Pembrolizumab associé au cétuximab pour le traitement du carcinome épidermoïde récurrent/métastatique de la tête et du cou
Un essai ouvert, non randomisé, à plusieurs bras et de phase II pour évaluer l'efficacité du pembrolizumab associé au cétuximab chez les patients atteints d'un carcinome épidermoïde de la tête et du cou (HNSCC) récurrent/métastatique
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.
Aperçu de l'étude
Statut
Les conditions
Intervention / Traitement
Description détaillée
Primary Objectives:
To determine the clinical efficacy of pembrolizumab combined with cetuximab for patients with R/M HNSCC.
- Cohort 1 (PD-1/PD-L1 inhibitor-naïve, cetuximab-naïve): clinical efficacy defined as overall response rate.
- Cohort 2 (PD-1/PD-L1 inhibitor-refractory, cetuximab-naïve): clinical efficacy defined as overall response rate.
- Cohort 3 (PD-1/PD-L1 inhibitor-refractory, cetuximab-refractory): clinical efficacy defined as overall response rate.
- Cohort 4 (cutaneous HNSCC): clinical efficacy defined as overall response rate.
Secondary Objectives:
- To determine 12 month progression-free survival probability.
- To determine overall survival.
- To determine duration of response.
- To assess safety and tolerability of pembrolizumab combined with cetuximab.
- To evaluate the correlation between molecular markers and disease outcome.
Type d'étude
Inscription (Réel)
Phase
- Phase 2
Contacts et emplacements
Lieux d'étude
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California
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La Jolla, California, États-Unis, 92093
- UCSD Moores Cancer Center
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Los Angeles, California, États-Unis, 90095
- University of California Los Angeles Cancer Center
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Michigan
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Ann Arbor, Michigan, États-Unis, 48109
- University of Michigan Cancer Center
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Missouri
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St Louis, Missouri, États-Unis, 63110
- Washington School of Medicine Cancer Center
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Critères de participation
Critère d'éligibilité
Âges éligibles pour étudier
Accepte les volontaires sains
Sexes éligibles pour l'étude
La description
Inclusion Criteria:
Patients must meet all of the inclusion criteria to participate in this study.
- Ability to understand and the willingness to sign a written informed consent.
- 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.
- Platinum-refractory disease, or ineligible/unfit for platinum-based therapy
- Patients must have at least one measurable site of disease as defined by RECIST v.1.1, determined by investigator review
- Age ≥ 18 years.
- Eastern Cooperative Oncology Group (ECOG) Performance status 0 or 1.
- Patient has adequate hematologic, hepatic and renal function
- Female patient of childbearing potential has a negative serum or urine pregnancy within 72 hours prior to receiving the first dose of study medication.
- 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.
- 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 exclusion criteria at baseline will be excluded from study participation.
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Patient has salivary gland primary.
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Patient is currently receiving or has received another investigational agent within 4 weeks prior to Day 1 of study.
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Patient has received chemotherapy or radiotherapy within 4 weeks prior to Day 1 of study. Prior palliative radiotherapy to metastatic lesion(s) is permitted, provided there is at least one measurable lesion that has not been radiated.
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Patient has received a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or baseline) from adverse events due to a previously administered agents.
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Patient has had major surgery or insufficient recovery from surgical-related trauma or wound healing within 14 days of Study Day 1.
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Patient has had a prior Grade ≥ 3 immune-related adverse event (irAE) while receiving any previous immunotherapy agent, or any unresolved irAE > Grade 1.
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Patient has had prior Grade 4 infusion reaction to cetuximab.
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Patient has a known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer.
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Patient has known active central nervous system (CNS) metastases and/or carcinomatous meningitis.
Note: Patients with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment. This exception does not include carcinomatous meningitis which is excluded regardless of clinical stability.
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Patient has an active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs).
Notes:
- Patients with vitiligo, Grave's disease, or psoriasis not requiring systemic treatment within the past 2 years are not excluded.
- Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
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Patient has a diagnosis of immunodeficiency or is receiving systemic steroid therapy (>10mg prednisone daily, or steroid equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of pembrolizumab.
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Patient has a known history of active TB (Baccillus Tuberculosis).
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Patient has a known history of, or any evidence of active, non-infectious pneumonitis.
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Patient has a known history of chronic interstitial lung disease.
