Head and Neck Cancer
Conditions
Keywords
Unresected, Combination with CRT, Stage III, Stage IVA, Stage IVB, Oropharynx, Hypopharynx, Larynx
Brief summary
The purpose of this study is to evaluate the tolerability and safety of Xevinapant when added to weekly cisplatin-based concurrent chemoradiotherapy (CRT) in the treatment of participants with unresectable locally advanced squamous cell carcinoma of the head and neck, suitable for definitive chemoradiotherapy.
Interventions
DRUGXevinapant
Participants will receive xevinapant once daily from Day 1 to Day 14, per 3-week cycle (Each cycle is of 3 weeks). The first three cycles are given in combination with weekly cisplatin and radiotherapy, followed by 3 cycles of monotherapy xevinapant.
DRUGCisplatin
Participants will receive weekly cisplatin for 7 weeks on Cycle 1 Day 2 (C1D2), C1D9, C1D16, C2D2, C2D9, C2D16, and C3D2).
RADIATIONintensity-modulated radiation therapy (IMRT)
Participants will receive 70 Gray (Gy) of IMRT in 35 fractions, 2 Gy/fraction, 5 days/week
Sponsors
Merck KGaA, Darmstadt, Germany
EMD Serono Research & Development Institute, Inc.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Participants having an Eastern Cooperative Oncology Group Performance Score (ECOG PS) of 0 - 1 * Histologically confirmed diagnosis in previously untreated Locally Advanced Squamous Cell Carcinoma of Head and neck (LA SCCHN) patient (Stage III, IVA, or IVB according to the American Joint Committee on Cancer \[AJCC\]/ Tumor Nodes and metastases (TNM) Staging System, 8th Edition) suitable for definitive Chemoradiotherapy (CRT), with one of the following primary sites: oropharynx (OPC) Human Papillomavirus (HPV)-negative, hypopharynx, and larynx * Participant should be able to swallow liquids or has an adequately functioning feeding tube, gastrostomy, or jejunostomy in place. For participants requiring liquid nutrition at baseline or during the study including the follow-up period, access to liquid nutrition supply should be ensured * Participant with evaluable tumor burden (measurable and/or non-measurable tumor lesions) assessed by CT scan and/or MRI, based on RECIST v 1.1. * Adequate hematological, hepatic, and renal function as defined in the protocol * Other protocol defined inclusion criteria could apply
Exclusion criteria
* 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 Edition) * Existing need of a hearing aid or greater than or equal to (\>=) 25 decibel shift over 2 contiguous frequencies on a pretreatment hearing test as clinically indicated * Known history of infection with human immunodeficiency virus (HIV). If unknown history of HIV, an HIV screening test is to be performed and participants with positive serology for HIV-1/2 must be excluded * Known gastrointestinal disorder with clinically established malabsorption syndrome and major gastrointestinal surgery in the last 12 months that may limit oral absorption * Other protocol defined
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Dose Limiting Toxicity (DLT)-Like Events | Time from the first dose of study intervention day upto 35 days (5 weeks) | DLT-like events defined as any of the following treatment-related adverse events (AEs) or lab abnormalities occurring during the 5-week DLT-like assessment period and assessed as related to the study intervention: Grade 4 asymptomatic neutropenia more than (\>) 7 days; Grade 2-3 febrile neutropenia; Grade 4 thrombocytopenia without bleeding more than and equal to (\>=) 5 days or Grade 2-3 with bleeding or requiring transfusion; Grade 2-3 nonhematologic toxicity (e.g., renal impairment based on eGFR, Grade 4 skin toxicity/mucositis interfering with treatment); less than (\<) 60% planned cumulative dose of xevinapant or cisplatin due to AE; \>2-week Radiation therapy (RT) delay due to AE; Grade \>=2 ototoxicity worsening \>=2 grades from baseline and considered treatment-limiting; Hy's Law DILI; Grade \>=3 lab abnormalities; any life-threatening or Grade 5 toxicity. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Absolute Estimated Glomerular Filtration Rate (eGFR) Values | At Cycle1 Day 4 (C1D4), C1D11, C1D18, C2D1, C2D4, C2D11, C2D18, C3D1, C3D4, C4D1, C5D1, C6D1 and End of treatment (Day 134) (each cycle is of 3 weeks) | eGFR creatinine was evaluated using Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula. Absolute values in eGFR was presented. Here, mL/min/1.73 m\^2 is defined as milliliters per minute per 1.73 square meters. |
