Head and Neck Cancer
Conditions
Keywords
Adjuvant radiotherapy (RT), Stage III, Stage IVA, Stage IVB, Oral cavity, Oropharynx, Larynx, Hypopharynx, Unfit
Brief summary
The purpose of this study is to demonstrate the superior efficacy of Xevinapant (Debio 1143) versus placebo when added to radiotherapy in the treatment of high-risk participants with resected locally advanced squamous cell carcinoma of the head and neck (LA SCCHN) who are ineligible to receive cisplatin-based chemoradiation concurrently. Study details include: Study duration: Participants will be followed until the last on-study participant reaches his/her 60-month post-randomization visit, a decision to end the study has been triggered, or until premature discontinuation from study, whichever occurs first. Treatment duration: 18 weeks, consisting of six 3-week cycles. Health measurement/observation: Improved Disease-Free Survival. Visit frequency: Weekly visit during combination therapy period, once every 3 weeks during monotherapy period, and every 3, 4, or 6 months during the Disease-Free Survival Follow-up period in Year 1, 2 and 3, or 4 and 5 (with telephone contact in between), respectively, and every 3 months (telephone visits allowed) during the Overall Survival Follow-up period.
Interventions
DRUGXevinapant
Participants received 3 cycles of oral solution of Xevinapant at a dose of 200 milligrams per day (mg/day) once daily from Day 1 to 14, per 3-week cycle.
RADIATIONIMRT
Participants received 66 Gray (Gy) of intensity modulated radiation therapy (IMRT) in 33 fractions, 2 Gy/fraction, 5 days per week.
DRUGPlacebo
Participants received 3 cycles of oral solution of placebo matched to Xevinapant once daily from Day 1 to 14 per 3-week cycle.
Sponsors
EMD Serono Research & Development Institute, Inc.
Merck KGaA, Darmstadt, Germany
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Participants with Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0-2 and able to tolerate standard of care IMRT treatment according to Investigator assessment * Participants with histologically confirmed squamous cell carcinoma with one of the following primary sites: oral cavity, oropharynx, hypopharynx or larynx. Participants have received surgery with curative intent on these sites in the past 4 to 10 weeks before start of treatment (Cycle 1 Day 1) * Oropharynx (OPC) participants must have known human papillomavirus (HPV) status as determined by p16 expression using immunohistochemistry (ICH) * Participants with no residual disease by computed tomography (CT) or magnetic resonance imaging (MRI) and have a high risk of relapse with 1 or 2 of the following criteria, confirmed by local histopathology: • nodal extra-capsular extension (ECE) and positive resection margins (R1 or close margin less than or equal to (\<=) 1 millimeter (mm) * Are unfit to receive high-dose cisplatin by meeting one or more of the following criteria: estimated glomerular filtration rate (eGFR) \< 60 milliliter per minute per 1.73 meter square (mL/min /1.73 m\^2); History of hearing impairment, defined as Grade \>= 2 audiometric hearing loss or tinnitus Grade \>= 2. An audiogram is not required if one of the other criteria meets unfitness to receive high-dose cisplatin; Peripheral neuropathy \> = Grade 2 and if \>= 70 years, unfit according to G8 questionnaire (Score \<= 14) or ineligible for cisplatin treatment due to age limit according to national guidelines * Participants with adequate renal, hematologic and hepatic function as defined in the protocol * Other protocol-defined inclusion criteria could apply
Exclusion criteria
* Any condition, including any uncontrolled disease state other than SCCHN that in the Investigator's opinion constitutes an inappropriate risk or a contraindication for participation in the study or that could interfere with the study objectives, conduct, or evaluation * Participants with incomplete surgery * Participants with recurrent or metastatic disease * Primary tumor of nasopharyngeal, paranasal sinuses, nasal cavity, salivary, thyroid or parathyroid gland, skin or unknown primary site * Prior definitive, neoadjuvant, concurrent or adjuvant (C)RT to the head and neck region which may jeopardize the primary tumor irradiation plan, or any other prior SCCHN systemic treatment, including investigational agents * Participation in any interventional clinical study within 28 days prior to screening or during participation in this study * Known contraindication to undergoing positron emission tomography with 18F-FDG-PET-CT scans, or both contrast-enhanced MRI and contrast-enhanced CT scans * Known allergy to Xevinapant (Debio 1143) or any excipient known to be present in Xevinapant (Debio 1143) or in the placebo formulation * Other protocol-defined