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Patient has an active infection requiring systemic therapy.
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Patient has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator.
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Patient has a known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
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Patient is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial.
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Patient has known active Hepatitis B infection (defined as presence of HepB sAg and/ or Hep B DNA), active hepatitis C infection (defined as presence of Hep C RNA) and/or known Human Immunodeficiency Virus (HIV) carrier (HIV 1/2 antibodies).
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Patient has received a live vaccine within 30 days of study Day 1.
Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live attenuated vaccines, and are not allowed.
Additional Exclusion Criterion for Cohorts 1 (PD-1/PD-L1 inhibitor-naïve, cetuximab-naïve) and 4 (cutaneous):
1. Patient has received any prior immunotherapy with inhibitors of PD-1 or PD-L1.
Plan d'étude
Comment l'étude est-elle conçue ?
Détails de conception
- Objectif principal: Traitement
- Répartition: Non randomisé
- Modèle interventionnel: Affectation parallèle
- Masquage: Aucun (étiquette ouverte)
Armes et Interventions
Groupe de participants / Bras |
Intervention / Traitement |
|---|---|
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Expérimental: Cohort 1
PD-1/PD-L1 inhibitor-naïve, cetuximab-naïve Pembrolizumab (Keytruda®): Pembrolizumab is administered on an outpatient basis. 200 mg pembrolizumab will be administered as a 30 minute (-5 min/+10 min) intravenous (IV) infusion every 3 weeks. Cetuximab (Erbitux®): The initial cetuximab dose of 400mg/m2 is administered on Cycle 1, Day 1 as a 120-minute IV infusion (maximum infusion rate 10mg/min).1 Subsequent weekly cetuximab doses of 250mg/m2 are administered as 60-minute IV infusions (maximum infusion rate 10mg/min). |
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.
Autres noms:
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Expérimental: Cohort 2
PD-1/PD-L1 inhibitor-refractory, cetuximab-naïve Pembrolizumab (Keytruda®): Pembrolizumab is administered on an outpatient basis. 200 mg pembrolizumab will be administered as a 30 minute (-5 min/+10 min) intravenous (IV) infusion every 3 weeks. Cetuximab (Erbitux®): The initial cetuximab dose of 400mg/m2 is administered on Cycle 1, Day 1 as a 120-minute IV infusion (maximum infusion rate 10mg/min).1 Subsequent weekly cetuximab doses of 250mg/m2 are administered as 60-minute IV infusions (maximum infusion rate 10mg/min). |
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.
Autres noms:
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Expérimental: Cohort 3
PD-1/PD-L1 inhibitor-refractory, cetuximab-refractory Pembrolizumab (Keytruda®): Pembrolizumab is administered on an outpatient basis. 200 mg pembrolizumab will be administered as a 30 minute (-5 min/+10 min) intravenous (IV) infusion every 3 weeks. Cetuximab (Erbitux®): The initial cetuximab dose of 400mg/m2 is administered on Cycle 1, Day 1 as a 120-minute IV infusion (maximum infusion rate 10mg/min).1 Subsequent weekly cetuximab doses of 250mg/m2 are administered as 60-minute IV infusions (maximum infusion rate 10mg/min). |
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.
Autres noms:
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Expérimental: Cohort 4
cutaneous HNSCC Pembrolizumab (Keytruda®): Pembrolizumab is administered on an outpatient basis. 200 mg pembrolizumab will be administered as a 30 minute (-5 min/+10 min) intravenous (IV) infusion every 3 weeks. Cetuximab (Erbitux®): The initial cetuximab dose of 400mg/m2 is administered on Cycle 1, Day 1 as a 120-minute IV infusion (maximum infusion rate 10mg/min).1 Subsequent weekly cetuximab doses of 250mg/m2 are administered as 60-minute IV infusions (maximum infusion rate 10mg/min). |
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.
Autres noms:
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Que mesure l'étude ?
