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)

• ClinicalTrials.gov Identifier: NCT04459715
• Recruitment Status: Recruiting
• First Posted: July 7, 2020
• Last Update Posted: November 22, 2022
• Sponsor: EMD Serono Research & Development Institute, Inc.
• Collaborators: GORTEC (Head and Neck Oncology and Radiotherapy Group); Merck KGaA, Darmstadt, Germany
• Information provided by (Responsible Party): EMD Serono ( EMD Serono Research & Development Institute, Inc. )

Tracking Information

• First Submitted Date: June 30, 2020
• First Posted Date: July 7, 2020
• Last Update Posted Date: November 22, 2022
• Actual Study Start Date: August 7, 2020
• Estimated Primary Completion Date: December 1, 2024 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: August 5, 2020)

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.

• Original Primary Outcome Measures (submitted: July 3, 2020): Event-Free Survival (EFS) [ Time Frame: From randomization to the earliest between any EFS event (death or progression or primary treatment failure or relapse after achieving complete response or second cancers) or End of study (EOS); (within 60 months post randomization) ]

Current Secondary Outcome Measures (submitted: August 22, 2022)

• Overall survival (OS) [ Time Frame: Up to 5 years ]
  OS is the time from randomization to death due to any cause.
• Progression-Free Survival (PFS) [ Time Frame: Up to 5 years ]
  PFS is the time from randomization to the earliest between PFS event or End of Study (EOS)
• Locoregional Control (LRC) [ Time Frame: From randomization to the earliest between PFS event (progression at the site of the primary tumor or the locoregional lymph nodes) or EOS (Up to 5 years) ]
• Objective Response Rate (ORR) [ Time Frame: Up to 5 years ]
  ORR defined as proportion of participants with complete response (CR) or partial response (PR) by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, as assessed by Blinded Independent Review Committee (BIRC).
• Complete Response Rate (CRR) [ Time Frame: Up to 5 years ]
  CRR defined as proportion of participants with complete response (CR) as assessed by Blinded Independent Review Committee (BIRC).
• Duration of Response (DOR) [ Time Frame: Up to 5 years ]
  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.
• Number of Participants with Radical Salvage Surgery [ Time Frame: Up to 5 years ]
• Time to Subsequent Systemic Cancer Treatments [ Time Frame: Up to 5 years ]
• 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 [ Time Frame: From signed informed consent to EOS (within 6.8 years) ]
• Changes from Baseline in Global Health Status/Quality of Life (GHS/QoL) and Fatigue Symptom [ Time Frame: Prior to the first dose of study treatment (Baseline) and at the time of last follow-up (Up to 5 years) ]
  Change from baseline in GHS/QoL and Fatigue Symptom using the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Core Questionnaire (EORTC QLQ-C30)
• Changes from Baseline in Swallowing and Pain Symptoms [ Time Frame: Prior to the first dose of study treatment (Baseline) and at the time of last follow-up (Up to 5 years) ]
  Change from baseline in swallowing, and pain symptoms using the EORTC Head and Neck Questionnaire (EORTC QLQ-H&N35)

Original Secondary Outcome Measures (submitted: July 3, 2020)

• Progression-Free Survival (PFS) [ Time Frame: From randomization to the earliest between PFS event or EOS (within 60 months post randomization) ]
• Locoregional Control (LRC) [ Time Frame: From randomization to the earliest between PFS event (progression at the site of the primary tumor or the locoregional lymph nodes) or EOS (within 60 months post randomization) ]
• Overall Response Rate (ORR) [ Time Frame: From randomization to the earliest between progression, start of a new anticancer therapy for this disease or participant's EOS (within 12 months post randomization) ]
• Complete Response Rate (CRR) [ Time Frame: From randomization to the earliest between progression, start of a new anticancer therapy for this disease or participant's EOS (within 12 months post randomization) ]
• Duration of response (DoR) [ Time Frame: From first evidence of response (partial or complete) to the earliest between DoR event (progression) or EOS (within 24 months post first evidence of response) ]
• Overall survival (OS) [ Time Frame: From randomization to the earliest between death or EOS (within 60 months post randomization) ]
• Percentage of Participants With Radical Salvage Surgery [ Time Frame: From randomization to the earliest between radical salvage surgery or EOS (within 60 months post randomization) ]
• Time to Subsequent Systemic Cancer Treatments [ Time Frame: From randomization to EOS (within 60 months post randomization) ]
• Number of Participants with Adverse Events (AEs), Serious Adverse Events (SAEs) and Adverse Events of Special Interest (AESIs) [ Time Frame: From signed informed consent to EOS (within 6.8 years) ]
• Number of Participants with Clinically Significant Laboratory Abnormalities Assessed by NCI-CTCAE v 5.0 [ Time Frame: From signed informed consent to EOS (within 6.8 years) ]
• Number of Participants with Clinically Significant Vital Signs Assessed by NCI-CTCAE v 5.0 [ Time Frame: From signed informed consent to EOS (within 6.8 years) ]
• Number of Participants with Clinically Significant Electrocardiograms Assessed by NCI-CTCAE v 5.0 [ Time Frame: From signed informed consent to EOS (within 6.8 years) ]
• Extent of exposure [ Time Frame: From first study treatment dose to End of Treatment (EOT); (Up to 15 days after Cycle 6 (each cycle is of 15 days) ]
• Changes from baseline in Quality of Life and Fatigue using European Organisation for Research and Treatment of Cancer Quality of life Questionnaire (EORTC QLQ-C30) Score [ Time Frame: From randomization to EOS (within 60 months post randomization) ]
  The EORTC QLQ-C30 version 3.0 questionnaire captures Health-Related Quality of Life (HRQL) dimensions that are common to cancer participants independently of the cancer type by which they are affected. The total scores are transformed from 0 to 100, where higher score indicates better outcome.
• Changes from baseline in Swallowing and Pain using EORTC QLQ Head and Neck Cancer Module (EORTC QLQ-HN35) Score [ Time Frame: From randomization to EOS (within 60 months post randomization) ]
  The EORTC QLQ-HN35 is a disease-specific module capturing HRQL dimensions that affect head and neck cancer patients. The total scores are transformed from 0 to 100, where higher score indicates more severe symptoms.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: 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)
• Official Title: 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)
• Brief Summary: The primary objective of the study is 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).
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Squamous Cell Carcinoma of the Head and Neck

