Carcinoma, Squamous Cell of Head and Neck
Conditions
Keywords
SCCHN, HNSCC
Brief summary
The purpose of this study is to compare the progression-free survival of patients with recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN) treated with VTX-2337 + cisplatin or carboplatin + 5-FU + cetuximab versus patients treated with cisplatin or carboplatin + 5-FU + cetuximab alone (standard-of-care; SOC). Safety and overall survival will also be evaluated.
Detailed description
This is a randomized, double-blind, placebo-controlled, parallel group study to evaluate the safety and efficacy of VTX 2337 in combination with cisplatin or carboplatin, 5-FU and cetuximab in prolonging the progression-free survival in subjects with recurrent or metastatic squamous cell carcinoma of the head and neck. OBJECTIVES: Primary Objective: To compare the efficacy of VTX 2337 plus SOC to SOC alone in prolonging the PFS of patients with recurrent or metastatic SCCHN using irRECIST evaluated by independent radiology review. Secondary Objectives: To compare the following between the two treatment groups: * Safety of VTX 2337 by adverse events, including clinically significant changes in physical examination, peripheral blood hematology, serum chemistry, urinalysis, and ECG. * Efficacy of VTX 2337 plus SOC in prolonging the OS of patients with recurrent or metastatic SCCHN. * Efficacy of VTX-2337 plus SOC on ORR, DOBR, DCR, and DDC by irRECIST and evaluation by independent radiology review. * Efficacy of VTX-2337 plus SOC on ORR, DOBR, DCR, and DDC by RECIST v1.1 and evaluation by independent radiology review. * Efficacy of VTX 2337 plus SOC to SOC alone in prolonging the PFS by RECIST v1.1 and evaluation by independent radiology review. * Efficacy of VTX 2337 plus SOC to SOC alone in prolonging the PFS by irRECIST and evaluation by investigators. Exploratory Objectives: * To compare genetic polymorphisms that may impact the response of patients to a TLR8 agonist or to cetuximab between the two treatment groups. * To compare immune biomarker response to VTX 2337 plus SOC as measured by a multiplexed panel of cytokines, chemokines, and inflammatory markers between the two treatment groups. * To compare the effect of immune cell subsets within the tumor on response to VTX-2337 and/or clinical outcome, as measured by immunohistochemistry in primary tumor tissue between the two treatment groups. * To assess the PK of VTX-2337. OUTLINE: Subjects will be screened for eligibility (within 14 days) and qualified subjects will be randomized 1:1 to 1 of 2 treatment groups: SOC + VTX 2337 or SOC + placebo. Tumor assessments will be by CT or MRI starting at Week 12 (± 3 days), then at Week 18 (± 3 days) and every 8 weeks (± 7 days) thereafter. Response will be evaluated by immune-related RECIST criteria (irRECIST) and confirmed by an independent radiologist. Upon independent confirmation of disease progression, active participation in the study is complete and subjects will undergo the End of Treatment evaluations. Subjects will be followed for survival until \ 12 months after the last subject is randomized.
Interventions
Sponsors
Celgene
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
* Ability and willingness to provide written informed consent * Histologically or cytologically confirmed squamous cell carcinoma of the head and neck * Locoregionally recurrent or metastatic disease that has not previously been treated with systemic therapy of recurrent or metastatic disease * At least one measurable lesion on screening CT or MRI * 18 years of age or older * ECOG performance status of 0 or 1 * Acceptable bone marrow, renal, and hepatic function based upon screening lab tests * Willingness to use medically acceptable contraception * For females with reproductive potential: a negative serum pregnancy test
Exclusion criteria
* Disease which is amenable to curative local therapy * Nasopharyngeal, salivary gland, lip or sinonasal carcinoma * Surgery or irradiation ≤ 4 weeks prior to randomization * Prior systemic anti-cancer therapy, unless administered for localized SCCHN and completed at least 6 months prior to disease recurrence * Treatment with an investigational agent ≤ 30 days prior to randomization * Treatment with corticosteroids within 2 weeks * A requirement for chronic systemic immunosuppressive therapy for any reason * Prior serious infusion reaction to cetuximab * Treatment with an immunotherapy within 30 days * Known brain metastases, unless stable for at least 28 days * Active autoimmune disease currently requiring therapy * Known infection with HIV * Significant cardiac disease within 6 months * Pregnant or breast-feeding females * History of another primary malignancy, with the exception of (i) curatively resected non-melanoma skin cancer, (ii) curatively treated in situ cervical cancer, or (iii) other malignancy curatively treated with no evidence of disease and no anticancer therapy administered for 3 years prior to randomization, with