A Study of Xevinapant (Debio 1143) in Combination With Platinum-Based Chemotherapy and Standard Fractionation Intensity-Modulated Radiotherapy in Participants With Locally Advanced Squamous Cell Carcinoma of the Head and Neck, Suitable for Definitive Chemoradiotherapy (TrilynX)

Phase 3TerminatedNCT04459715

EMD Serono Research & Development Institute, Inc.730 enrolled

Overview

The primary objective of the study was to demonstrate superior efficacy of Xevinapant (Debio 1143) vs placebo when added to chemoradiotherapy (CRT) in locally advanced squamous cell carcinoma of the head and neck (LA-SCCHN).

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

QUADRUPLE

Enrollment

730

Conditions

Squamous Cell Carcinoma of the Head and Neck

Interventions

Xevinapant (Debio 1143)DRUG

Xevinapant (Debio 1143) administrated as oral solution from Day 1 to 14, every 21-day cycle.

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria: * Eastern Cooperative Oncology Group performance status (ECOG PS) 0 or 1 * Histologically confirmed diagnosis of previously untreated Locally Advanced Squamous Cell Carcinoma of the Head and Neck (LA-SCCHN) participant (stage III, IVa or IVb according to the American Joint Committee on Cancer(AJCC))/Classification of malignant tumors: T=size of the primary tumor, N=regional lymph node involvement, M=distant metastasis (TNM) Staging System, 8th Edition.) suitable for definitive ChemoRadiotherapy (CRT), of at least one of the following sites: oropharynx, hypopharynx and larynx * For OroPharyngeal Cancer (OPC) participants, primary tumors must be human papillomavirus (HPV)-negative as determined by p16 expression using immunohistochemistry * Evaluable tumor burden (measurable and/or non-measurable tumor lesions) assessed by computed tomography scan (CT-scan) or magnetic resonance imaging (MRI), based on Response evaluation criteria in solid tumors (RECIST) version 1.1 * Peripheral neuropathy less than (\<) grade 2 * Adequate hematologic, renal and hepatic function * Other protocol defined inclusion criteria may apply Exclusion Criteria: * Primary tumor of nasopharynx, 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 Radiotherapy (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 Xevinapant (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

Locations (288)

The University of Alabama at Birmingham - Hazelrig-Salter Radiation Oncology Center (HSROC)

Birmingham, Alabama, United States

Banner MD Anderson Cancer Center

Gilbert, Arizona, United States

University of Arizona Cancer Center

Tucson, Arizona, United States

UC San Diego Moores Cancer Center

La Jolla, California, United States

Regents of the University of California

San Francisco, California, United States

Outcomes

Primary Outcomes

Event-Free Survival (EFS) as Assessed by Blinded Independent Review Committee (BIRC)

Event-Free Survival (EFS) as assessed by BIRC is the time from randomization to the first of: (1) Death from any cause; (2) Progression: either radiological (per RECIST v1.1) or clinical (with/without radiologic proof, assessed endoscopically); (3) Primary treatment failure prior to complete response (CR): requirement for radical salvage surgery at primary tumor site with viable tumor confirmed histologically, even without RECIST progression; (4) Relapse after CR (locoregional): including radical salvage surgery or elective neck dissection/biopsy more than equal to (\>=) 22 weeks post-randomization showing viable tumor cells regardless of radiologic status; (5) Second cancers, unless histology excludes squamous origin. Calculated via Kaplan Meier method.

Time frame: From randomization to the earliest between any EFS event or End of Study (EOS) (up to 188 weeks and 5 days)

Secondary Outcomes

Overall Survival (OS)

Overall survival is defined as the time from randomization to the date of death. Calculated via Kaplan Meier method.

Time frame: From randomization to the earliest between death or EOS (up to 188 weeks and 5 days)

Progression Free Survival (PFS) According to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 as Assessed by Blinded Independent Review Committee (BIRC)

PFS according to RECIST v1.1 defined as the time from randomization to the first occurrence of progression (radiological or clinical, as assessed by the BIRC) or death from any cause. According to RECIST 1.1, progressive disease (PD) was defined as a 20% relative increase in the sum of diameters (SOD) of target lesions, taking as reference the nadir SOD and an absolute increase of \>5 millimeter (mm) in the SOD, or the appearance of new lesions. Calculated via Kaplan Meier method.

Time frame: From randomization to the first occurrence of progression (radiological or clinical, as assessed by the BIRC) or death from any cause or EOS (up to 188 weeks and 5 days )

Locoregional Control (LRC) Time

LRC time is defined as the time from randomization to the first occurrence of progression at the site of the primary tumor or the locoregional lymph nodes, either according to RECIST v1.1 or based on clinical assessment (radiological or clinical, as assessed by the Investigator). According to RECIST 1.1, progressive disease (PD) was defined as a 20% relative increase in the sum of diameters (SOD) of target lesions, taking as reference the nadir SOD and an absolute increase of \>5 millimeter (mm) in the SOD, or the appearance of new lesions. Calculated via Kaplan Meier method.