Intervention

• Drug: Xevinapant (Debio 1143)
  Xevinapant (Debio 1143) administrated as oral solution from Day 1 to 14, every 21-day cycle.
• Drug: Cisplatin
  Cisplatin administered as an IV infusion every 3 weeks (Q3W).
• Radiation: Intensity Modulation Radiation Therapy (IMRT)
  70 Gy given in 35 fractions over 7 weeks.
• Drug: Placebo
  Matched placebo administrated as oral solution from Day 1 to 14, every 21-day cycle.

Study Arms

• Experimental: Xevinapant (Debio 1143)

  Participants will receive:

  Concomitant chemo-radiation therapy period (Cycles 1-3):

  • Radiotherapy
  • Cisplatin
  • Xevinapant (Debio 1143)

  Monotherapy period (Cycles 4-6):

  • Xevinapant (Debio 1143)

  Interventions:

  • Drug: Xevinapant (Debio 1143)
  • Drug: Cisplatin
  • Radiation: Intensity Modulation Radiation Therapy (IMRT)
• Active Comparator: Placebo

  Participants will receive:

  Concomitant chemo-radiation therapy period (Cycles 1-3):

  • Radiotherapy
  • Cisplatin
  • Matched placebo

  Monotherapy period (Cycles 4-6):

  • Matched placebo

  Interventions:

  • Drug: Cisplatin
  • Radiation: Intensity Modulation Radiation Therapy (IMRT)
  • Drug: Placebo

• Publications *: Bourhis J, Burtness B, Licitra LF, Nutting C, Schoenfeld JD, Omar M, Bouisset F, Nauwelaerts H, Urfer Y, Zanna C, Cohen EE. Xevinapant or placebo plus chemoradiotherapy in locally advanced squamous cell carcinoma of the head and neck: TrilynX phase III study design. Future Oncol. 2022 May;18(14):1669-1678. doi: 10.2217/fon-2021-1634. Epub 2022 Feb 17.

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: July 3, 2020): 700
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: April 30, 2027
• Estimated Primary Completion Date: December 1, 2024 (Final data collection date for primary outcome measure)

Eligibility Criteria

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: US Medical Information; 888-275-7376; eMediUSA@emdserono.com

Contact: Communication Center; +49 6151 72 5200; service@emdgroup.com

• Listed Location Countries: Argentina, Australia, Austria, Belgium, Brazil, Canada, China, Czechia, France, Georgia, Germany, Greece, Hungary, Israel, Italy, Japan, Korea, Republic of, Poland, Portugal, Russian Federation, Spain, Switzerland, Taiwan, Ukraine, United Kingdom, United States

Administrative Information

• NCT Number: NCT04459715
• Other Study ID Numbers: MS202359_0006; 2020-000377-25 ( EudraCT Number ); Debio 1143-SCCHN-301 ( Other Identifier: Previous Sponsor Identifier )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No

IPD Sharing Statement

• Plan to Share IPD: Yes
• Plan Description: We are committed to enhancing public health through responsible sharing of clinical trial data. Following approval of a new product or a new indication for an approved product in both the US and European Union, the study sponsor and/or its affiliated companies will share study protocols, anonymized patient data and study level data, and redacted clinical study reports with qualified scientific and medical researchers, upon request, as necessary for conducting legitimate research. Further information on how to request data can be found on our website bit.ly/IPD21
• Supporting Materials: Study Protocol
• Supporting Materials: Statistical Analysis Plan (SAP)
• Supporting Materials: Clinical Study Report (CSR)
• Supporting Materials: Analytic Code
• Time Frame: Within six months after the approval of a new product or a new indication for an approved product in both the United States and the European Union
• Access Criteria: Within six months after the approval of a new product or a new indication for an approved product in both the United States and the European Union
• URL: http://bit.ly/IPD21

• Current Responsible Party: EMD Serono ( EMD Serono Research & Development Institute, Inc. )
• Original Responsible Party: Debiopharm International SA
• Current Study Sponsor: EMD Serono Research & Development Institute, Inc.
• Original Study Sponsor: Debiopharm International SA

Collaborators

• GORTEC (Head and Neck Oncology and Radiotherapy Group)
• Merck KGaA, Darmstadt, Germany

Investigators

• Study Director: Medical Responsible; Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany

• PRS Account: EMD Serono
• Verification Date: November 2022