Principaux critères de jugement
Mesure des résultats |
Description de la mesure |
Délai |
|---|---|---|
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Overall Response Rate
Délai: 6 months from the time of study enrollment
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Proportion of patients with partial or complete response in tumor burden as defined by RECIST |
6 months from the time of study enrollment
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Mesures de résultats secondaires
Mesure des résultats |
Description de la mesure |
Délai |
|---|---|---|
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Progression Free Survival
Délai: 12 months from the time of study enrollment
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No disease progression or death from any cause at 12 months from the time of study enrollment |
12 months from the time of study enrollment
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Overall Survival
Délai: 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
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Time from study enrollment to death from any cause |
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
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Duration of Response
Délai: 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
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Time from documentation of tumor response to disease progression |
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
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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
Délai: 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
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Description, grade (per CTCAE v4.03), seriousness and relatedness |
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
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Correlative Analyses
Délai: Tumor specimens (archival or new specimen) should be obtained within 42 days of screening
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Tumor tissue biomarkers correlated with outcome to pembrolizumab or cetuximab, such as PD-L1 expression, EGFR expression, p16 status, and immunophenotyping |
Tumor specimens (archival or new specimen) should be obtained within 42 days of screening
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Correlative Analyses
Délai: Blood samples will be collected at screening, at time of first radiographic disease assessment on treatment (prior to initiation of cycle 4), and at time of clinical or radiographic disease progression, up to 36 months
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Blood biomarkers correlated with outcome to pembrolizumab or cetuximab, including T cell receptor (TCR) sequencing |
Blood samples will be collected at screening, at time of first radiographic disease assessment on treatment (prior to initiation of cycle 4), and at time of clinical or radiographic disease progression, up to 36 months
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Correlative Analyses
Délai: Blood samples will be collected at screening, at time of first radiographic disease assessment on treatment (prior to initiation of cycle 4), and at time of clinical or radiographic disease progression, up to 36 months
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Blood biomarkers correlated with outcome to pembrolizumab or cetuximab, including Epstein-Barr virus plasma DNA titers |
Blood samples will be collected at screening, at time of first radiographic disease assessment on treatment (prior to initiation of cycle 4), and at time of clinical or radiographic disease progression, up to 36 months
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Correlative Analyses
Délai: Newly obtained tumor specimen within 42 days of screening (when feasible)
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Whole exome sequencing for neoantigen discovery |
Newly obtained tumor specimen within 42 days of screening (when feasible)
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Collaborateurs et enquêteurs
Parrainer
Collaborateurs
Les enquêteurs
- Chercheur principal: Assuntina Sacco, M.D., University of California, San Diego
Publications et liens utiles
Dates d'enregistrement des études
Dates principales de l'étude
Début de l'étude (Réel)
Achèvement primaire (Réel)
Achèvement de l'étude (Réel)
Dates d'inscription aux études
Première soumission
Première soumission répondant aux critères de contrôle qualité
Première publication (Réel)
Mises à jour des dossiers d'étude
Dernière mise à jour publiée (Réel)
Dernière mise à jour soumise répondant aux critères de contrôle qualité
Dernière vérification
Plus d'information
Termes liés à cette étude
Mots clés
Termes MeSH pertinents supplémentaires
- Maladies de la bouche
- Maladies stomatognathiques
- Processus pathologiques
- Tumeurs par site
- Tumeurs
- Attributs de la maladie
- Maladies des voies respiratoires
- Tumeurs par type histologique
- Tumeurs, glandulaires et épithéliales
- Tumeurs des voies respiratoires
- Processus néoplasiques
- Carcinome
- Maladies oto-rhino-laryngologiques
- Tumeurs pharyngées
- Tumeurs oto-rhino-laryngologiques
- Maladies nasopharyngées
- Maladies pharyngées
- Carcinome épidermoïde
- Maladies laryngées
- Conditions pathologiques, signes et symptômes
- Carcinome épidermoïde de la tête et du cou
- Récurrence
- Métastase néoplasmique
- Tumeurs de la tête et du cou
- Tumeurs du nasopharynx
- Tumeurs laryngées
- Tumeurs de la bouche
- Tumeurs oropharyngées
- Tumeurs hypopharyngées
- Acides aminés, peptides et protéines
- Protéines
- Anticorps, monoclonal, humanisé
- Anticorps, monoclonal
- Anticorps
- Immunoglobulines
- Immunoprotéines
- Protéines sanguines
- Globulines sériques
- Globulines
- Cétuximab
- pembrolizumab
Autres numéros d'identification d'étude
- 160621
- MISP 52211 (Autre identifiant: MERCK SHARP & DOHME CORP)
Plan pour les données individuelles des participants (IPD)
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Informations sur les médicaments et les dispositifs, documents d'étude
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