| Absolute Change From Baseline in eGFR | Baseline, C1D4, C1D11, C1D18, C2D1, C2D4, C2D11, C2D18, C3D1, C3D4, C4D1, C5D1, C6D1 and End of treatment (Day 134) (each cycle is of 3 weeks) | eGFR creatinine was evaluated using CKD-EPI formula. Absolute change from baseline in eGFR was presented. |
| Objective Response (OR) According to Response Evaluation Criteria in Solid Tumor (RECIST) Version 1.1 Criteria as Assessed by Investigator | Up to approximately 6 months | OR is defined as the number of participants who have a best overall response of complete response (CR) or partial response (PR) CR: Disappearance of target and non-target lesions and normalization of tumor markers. PR: At least a 30% decrease in the sum of measures (longest diameter for tumor lesions and short axis measure for nodes) of target lesions, taking as reference the baseline sum of diameters. Non target lesions must be non-progressive disease. |
| Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment-Related TEAEs | Screening up to end of treatment (Day 134) and then follow up every 3 months (assessed up to maximum 6 months) | AEs were defined as 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. TEAEs were defined as AEs emerging or worsening after start of treatment until 30 days after end of treatment. Adverse events were coded according to the latest available version of the Medical Dictionary for Regulatory Activities (MedDRA). Treatment-Related TEAEs was defined as any AE considered as related to study treatment. |
| Locoregional Control (LRC) According to RECIST Version 1.1 Criteria As Assessed by Investigator | Time from date of the first treatment until date of the first occurrence of progression at the site of the primary tumor or the locoregional lymph nodes or End of Study, assessed approximately up to 6 months | LRC is defined as the time from date of the first treatment until date of the first occurrence of progression at the site of the primary tumor or the locoregional lymph nodes. |
| Time to Subsequent Systemic Cancer Treatments | Time from date of the first treatment administration until the start date of the first subsequent systemic cancer treatment for SCCHN or End of study, assessed up to approximately 6 months | Time to subsequent systematic cancer treatments was defined as time from date of the first treatment administration until the start date of the first subsequent systemic cancer treatment for squamous cell carcinoma of the head and neck (SCCHN). |
| Progression Free Survival (PFS) According to RECIST Version 1.1 Criteria as Assessed by Investigator | Time from randomization to the first documented disease progression, or death due to any cause, whichever occurs first (up to approximately 6 months) | PFS was defined as the time from randomization to the first documented disease progression per RECIST 1.1 based on Blinded Independent Central Review (BICR), or death due to any cause, whichever occurs first. 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. |
Countries
Belgium, Israel, South Korea, Spain, Taiwan, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Sequence 1 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. The first three cycles are given in combination with Cisplatin at dose of 40 milligrams per square meter (mg/m2) once daily on Cycle 1 Day 2 (C1D2, C1D9, C1D16, C2D2, C2D9, C2D16, and C3D2) With 70 Gray (Gy) of intensity modulated radiation therapy (IMRT) in 35 fractions, 2 Gy/fraction, 5 days/week followed by 3 cycles of monotherapy of Xevinapant at a dose of 200 mg/day from Day 1 to 14, per 3-week cycle (Each cycle is of 3 weeks). | 18 |