Time frame: From randomization to the first occurrence of progression at the site of the primary tumor or the locoregional lymph nodes or End Of Study (EOS) (188 weeks and 5 days)

Objective Response Rate (ORR) as Assessed by BIRC

Objective response rate was defined as percentage of participants with either a confirmed complete response (CR) or partial response (PR). CR: Disappearance of all target and non-target lesions. PR: At least a 30 percent (%) decrease in the sum of diameters of target lesions, taking as reference the baseline sum of their diameters, and no unequivocal progression of non-target lesions. Progression is defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on the study, or unequivocal progression of non-target lesions, or appearance of any new lesion.

Time frame: At 9 and 12 months post randomization

Complete Response Rate (CRR)

CRR defined as the number of participants with Complete Response by RECIST v1.1, as assessed by the BIRC. Complete response is defined as disappearance of all target and non-target lesions.

Time frame: At 9 and 12 months post randomization

Duration of Response (DOR)

Duration of response (DoR) defined as the time from the first evidence of response (partial or complete, as assessed by the BIRC according to RECIST v1.1) to the first occurrence of progression (radiological or clinical, as assessed by the BIRC) or death from any cause. Kaplan Meier method was used for calculation.

Time frame: Time from first evidence of response to the first occurrence of progression or death from any cause, assessed up to 24 months

Number of Participants With Radical Salvage Surgery

Number of Participants with Radical Salvage Surgery (excluding elective neck dissection without anatomopathological evidence of residual malignant cells) was reported.

Time frame: At 9, 12, 24 and 36 months post randomization

Time to Subsequent Systemic Cancer Treatments

Time to new subsequent systemic cancer treatment (in months) was derived as (date of event/censoring - randomization date +1) / 30.4375. Calculated via kaplan meier method.

Time frame: Up to 188 weeks and 5 days post randomization

Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs, Adverse Events (AEs) of Special Interest

An AE is any unfavorable/unintended sign (e.g., abnormal lab result), symptom or disease temporally linked to study drug, whether or not related. A serious AE leads to death, is life-threatening, causes significant/persistent disability, hospitalization, congenital anomaly, or is medically important. TEAEs include both serious and non-serious AEs after treatment. AESIs are events of clinical interest needing close monitoring. In this study, AESIs include: infusion reactions including hypersensitivity, immune-related AEs, aspartate aminotransferase/alanine transaminase increases, lipase/amylase elevation, acute renal failure, QTcF more than 30 milliseconds above baseline, and ≥Grade 2 inflammatory cutaneous AEs.

Time frame: From signed informed consent to EOS (up to 188 weeks and 5 days)

Number of Participants With Severity of Grade Greater or Equal to 3 TEAEs

Severity of TEAEs were evaluated using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version. The grade are as follows: grade 1 : mild grade 2 : moderate grade 3 : severe or medically significant but not immediately life-threatening grade 4 : life threatening or disabling grade 5 : death related to AE.

Time frame: From signed informed consent to EOS (up to 188 weeks and 5 days)

Change From Baseline in Laboratory Parameters: Basophils, Leukocytes, Lymphocytes, Monocytes, Neutrophils, Platelets

Change from Baseline in Laboratory Parameters: Basophils, Leukocytes, Lymphocytes, Monocytes, Neutrophils, Platelets was reported.

Time frame: At Baseline, Cycle 3 Day 1 (C3D1) (combination period), EOT (15 days after last study treatment administration) and baseline upto event free survival (EFS) follow up Month 18 after EOT (max on treatment change)

Percent Change From Baseline in Laboratory Parameters: Basophils/Leukocytes, Eosinophils/Leukocytes, Lymphocytes/Leukocytes, Monocytes/Leukocytes, Neutrophils/Leukocytes

Change from Baseline in Laboratory Parameters: Basophils/Leukocytes, Eosinophils/Leukocytes, Lymphocytes/Leukocytes, Monocytes/Leukocytes, Neutrophils/Leukocytes was reported.

Time frame: At Cycle 3 Day 1 (C3D1) (combination period), EOT (15 days after last study treatment administration) and baseline upto event free survival (EFS) follow up Month 18 after EOT (max on treatment change)

Change From Baseline in Laboratory Parameters: Erythrocytes

Change from Baseline in Laboratory Parameters: Erythrocytes was reported.

Change From Baseline in Laboratory Parameters: Hemoglobin, Albumin, Protein

Change from Baseline in Laboratory Parameters: Hemoglobin, Albumin, Protein was reported.

Change From Baseline in Laboratory Parameters: Alanine Aminotransferase, Alkaline Phosphatase, Amylase, Aspartate Aminotransferase, Lipase

Change from Baseline in Laboratory Parameters: Alanine Aminotransferase, Alkaline Phosphatase, Amylase, Aspartate Aminotransferase, Lipase was reported.

Change From Baseline in Laboratory Parameters: Bilirubin, Creatinine, Direct Bilirubin, Urate

Change from Baseline in Laboratory Parameters: Bilirubin, Creatinine, Direct Bilirubin, Urate was reported.

Change From Baseline in Laboratory Parameters: C Reactive Protein

Change from Baseline in Laboratory Parameters: C Reactive Protein was reported.