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Disease-Free Survival (DFS) | Time from randomization to the first occurrence of death from any cause or objective disease recurrence, assessed up to 22.7 months | DFS defined as the time from randomization to the first occurrence of any of the following events: Death from any cause; Objective Disease Recurrence (earlier date of first imaging or biopsy collection confirming event at a DFS assessment): Local or regional relapse which is subsequently confirmed by histopathology unless medically contraindicated or medical risk of biopsy deemed too high: Distant metastases. Confirmation of pathology is recommended in case of solitary metastasis (especially in the lung) after considering potential contraindication and/or medical risk associated with biopsy. DFS time was estimated according to Kaplan-Meier method. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) | Time from randomization to death from any cause, assessed up to 22.7 months | Overall Survival was defined as the time from randomization to the date of death due to any cause. The overall survival was analyzed by using the Kaplan-Meier method. |
| Time to Subsequent Cancer Treatments | Time from randomization to the start of first subsequent cancer treatment, assessed up to 22.7 months | Time to subsequent cancer treatments was defined as the time from randomization to the start for the first new anticancer treatment. |
| Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment-related TEAEs | Time from randomization up to 22.7 months | Adverse event (AE): any unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of study drug, whether or not considered related to the study drug. Serious AE: an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. TEAE: events that start with onset or worsening (seriousness or severity) dates occurring within the on-treatment periods. TEAEs included both serious and non-serious TEAEs. Related TEAEs are events with relationship missing or related. |
| Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Head and Neck Module (EORTC QLQ-HN35) Score | Baseline, Day 64 and End of treatment (Day 134) | The EORTC QLQ-HN35 is designed to be used together with the core QLQ-C30. The recall period for the items in the module was "the past week". Items hn1 to hn30 were scored on 4 point Likert type categorical scales ("not at all", "a little", "quite a bit", "very much").Items hn31 to hn35 had a "no/yes" response format. The scores were transformed into 0 to 100 scales, with a high score implying a high level of symptoms. Negative changes from baseline indicate deterioration in functioning / global QoL scales and improvement in symptom scales. |
| Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Core Questionnaire (EORTC QLQ-C30) Score | Baseline, Day 64 and End of treatment (Day 134) | EORTC QLQ-C30 is a 30 item questionnaire composed of 5 multi-item functional subscales (physical, role, cognitive, emotional, and social functioning), 3 multi-item symptom scales (fatigue, nausea/vomiting, and pain), a global health/quality of life (QOL) subscale, and 6 single items assessing other cancer related symptoms (dyspnea, sleep disturbance, appetite, diarrhea, constipation, and the financial impact of cancer). The questionnaire employed twenty-eight 4 point Likert scales with responses from "not at all" to "very much" and two 7 point Likert scales for global health and overall QOL. For functional and global QOL scales, higher scores represented a better level of functioning and all scores were converted to a 0 to 100 scale. For symptom oriented scales, a higher score represented more severe symptoms, and all scores were converted to a 0-100 scale. Negative changes from baseline indicate deterioration in functioning / global QoL scales and improvement in symptom scales. |
| Change From Baseline in EuroQOL 5 Dimension 5 Level Health-Related Quality of Life Measure Visual Analog Scale Score (EQ-5D-5L VAS) | Baseline, Day 64 and End of treatment (Day 134) | EQ-5D-5L is comprised of the following 5 participant-reported dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension has 5 levels: no problems, slight problems, moderate problems, severe problems, and extreme problems. The responses are used to derive overall score using a visual analog scale (VAS) that ranged from 0 to 100, where 0 is the worst health you can imagine and 100 is the best health you can imagine. |
Countries
Argentina, Austria, Belgium, Brazil, Canada, China, Czechia, France, Georgia, Germany, Greece, India, Israel, Italy, Japan, Mexico, Netherlands, Poland, Portugal, Romania, South Korea, Spain, Switzerland, Taiwan, United Kingdom, United States
Contacts
STUDY_DIRECTORMedical Responsible
Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 69 Years STANDARD_DEVIATION 9.89 |
| Race/Ethnicity, Customized Ethnicity-Hispanic or Latino | 8 Participants |
| Race/Ethnicity, Customized Ethnicity-Not Hispanic or Latino | 63 Participants |
| Race/Ethnicity, Customized Ethnicity-Not Reported | 23 Participants |
| Race/Ethnicity, Customized Ethnicity-Unknown or Not Reported | 1 Participants |
| Race/Ethnicity, Customized Race-American Indian or Alaska Native | 1 Participants |
| Race/Ethnicity, Customized Race-Asian | 45 Participants |
| Race/Ethnicity, Customized Race-Black or African American | 0 Participants |
| Race/Ethnicity, Customized Race-More than one race | 1 Participants |
| Race/Ethnicity, Customized Race-Unknown or Not Reported | 14 Participants |
| Race/Ethnicity, Customized Race-White | 55 Participants |
| Sex: Female, Male Female | 18 Participants |
| Sex: Female, Male Male | 63 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 9 / 82 | 14 / 83 |
| other Total, other adverse events | 81 / 82 | 81 / 83 |
| serious Total, serious adverse events | 19 / 82 | 15 / 83 |
Outcome results
None listed