| Total | 18 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Other Reasons | 2 |
| Overall Study | Sponsor Request | 16 |
Baseline characteristics
| Characteristic | Sequence 1 |
|---|---|
| Age, Continuous | 60 Years STANDARD_DEVIATION 12.19 |
| Race/Ethnicity, Customized Ethnicity-Hispanic or Latino | 1 Participants |
| Race/Ethnicity, Customized Ethnicity-Not Hispanic or Latino | 17 Participants |
| Race/Ethnicity, Customized Race-Asian | 11 Participants |
| Race/Ethnicity, Customized Race-Black or African American | 1 Participants |
| Race/Ethnicity, Customized Race-White | 6 Participants |
| Sex: Female, Male Female | 3 Participants |
| Sex: Female, Male Male | 15 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 18 |
| other Total, other adverse events | 18 / 18 |
| serious Total, serious adverse events | 5 / 18 |
Outcome results
Primary
Number of Participants With Dose Limiting Toxicity (DLT)-Like Events
DLT-like events defined as any of the following treatment-related adverse events (AEs) or lab abnormalities occurring during the 5-week DLT-like assessment period and assessed as related to the study intervention: Grade 4 asymptomatic neutropenia more than (\>) 7 days; Grade 2-3 febrile neutropenia; Grade 4 thrombocytopenia without bleeding more than and equal to (\>=) 5 days or Grade 2-3 with bleeding or requiring transfusion; Grade 2-3 nonhematologic toxicity (e.g., renal impairment based on eGFR, Grade 4 skin toxicity/mucositis interfering with treatment); less than (\<) 60% planned cumulative dose of xevinapant or cisplatin due to AE; \>2-week Radiation therapy (RT) delay due to AE; Grade \>=2 ototoxicity worsening \>=2 grades from baseline and considered treatment-limiting; Hy's Law DILI; Grade \>=3 lab abnormalities; any life-threatening or Grade 5 toxicity.
Time frame: Time from the first dose of study intervention day upto 35 days (5 weeks)
Population: DLT analysis set: all participants who received any study dose, met at least 1 of criteria: Had at least one DLT like event confirmed by SMC during DLT like assessment period or for whom ICE strategy led to DLT event, regardless of administered number of doses; Received at least 60% planned cumulative dose of xevinapant, cisplatin, regardless of completion in assessment period.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Sequence 1 | Number of Participants With Dose Limiting Toxicity (DLT)-Like Events | 0 Participants |
Secondary
Absolute Change From Baseline in eGFR
eGFR creatinine was evaluated using CKD-EPI formula. Absolute change from baseline in eGFR was presented.
Time frame: Baseline, C1D4, C1D11, C1D18, C2D1, C2D4, C2D11, C2D18, C3D1, C3D4, C4D1, C5D1, C6D1 and End of treatment (Day 134) (each cycle is of 3 weeks)
Population: SAS included all participants who were administered any dose of any study intervention. Here number analyzed signifies participants who were evaluable at specified timepoints.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Sequence 1 | Absolute Change From Baseline in eGFR | Baseline | 89.6908 mL/min/1.73 m^2 | Standard Deviation 13.35296 |
| Sequence 1 | Absolute Change From Baseline in eGFR | C2D1 | 2.3052 mL/min/1.73 m^2 | Standard Deviation 10.00664 |
| Sequence 1 | Absolute Change From Baseline in eGFR | C2D4 | -6.3632 mL/min/1.73 m^2 | Standard Deviation 13.5006 |
| Sequence 1 | Absolute Change From Baseline in eGFR | C2D11 | -9.3021 mL/min/1.73 m^2 | Standard Deviation 16.44543 |
| Sequence 1 | Absolute Change From Baseline in eGFR | C2D18 | -4.7388 mL/min/1.73 m^2 | Standard Deviation 12.75881 |
| Sequence 1 | Absolute Change From Baseline in eGFR | C3D1 | -2.9103 mL/min/1.73 m^2 | Standard Deviation 14.80991 |