Change From Baseline in Laboratory Parameters: Calcium, Magnesium, Potassium, Sodium, Urea

Change from Baseline in Laboratory Parameters: Calcium, Magnesium, Potassium, Sodium, Urea was reported.

Change From Baseline in Estimated Glomerular Filtration Rate

Change from baseline in biochemistry parameter eGFR was reported. The Glomerular Filtration Rate was measured as milliliter per minute per 1.73 square meter (mL/min/1.73m\^2).

Change From Baseline in Activated Partial Thromboplastin Time (PTT)/ Standard and Prothrombin Time

Change from Baseline in coagulation parameter activated PTT/standard and prothrombin Time was reported.

Change From Baseline in Fibrinogen

Change from Baseline in coagulation parameter fibrinogen was reported.

Change From Baseline in Prothrombin International Normalized Ratio

Change from baseline in coagulation parameters prothrombin international normalized ratio was reported.

Change From Baseline in Vital Signs: Systolic Blood Pressure, Diastolic Blood Pressure

Change from Baseline in Vital Signs: Systolic Blood Pressure, Diastolic Blood Pressure was reported.

Change From Baseline in Vital Signs: Heart Rate

Change from Baseline in Vital Signs: Heart Rate was reported.

Change From Baseline in Vital Signs: Respiratory Rate

Change from Baseline in Vital Signs: Respiratory Rate was reported.

Change From Baseline in Vital Signs: Body Temperature

Change from Baseline in Vital Signs: Body Temperature was reported.

Change From Baseline in Vital Signs: Body Weight

Change from Baseline in Vital Signs: Body Weight was reported.

Time frame: At Baseline, C3D1 (combination period), EOT (15 days after last study treatment administration) and baseline upto event free survival (EFS) follow up Month 18 after EOT (max on treatment increase & decrease)

Change From Baseline in ECG Parameters

The 12-lead ECGs were recorded after the participants have rested for at least 5 minutes in supine position. The parameters included Respiratory Rate (RR), Pulse Rate (PR), QRS, QT and QTcF calculated by the Bazett formula.

Time frame: At Baseline, and upto event free survival (EFS) follow up Month 18 after EOT (max on treatment increase)

Treatment Duration

Treatment duration is calculated by study treatment component as (last dose date minus first dose date plus x)/7, where x=8 for xevinapant/matched placebo, x=21 for cisplatin/carboplatin, x=3 for IMRT.

Time frame: Up to end of study (up to 188weeks and 5 days)

Number of Participants Who Completed Cycle 1, 2, 3, 4, 5 and 6

Number of participants who completed cycle 1, 2, 3, 4, 5 or 6 of xevinapant/matched placebo were reported.

Time frame: Cycle 1, 2, 3, 4, 5 and 6 (each cycle is of 3 weeks)

Total Cumulative Dose of Xevinapant/ Matched Placebo

Total cumulative dose of Xevinapant/ Matched Placebo was reported in form of mean and standard deviation.

Time frame: Up to end of treatment (Day 134)

Total Cumulative Dose of Cisplatin

Total cumulative dose of cisplatin was reported.

Time frame: Up to end of treatment (Day 134)

Total Cumulative Dose of Carboplatin

Total cumulative dose of carboplatin was reported as mean and standard deviation.

Time frame: Up to end of treatment (Day 134)

Total Cumulative Dose of Intensity-Modulated Radiation Therapy (IMRT)

Total cumulative dose of IMRT were reported in form of mean and standard deviation.

Time frame: Up to end of treatment (Day 134)

Overall Dose Intensity of Xevinapant/Matched Placebo

Overall dose intensity of Xevinapant/ matched placebo is calculated as the mean of the dose intensities of the individual cycles.

Time frame: Cycle 1, 2, 3, 4 5, 6 (each cycle is of 3 weeks) or End of Treatment (Day 134)

Overall Dose Intensity of Cisplatin

Overall dose intensity of Cisplatin is calculated as the mean of the dose intensities of the individual cycles. This was reported with the unit of measure milligrams per meter square per week (mg/m2/week).

Time frame: Cycle 1, 2, 3, 4 5, 6 (each cycle is of 3 weeks) or End of Treatment (Day 134)

Overall Dose Intensity of Carboplatin

Overall dose intensity of Carboplatin is calculated as the mean of the dose intensities of the individual cycles. This was reported with unit of measure Milligrams per minute per milliliter per week (mg min/mL/week).

Time frame: Cycle 1, 2, 3, 4 5, 6 (each cycle is of 3 weeks) or End of Treatment (Day 134)

Relative Dose Intensity

Relative dose intensity (RDI) represents the percentage of the amount of a drug actually delivered \[actual dose intensity (DI)\] to the amount planned (planned DI). The purpose of calculating RDI is to evaluate whether the planned DI of an anti-cancer treatment was actually achieved which may suggest the feasibility of planned treatment regimen.

Time frame: Up to 50 months

Number of Participants With Treatment Interruption, Treatment Reduction and Treatment Discontinuation for Xevinapant/ Matched Placebo

Number of participants with Treatment Interruption, Treatment Reduction and Treatment Discontinuation was reported.

Time frame: Up to end of treatment (Day 134)