: -2.354, SD: 2.4137 [Leukocytes: Max on-treatment change] -Debio1143 + CRT: 357 Participants, Mean: -3.045, SD: 7.5455 -Placebo + CRT: 345 Participants, Mean: -3.444, SD: 6.7059 [Lymphocytes: Baseline] -Debio1143 + CRT: 363 Participants, Mean: 1.753, SD: 0.5734 -Placebo + CRT: 352 Participants, Mean: 1.753, SD: 0.6367 [Lymphocytes: C3D1] -Debio1143 + CRT: 283 Participants, Mean: -1.168, SD: 0.5804 -Placebo + CRT: 288 Participants, Mean: -1.251, SD: 0.5742 [Lymphocytes: EOT] -Debio1143 + CRT: 280 Participants, Mean: -0.884, SD: 0.5485 -Placebo + CRT: 287 Participants, Mean: -0.901, SD: 0.5536 [Lymphocyte: Max on-treatment change] -Debio1143 + CRT: 357 Participants, Mean: -1.382, SD: 0.6359 -Placebo + CRT: 345 Participants, Mean: -1.356, SD: 0.6150 [Monocytes: Baseline] -Debio1143 + CRT: 363 Participants, Mean: 0.518, SD: 0.2156 -Placebo + CRT: 352 Participants, Mean: 0.506, SD: 0.2072 [Monocytes: C3D1] -Debio1143 + CRT: 283 Participants, Mean: -0.139, SD: 0.2389 -Placebo + CRT: 288 Participants, Mean: -0.169, SD: 0.2063 [Monocytes: EOT] -Debio1143 + CRT: 280 Participants, Mean: -0.114, SD: 0.1991 -Placebo + CRT: 287 Participants, Mean: -0.100, SD: 0.1683 [Monocyte: Max on-treatment change] -Debio1143 + CRT: 357 Participants, Mean: -0.175, SD: 0.4050 -Placebo + CRT: 345 Participants, Mean: -0.152, SD: 0.3870 [Neutrophils: Baseline] -Debio1143 + CRT: 363 Participants, Mean: 5.669, SD: 2.6589 -Placebo + CRT: 352 Participants, Mean: 5.610, SD: 2.3663 [Neutrophils: C3D1] -Debio1143 + CRT: 283 Participants, Mean: -2.646, SD: 2.8532 -Placebo + CRT: 288 Participants, Mean: -3.018, SD: 2.6744 [Neutrophils: EOT] -Debio1143 + CRT: 280 Participants, Mean: -1.081, SD: 2.9287 -Placebo + CRT: 287 Participants, Mean: -1.275, SD: 2.2696 [Neutrophils: Max on-treatment change] -Debio1143 + CRT: 357 Participants, Mean: -0.528, SD: 7.2775 -Placebo + CRT: 345 Participants, Mean: -1.095, SD: 6.3143 [Platelets: Baseline] -Debio1143 + CRT: 362 Participants, Mean: 292.6, SD: 104.86 -Placebo + CRT: 351 Participants, Mean: 287.7, SD: 107.38 [Platelets: C3D1] -Debio1143 + CRT: 282 Participants, Mean: -48.2, SD: 112.13 -Placebo + CRT: 277 Participants, Mean: -56.5, SD: 109.52 [Platelets: EOT] -Debio1143 + CRT: 278 Participants, Mean: -24.8, SD: 94.59 -Placebo + CRT: 284 Participants, Mean: -38.6, SD: 87.16 [Platelets: Max on-treatment change] -Debio1143 + CRT: 356 Participants, Mean: -63.2, SD: 203.40 -Placebo + CRT: 344 Participants, Mean: -88.7, SD: 171.61

This study has crossed the pre-defined futility boundary at the first Interim Analysis (IA). An imbalance was also seen for reported Adverse Events in the xevinapant arm compared to placebo.

Yes

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https://jrct.mhlw.go.jp/latest-detail/jRCT2031210525

Suzuki Tomoya

Merck Biopharma Co., Ltd.

1-3-1 Azabudai, Minato-ku, Tokyo

MBJ_clinicaltrial_information@merckgroup.com

Clinical Trial Information for Contact

Merck Biopharma Co., Ltd.