| Sequence 1 | Absolute Change From Baseline in eGFR | C3D4 | -6.7050 mL/min/1.73 m^2 | Standard Deviation 14.90582 |
| Sequence 1 | Absolute Change From Baseline in eGFR | C4D1 | -3.3451 mL/min/1.73 m^2 | Standard Deviation 25.03351 |
| Sequence 1 | Absolute Change From Baseline in eGFR | C5D1 | -5.3312 mL/min/1.73 m^2 | Standard Deviation 12.52264 |
| Sequence 1 | Absolute Change From Baseline in eGFR | C6D1 | -26.5000 mL/min/1.73 m^2 | Standard Deviation 7.77817 |
| Sequence 1 | Absolute Change From Baseline in eGFR | End of treatment | -2.4789 mL/min/1.73 m^2 | Standard Deviation 16.82505 |
| Sequence 1 | Absolute Change From Baseline in eGFR | C1D4 | -7.1908 mL/min/1.73 m^2 | Standard Deviation 10.69578 |
| Sequence 1 | Absolute Change From Baseline in eGFR | C1D11 | -8.2532 mL/min/1.73 m^2 | Standard Deviation 17.46117 |
| Sequence 1 | Absolute Change From Baseline in eGFR | C1D18 | -5.8696 mL/min/1.73 m^2 | Standard Deviation 6.03911 |
Secondary
Absolute Estimated Glomerular Filtration Rate (eGFR) Values
eGFR creatinine was evaluated using Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula. Absolute values in eGFR was presented. Here, mL/min/1.73 m\^2 is defined as milliliters per minute per 1.73 square meters.
Time frame: At Cycle1 Day 4 (C1D4), C1D11, C1D18, C2D1, C2D4, C2D11, C2D18, C3D1, C3D4, C4D1, C5D1, C6D1 and End of treatment (Day 134) (each cycle is of 3 weeks)
Population: SAS included all participants who were administered any dose of any study intervention. Here overall number of participants analyzed signified participants who were evaluable for this outcome measure and number analyzed signifies participants who were evaluable at specified timepoints.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Sequence 1 | Absolute Estimated Glomerular Filtration Rate (eGFR) Values | C1D4 | 83.2080 mL/min/1.73 m^2 | Standard Deviation 17.72417 |
| Sequence 1 | Absolute Estimated Glomerular Filtration Rate (eGFR) Values | C1D11 | 83.3678 mL/min/1.73 m^2 | Standard Deviation 15.16465 |
| Sequence 1 | Absolute Estimated Glomerular Filtration Rate (eGFR) Values | C1D18 | 85.0461 mL/min/1.73 m^2 | Standard Deviation 15.67478 |
| Sequence 1 | Absolute Estimated Glomerular Filtration Rate (eGFR) Values | C2D1 | 93.4136 mL/min/1.73 m^2 | Standard Deviation 14.5759 |
| Sequence 1 | Absolute Estimated Glomerular Filtration Rate (eGFR) Values | C2D4 | 83.4911 mL/min/1.73 m^2 | Standard Deviation 14.94634 |
| Sequence 1 | Absolute Estimated Glomerular Filtration Rate (eGFR) Values | C2D11 | 81.6135 mL/min/1.73 m^2 | Standard Deviation 17.53286 |
| Sequence 1 | Absolute Estimated Glomerular Filtration Rate (eGFR) Values | C2D18 | 85.1155 mL/min/1.73 m^2 | Standard Deviation 16.1424 |
| Sequence 1 | Absolute Estimated Glomerular Filtration Rate (eGFR) Values | C3D1 | 87.1169 mL/min/1.73 m^2 | Standard Deviation 12.80356 |
| Sequence 1 | Absolute Estimated Glomerular Filtration Rate (eGFR) Values | C3D4 | 82.8900 mL/min/1.73 m^2 | Standard Deviation 17.87483 |
| Sequence 1 | Absolute Estimated Glomerular Filtration Rate (eGFR) Values | C4D1 | 90.0343 mL/min/1.73 m^2 | Standard Deviation 15.56475 |
| Sequence 1 | Absolute Estimated Glomerular Filtration Rate (eGFR) Values | C5D1 | 90.0000 mL/min/1.73 m^2 | Standard Deviation 13.74773 |
| Sequence 1 | Absolute Estimated Glomerular Filtration Rate (eGFR) Values | C6D1 | 69.5000 mL/min/1.73 m^2 | Standard Deviation 14.84924 |
| Sequence 1 | Absolute Estimated Glomerular Filtration Rate (eGFR) Values | End of treatment | 87.1937 mL/min/1.73 m^2 | Standard Deviation 18.00761 |
Secondary
Locoregional Control (LRC) According to RECIST Version 1.1 Criteria As Assessed by Investigator
LRC is defined as the time from date of the first treatment until date of the first occurrence of progression at the site of the primary tumor or the locoregional lymph nodes.