the exception of adjuvant hormonal therapy for breast cancer * Other conditions or circumstances that could interfere with the study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Comparison of Progression Free Survival (PFS) Between Treatment Groups Using irRECIST and Evaluated by Independent Radiology. | PFS is the time from randomization until disease progression or death, whichever comes first. | PFS was based on central assessment by a blinded independent radiologist per immune related response evaluation criteria for solid tumors (irRECIST) and was summarized and displayed by treatment arm using Kaplan-Meier methods. Treatments were compared using a stratified log-rank test controlling for randomization stratification factors. The hazard ratio between the 2 treatment arms, as well as the associated one-sided 90% CI and p-value, were presented using a Cox proportional hazards regression model. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Comparison of Adverse Events (AEs) Between the Two Treatment Groups. | AEs were collected from the first dose of study drug given on Cycle 1 Day 1 until 7 days after the dose of study drug or End of Treatment visit, whichever occurred first. Overall mean duration of exposure was 25.3 weeks. | The frequency and severity of adverse events, including any clinically significant changes in physical exam, laboratory values, or other clinical assessment. |
| Comparison of Overall Survival (OS) Between the 2 Treatment Groups. | OS is the time from randomization until death due to any cause or the date last confirmed to be alive. | Estimated using Kaplan-Meier product limit estimates, 1-sided stratified log-rank test, and Cox proportional hazard model; all with 90% 1-sided confidence intervals. |
| Comparison of the Objective Response Rate Between the Two Treatment Groups p | From the time of randomization until the best response on treatment is documented. | Objective response rate is defined as the percentage of subjects who achieve best overall response of irCR or irPR pr irRECIST and evaluated by independent radiology.. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Chemotherapy and Cetuximab Plus VTX-2337 VTX-2337 (3.0 mg/m2) will be administered on Day 8 and Day 15 of a 21-day cycle for 6 cycles, followed by dosing on Days 8 and 22 of 28-day cycles until disease progression. Cisplatin (100 mg/m2) OR carboplatin (AUC 5 mg/mL/min) will be administered on Day 1 of a 21-day cycle for a maximum of 6 cycles. 5-FU (1000 mg/m2) will be administered on Days 1-4 of a 21-day cycle for a maximum of 6 cycles. Cetuximab (initial dose: 400 mg/m2; remaining doses: 250 mg/m2) will be administered weekly until disease progression. VTX-2337: TLR8 Agonist Carboplatin Cisplatin 5-fluorouracil | 100 |
| Chemotherapy and Cetuximab Plus Placebo Placebo (3.0 mg/m2) will be administered on Day 8 and Day 15 of a 21-day cycle for 6 cycles, followed by dosing on Days 8 and 22 of 28-day cycles until disease progression. Cisplatin (100 mg/m2) OR carboplatin (AUC 5 mg/mL/min) will be administered on Day 1 of a 21-day cycle for a maximum of 6 cycles. 5-FU (1000 mg/m2) will be administered on Days 1-4 of a 21-day cycle for a maximum of 6 cycles. Cetuximab (initial dose: 400 mg/m2; remaining doses: 250 mg/m2) will be administered weekly until disease progression. Carboplatin Cisplatin 5-fluorouracil Placebo | 95 |
| Total | 195 |
Baseline characteristics
| Characteristic | Chemotherapy and Cetuximab Plus Placebo | Total | Chemotherapy and Cetuximab Plus VTX-2337 |
|---|---|---|---|
| Age, Continuous | 59.9 years STANDARD_DEVIATION 9.08 | 58.5 years STANDARD_DEVIATION 9.68 | 57.1 years STANDARD_DEVIATION 10.07 |
| Age, Customized 40-49 years | 9 Participants | 18 Participants | 9 Participants |
| Age, Customized <40 years | 1 Participants | 7 Participants | 6 Participants |
| Age, Customized 50-59 years | 35 Participants | 82 Participants | 47 Participants |
| Age, Customized 60-69 years | 37 Participants | 66 Participants | 29 Participants |
| Age, Customized 70-79 years | 13 Participants | 21 Participants | 8 Participants |
| Age, Customized >=80 years | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 3 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 12 Participants | 27 Participants | 15 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 3 Participants | 6 Participants | 3 Participants |
| Race (NIH/OMB) White | 78 Participants | 159 Participants | 81 Participants |
| Region of Enrollment United States | 95 Participants | 195 Participants | 100 Participants |
| Sex: Female, Male Female | 14 Participants | 29 Participants | 15 Participants |
| Sex: Female, Male Male | 81 Participants | 166 Participants | 85 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 89 / 89 | 86 / 86 |
| serious Total, serious adverse events | 35 / 89 | 34 / 86 |
Outcome results
Primary
Comparison of Progression Free Survival (PFS) Between Treatment Groups Using irRECIST and Evaluated by Independent Radiology.