1-3-1 Azabudai, Minato-ku, Tokyo

+81-3-6756-0674

MBJ_clinicaltrial_information@merckgroup.com

Complete

Dec. 15, 2021

Interventional

randomized controlled trial

double blind

placebo control

parallel assignment

treatment purpose

- Eastern Cooperative Oncology Group performance status (ECOG PS) 0 or 1.
- Histologically confirmed diagnosis in previously untreated LA-SCCHN patient (stage III, IVA or IVB according to the American Joint Committee on Cancer [AJCC]/TNM Staging System, 8th Edition.) suitable for definitive CRT, of at least one of the following sites: oropharynx, hypopharynx, and larynx.
- For OroPharyngeal Cancer (OPC) patients, primary tumors must be HPV-negative as determined by p16 expression using immunohistochemistry.
- Evaluable tumor burden (measurable and/or non-measurable tumor lesions) assessed by computed tomography scan or magnetic resonance imaging, based on Response evaluation sriteria in solid tumors (RECIST ) version 1.1.
- Peripheral neuropathy less than or equal to (<=) grade 2.
- Adequate hematologic, renal, and hepatic function.
- Other protocol defined inclusion criteria may apply.

- Primary tumor of nasopharyngeal, paranasal sinuses, nasal, or oral cavity, salivary, thyroid or parathyroid gland pathologies, skin or unknown primary site.
- Metastatic disease (stage IVC as per AJCC/TNM, 8th Ed.).
- Prior definitive or adjuvant RT and/or radical surgery to the head and neck region which may jeopardize the primary tumor irradiation plan, or any other prior SCCHN systemic treatment, including investigational agents.
- Documented weight loss of >10% during the last 4 weeks prior to randomization (unless adequate measures are undertaken for nutritional support), OR plasmatic albumin < 3.0 g/dL. No albumin transfusions are allowed within 2 weeks before randomization.
- Known allergy to Debio 1143, cisplatin, carboplatin, other platinum-based agent or any excipient known to be present in any of these products or in the placebo formulation.
- other protocol defined exclusion criteria may apply.

Both

Locally Advanced Squamous Cell Carcinoma of the Head and Neck

Experimental arm:
Concomitant chemo-radiation therapy period (Cycles 1-3):
- Debio1143 (Xevinapant): Debio1143 administrated as oral solution from Day 1 to 14, every 21-day cycle.
- Cisplatin: Cisplatin administered as an IV infusion every 3 weeks (Q3W).
- Intensity Modulation Radiation Therapy (IMRT): 70 Gy given in 35 fractions over 7 weeks.
Monotherapy period (Cycles 4-6):
- Debio1143 (Xevinapant): Debio1143 administrated as oral solution from Day 1 to 14, every 21-day cycle.

Active comparator arm:
Concomitant chemo-radiation therapy period (Cycles 1-3):
- Placebo: Matched placebo administrated as oral solution from Day 1 to 14, every 21-day cycle.
- Cisplatin: Cisplatin administered as an IV infusion every 3 weeks (Q3W).
- Intensity Modulation Radiation Therapy (IMRT): 70 Gy given in 35 fractions over 7 weeks.
Monotherapy period (Cycles 4-6):
- Placebo: Matched placebo administrated as oral solution from Day 1 to 14, every 21-day cycle.

Event-Free Survival (EFS) [Time Frame: Up to 5 years ]
EFS is the time from the date of randomization to the date of first record of disease progression or death.

- Overall survival (OS)
- Progression-Free Survival (PFS)
- Locoregional Control (LRC)
- Objective Response Rate (ORR)
- Complete Response Rate (CRR)
- Duration of Response (DOR)
- Number of Participants with Radical Salvage Surgery
- Time to Subsequent Systemic Cancer Treatments
- Safety and Tolerability as assessed by incidence and severity of Adverse Events (AEs), Serious Adverse Events (SAEs), AEs of Special Interest (AESIs), Changes in Laboratory Values, Vital Signs, Electrocardiogram (ECGs) and Extent of Exposure
- Changes from Baseline in Global Health Status/Quality of Life (GHS/QoL) and Fatigue Symptom
- Changes from Baseline in Swallowing and Pain Symptoms

+81-429844523

Nov. 24, 2021

Argentina/Australia/Austria/Belgium/Brazil/Canada/China/Czech Republic/France/Georgia/Germany/Greece/Hungary/Israel/Italy/Poland/Portugal/Russia/Republic of Korea/Spain/Switzerland/Taiwan/Ukraine/UK/USA