Time frame: Time from date of the first treatment until date of the first occurrence of progression at the site of the primary tumor or the locoregional lymph nodes or End of Study, assessed approximately up to 6 months
Population: Full Analysis Set included all participants who were randomized to study treatment. As pre-specified in SAP, efficacy analysis was not conducted in this study (samples were not processed) and therefore data could not be analyzed and reported in this outcome measure.
Secondary
Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment-Related TEAEs
AEs were defined as 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. TEAEs were defined as AEs emerging or worsening after start of treatment until 30 days after end of treatment. Adverse events were coded according to the latest available version of the Medical Dictionary for Regulatory Activities (MedDRA). Treatment-Related TEAEs was defined as any AE considered as related to study treatment.
Time frame: Screening up to end of treatment (Day 134) and then follow up every 3 months (assessed up to maximum 6 months)
Population: Safety analysis set (SAS) included all participants who were administered any dose of any study intervention.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Sequence 1 | Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment-Related TEAEs | TEAEs | 18 Participants |
| Sequence 1 | Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment-Related TEAEs | Treatment Related TEAEs | 18 Participants |
Secondary
Objective Response (OR) According to Response Evaluation Criteria in Solid Tumor (RECIST) Version 1.1 Criteria as Assessed by Investigator
OR is defined as the number of participants who have a best overall response of complete response (CR) or partial response (PR) CR: Disappearance of target and non-target lesions and normalization of tumor markers. PR: At least a 30% decrease in the sum of measures (longest diameter for tumor lesions and short axis measure for nodes) of target lesions, taking as reference the baseline sum of diameters. Non target lesions must be non-progressive disease.
Time frame: Up to approximately 6 months
Population: FAS included all participants who were administered any dose of any study intervention. As pre-specified in statistical analysis plan (SAP), efficacy analysis was not conducted in this study (samples were not processed) and therefore data could not be analyzed and reported in this outcome measure.
Secondary
Progression Free Survival (PFS) According to RECIST Version 1.1 Criteria as Assessed by Investigator
PFS was defined as the time from randomization to the first documented disease progression per RECIST 1.1 based on Blinded Independent Central Review (BICR), or death due to any cause, whichever occurs first. 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.
Time frame: Time from randomization to the first documented disease progression, or death due to any cause, whichever occurs first (up to approximately 6 months)
Population: Full Analysis Set included all participants who were randomized to study treatment. As pre-specified in SAP, efficacy analysis was not conducted in this study (samples were not processed) and therefore data could not be analyzed and reported in this outcome measure.
Secondary
Time to Subsequent Systemic Cancer Treatments
Time to subsequent systematic cancer treatments was defined as time from date of the first treatment administration until the start date of the first subsequent systemic cancer treatment for squamous cell carcinoma of the head and neck (SCCHN).
Time frame: Time from date of the first treatment administration until the start date of the first subsequent systemic cancer treatment for SCCHN or End of study, assessed up to approximately 6 months
Population: Full Analysis Set included all participants who were randomized to study treatment. As pre-specified in SAP, efficacy analysis was not conducted in this study (samples were not processed) and therefore data could not be analyzed and reported in this outcome measure.