PFS was based on central assessment by a blinded independent radiologist per immune related response evaluation criteria for solid tumors (irRECIST) and was summarized and displayed by treatment arm using Kaplan-Meier methods. Treatments were compared using a stratified log-rank test controlling for randomization stratification factors. The hazard ratio between the 2 treatment arms, as well as the associated one-sided 90% CI and p-value, were presented using a Cox proportional hazards regression model.
Time frame: PFS is the time from randomization until disease progression or death, whichever comes first.
Population: ITT population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Chemotherapy and Cetuximab Plus VTX-2337 | Comparison of Progression Free Survival (PFS) Between Treatment Groups Using irRECIST and Evaluated by Independent Radiology. | 185 days |
| Chemotherapy and Cetuximab Plus Placebo | Comparison of Progression Free Survival (PFS) Between Treatment Groups Using irRECIST and Evaluated by Independent Radiology. | 181 days |
p-value: 0.266Log Rank
Secondary
Comparison of Adverse Events (AEs) Between the Two Treatment Groups.
The frequency and severity of adverse events, including any clinically significant changes in physical exam, laboratory values, or other clinical assessment.
Time frame: AEs were collected from the first dose of study drug given on Cycle 1 Day 1 until 7 days after the dose of study drug or End of Treatment visit, whichever occurred first. Overall mean duration of exposure was 25.3 weeks.
Population: Safety population: subjects who received at least 1 dose of VTX-2337 or placebo.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Chemotherapy and Cetuximab Plus VTX-2337 | Comparison of Adverse Events (AEs) Between the Two Treatment Groups. | Subjects with Grade 3 and above TEAE | 84.3 percentage of participants |
| Chemotherapy and Cetuximab Plus VTX-2337 | Comparison of Adverse Events (AEs) Between the Two Treatment Groups. | Subjects with TEAE with outcome of death | 4.5 percentage of participants |
| Chemotherapy and Cetuximab Plus VTX-2337 | Comparison of Adverse Events (AEs) Between the Two Treatment Groups. | Subjects with serious TEAE | 39.3 percentage of participants |
| Chemotherapy and Cetuximab Plus VTX-2337 | Comparison of Adverse Events (AEs) Between the Two Treatment Groups. | Subjects discontinued treatment due to TEAE | 19.1 percentage of participants |
| Chemotherapy and Cetuximab Plus VTX-2337 | Comparison of Adverse Events (AEs) Between the Two Treatment Groups. | Subjects with TEAE | 100 percentage of participants |
| Chemotherapy and Cetuximab Plus Placebo | Comparison of Adverse Events (AEs) Between the Two Treatment Groups. | Subjects discontinued treatment due to TEAE | 18.6 percentage of participants |
| Chemotherapy and Cetuximab Plus Placebo | Comparison of Adverse Events (AEs) Between the Two Treatment Groups. | Subjects with TEAE | 100 percentage of participants |
| Chemotherapy and Cetuximab Plus Placebo | Comparison of Adverse Events (AEs) Between the Two Treatment Groups. | Subjects with Grade 3 and above TEAE | 83.7 percentage of participants |
| Chemotherapy and Cetuximab Plus Placebo | Comparison of Adverse Events (AEs) Between the Two Treatment Groups. | Subjects with serious TEAE | 39.5 percentage of participants |
| Chemotherapy and Cetuximab Plus Placebo | Comparison of Adverse Events (AEs) Between the Two Treatment Groups. | Subjects with TEAE with outcome of death | 8.1 percentage of participants |
Secondary
Comparison of Overall Survival (OS) Between the 2 Treatment Groups.
Estimated using Kaplan-Meier product limit estimates, 1-sided stratified log-rank test, and Cox proportional hazard model; all with 90% 1-sided confidence intervals.
Time frame: OS is the time from randomization until death due to any cause or the date last confirmed to be alive.
Population: ITT population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Chemotherapy and Cetuximab Plus VTX-2337 | Comparison of Overall Survival (OS) Between the 2 Treatment Groups. | 412 days |
| Chemotherapy and Cetuximab Plus Placebo | Comparison of Overall Survival (OS) Between the 2 Treatment Groups. | 343 days |
p-value: 0.399Log Rank
Secondary
Comparison of the Objective Response Rate Between the Two Treatment Groups p
Objective response rate is defined as the percentage of subjects who achieve best overall response of irCR or irPR pr irRECIST and evaluated by independent radiology..
Time frame: From the time of randomization until the best response on treatment is documented.
Population: ITT population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Chemotherapy and Cetuximab Plus VTX-2337 | Comparison of the Objective Response Rate Between the Two Treatment Groups p | 38.0 percentage of participants |
| Chemotherapy and Cetuximab Plus Placebo | Comparison of the Objective Response Rate Between the Two Treatment Groups p | 33.7 percentage of participants |
p-value: 0.536Cochran-Mantel-Haenszel