Cutaneous Squamous Cell Carcinoma, Head and Neck Cancer, Head and Neck Neoplasms, Head and Neck Squamous Cell Carcinoma, HNSCC, Hypopharynx Cancer, Larynx Cancer, Lip SCC, Nasopharynx Cancer, Oral Cavity Cancer, Oropharynx Cancer, Sinonasal Carcinoma
Conditions
Keywords
Head and Neck Cancer, Pembrolizumab, Keytruda®, Cetuximab, Erbitux®, Recurrent, Metastatic, PD-1, PD-L1, non-EBV related Nasopharynx
Brief summary
This is a prospective, multi-center, open-label, non-randomized, multi-arm phase II trial to evaluate the efficacy of combination therapy with pembrolizumab and cetuximab for patients with recurrent/metastatic HNSCC. There will be four patient cohorts, including a PD-1/PD-L1 inhibitor-naïve, cetuximab-naïve arm (Cohort 1), a PD-1/PD-L1 inhibitor-refractory, cetuximab-naïve arm (Cohort 2), a PD-1/PD-L1 inhibitor-refractory, cetuximab-refractory arm (Cohort 3), and a cutaneous HNSCC arm (Cohort 4). A total of 83 patients (33 in Cohort 1, 25 in Cohort 2, 15 in Cohort 3, and 10 in Cohort 4) will be eligible to enroll. Patients will be enrolled at 4 sites: UC San Diego Moores Cancer Center, UC Los Angeles Jonsson Comprehensive Cancer Center, University of Michigan Comprehensive Cancer Center, and University of Washington Siteman Cancer Center.
Detailed description
Primary Objectives: To determine the clinical efficacy of pembrolizumab combined with cetuximab for patients with R/M HNSCC. 1. Cohort 1 (PD-1/PD-L1 inhibitor-naïve, cetuximab-naïve): clinical efficacy defined as overall response rate. 2. Cohort 2 (PD-1/PD-L1 inhibitor-refractory, cetuximab-naïve): clinical efficacy defined as overall response rate. 3. Cohort 3 (PD-1/PD-L1 inhibitor-refractory, cetuximab-refractory): clinical efficacy defined as overall response rate. 4. Cohort 4 (cutaneous HNSCC): clinical efficacy defined as overall response rate. Secondary Objectives: 1. To determine 12 month progression-free survival probability. 2. To determine overall survival. 3. To determine duration of response. 4. To assess safety and tolerability of pembrolizumab combined with cetuximab. 5. To evaluate the correlation between molecular markers and disease outcome.
Interventions
DRUGPembrolizumab, Cetuximab
Pembrolizumab (KEYTRUDA®; MK-3475) is a potent and highly selective humanized monoclonal antibody (mAb) of the immunoglobulin G4 (IgG4)/kappa isotype designed to directly block the interaction between PD-1 and its ligands, programmed cell death ligand 1 (PD-L1) and programmed cell death ligand 2 (PD-L2). This blockade enhances functional activity of the target lymphocytes to facilitate tumor regression and ultimately immune rejection. Cetuximab (Erbitux®) binds specifically to the epidermal growth factor receptor (EGFR) on both normal and tumor cells, and competitively inhibits the binding of EGF and other ligands, such as transforming growth factor-alpha. Cetuximab can mediate antibody-dependent cellular cytotoxicity (ADCC), with in vitro assays and in vivo animal studies demonstrating that cetuximab inhibits the growth and survival of tumor cells expressing EGFR.
Sponsors
University of California, San Diego
Merck Sharp & Dohme LLC
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Open-label, non-randomized, multi-arm phase II trial of pembrolizumab combined with cetuximab for patients with recurrent/metastatic head and neck squamous cell carcinoma 1. Cohort 1 (PD-1/PD-L1 inhibitor-naïve, cetuximab-naïve): clinical efficacy defined as overall response rate. 2. Cohort 2 (PD-1/PD-L1 inhibitor-refractory, cetuximab-naïve): clinical efficacy defined as overall response rate. 3. Cohort 3 (PD-1/PD-L1 inhibitor-refractory, cetuximab-refractory): clinical efficacy defined as overall response rate. 4. Cohort 4 (cutaneous HNSCC): clinical efficacy defined as overall response rate.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Patients must meet all of the inclusion criteria to participate in this study. 1. Ability to understand and the willingness to sign a written informed consent. 2. Histologically or cytologically proven squamous cell carcinoma of the head and neck (lip, oral cavity, oropharynx, larynx, hypopharynx, non-EBV related nasopharynx, sinonasal, cutaneous), not amenable to curative intent therapy. 3. Platinum-refractory disease, or ineligible/unfit for platinum-based therapy 4. Patients must have at least one measurable site of disease as defined by RECIST v.1.1, determined by investigator review 5. Age ≥ 18 years. 6. Eastern Cooperative Oncology Group (ECOG) Performance status 0 or 1. 7. Patient has adequate hematologic, hepatic and renal function 8. Female patient of childbearing potential has a negative serum or urine pregnancy within 72 hours prior to receiving the first dose of study medication. 9. Female patient of childbearing potential agrees to use 2 methods of birth control or be surgically sterile, or abstain from heterosexual activity for the course of the study through 120 days after the last dose of study medication. 10. Male patient with a partner of childbearing potential agrees to use an adequate method of contraception starting with the first dose of study therapy through 120 days after the last dose of study therapy. Additional Inclusion Criterion for Cohort 1 (PD-1/PD-L1 Inhibitor-naïve, Cetuximab-naïve) and Cohort 2 (PD-1/PD-L1 Inhibitor-refractory, Cetuximab-naïve): 1\. Cetuximab-naïve patients may not have received cetuximab therapy in the recurrent/metastatic setting (treatment in curative setting permitted) Additional Inclusion Criterion for Cohorts 2 and 3 (PD-1/PD-L1 Inhibitor-refractory): 1\. PD-1/PD-L1 inhibitor-refractory patients must have documented disease progression after prior response to anti-PD-1/PD-L1 therapy (response defined as stable disease, partial or complete response) Additional Inclusion Criterion for Cohort 4 (Cutaneous HNSCC): 1\. Cutaneous HNSCC must not be amenable to local treatment modalities, including surgery and/or radiation.
Exclusion criteria
Patients meeting any of the
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response Rate | 6 months from the time of study enrollment | Proportion of patients with partial or complete response in tumor burden as defined by RECIST |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival Probability | 12 months from the time of study enrollment | Probability of no disease progression or death from any cause at 12 months from the time of study enrollment |
| Overall Survival | From the time of study enrollment until the date of death from any cause or completion of study, whichever came first, assessed up to 36 months | Time from study enrollment to death from any cause |
| Duration of Response | Every 9 weeks from first on-treatment scan until disease progression or patient withdrawal from study or date of death from any cause, whichever came first, assessed up to 36 months | Time from documentation of tumor response to disease progression |
| Number of patients with grade 3 through grade 5 adverse events that are related to pembrolizumab and cetuximab, graded according to NCI CTCAE v4.03 | Upon study enrollment, then subsequently at the first visit of each cycle (cycle length is 21 days), at the time of any adverse event, through end of treatment study visit, assessed up to 36 months | Description, grade (per CTCAE v4.03), seriousness and relatedness |
| Correlative analyses | Tumor specimens (archival or new specimen) should be obtained within 42 days of screening | Tumor tissue biomarkers correlated with outcome to pembrolizumab or cetuximab, such as PD-L1 expression, EGFR expression, p16 status, and immunophenotyping |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORAssuntina Sacco, M.D.
University of California, San Diego
Outcome results
None listed