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Pembrolizumab Combined With Cetuximab for Treatment of Recurrent/Metastatic Head & Neck Squamous Cell Carcinoma

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ClinicalTrials.gov Identifier: NCT03082534
Recruitment Status : Recruiting
First Posted : March 17, 2017
Last Update Posted : May 23, 2018
Sponsor:
Collaborator:
Merck Sharp & Dohme Corp.
Information provided by (Responsible Party):
Assuntina G. Sacco, University of California, San Diego

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.

Condition or disease Intervention/treatment Phase
HNSCC Lip SCC Oral Cavity Cancer Oropharynx Cancer Larynx Cancer Hypopharynx Cancer Nasopharynx Cancer Sinonasal Carcinoma Cutaneous Squamous Cell Carcinoma Head and Neck Neoplasms Head and Neck Cancer Head and Neck Squamous Cell Carcinoma Drug: Pembrolizumab, Cetuximab Phase 2

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.

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 83 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
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.
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: An Open-label, Non-randomized, Multi-arm, Phase II Trial to Evaluate the Efficacy of Pembrolizumab Combined With Cetuximab in Patients With Recurrent/Metastatic Head and Neck Squamous Cell Carcinoma (HNSCC)
Actual Study Start Date : March 28, 2017
Estimated Primary Completion Date : May 27, 2019
Estimated Study Completion Date : May 2020


Arm Intervention/treatment
Experimental: 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).

Drug: Pembrolizumab, 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.

Other Name: Keytruda®, Erbitux®

Experimental: 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).

Drug: Pembrolizumab, 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.

Other Name: Keytruda®, Erbitux®

Experimental: 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).

Drug: Pembrolizumab, 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.

Other Name: Keytruda®, Erbitux®

Experimental: 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).

Drug: Pembrolizumab, 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.

Other Name: Keytruda®, Erbitux®




Primary Outcome Measures :
  1. Overall Response Rate [ Time Frame: 6 months from the time of study enrollment ]
    Proportion of patients with partial or complete response in tumor burden as defined by RECIST


Secondary Outcome Measures :
  1. Progression Free Survival Probability [ Time Frame: 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

  2. Overall Survival [ Time Frame: 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

  3. Duration of Response [ Time Frame: 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

  4. 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 [ Time Frame: 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

  5. Correlative analyses [ Time Frame: 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

  6. Correlative analyses [ Time Frame: 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 ]
    Blood biomarkers correlated with outcome to pembrolizumab or cetuximab, including T cell receptor (TCR) sequencing

  7. Correlative analyses [ Time Frame: 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 ]
    Blood biomarkers correlated with outcome to pembrolizumab or cetuximab, including Epstein-Barr virus plasma DNA titers

  8. Correlative analyses [ Time Frame: Newly obtained tumor specimen within 42 days of screening (when feasible) ]
    Whole exome sequencing for neoantigen discovery



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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 exclusion criteria at baseline will be excluded from study participation.

  1. Patient has salivary gland primary.
  2. Patient is currently receiving or has received another investigational agent within 4 weeks prior to Day 1 of study.
  3. 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.
  4. 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.
  5. Patient has had major surgery or insufficient recovery from surgical-related trauma or wound healing within 14 days of Study Day 1.
  6. Patient has had a prior Grade ≥ 3 immune-related adverse event (irAE) while receiving any previous immunotherapy agent, or any unresolved irAE > Grade 1.
  7. Patient has had prior Grade 4 infusion reaction to cetuximab.
  8. 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.
  9. 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.

  10. 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.
  11. 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.
  12. Patient has a known history of active TB (Baccillus Tuberculosis).
  13. Patient has a known history of, or any evidence of active, non-infectious pneumonitis.
  14. Patient has a known history of chronic interstitial lung disease.
  15. Patient has an active infection requiring systemic therapy.
  16. 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.
  17. Patient has a known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
  18. Patient is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial.
  19. 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).
  20. 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.


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03082534


Contacts
Contact: Gerald Henderson, BA 858-822-5223 gehenderson@ucsd.edu
Contact: Mandy Natsuhara 858-534-7613 anatsuha@ucsd.edu

Locations
United States, California
UCSD Moores Cancer Center Recruiting
La Jolla, California, United States, 92093
Contact: Gerald Henderson, BA    858-822-5223    gehenderson@ucsd.edu   
Sponsors and Collaborators
Assuntina G. Sacco
Merck Sharp & Dohme Corp.
Investigators
Study Chair: Assuntina Sacco, M.D. University of California, San Diego

Responsible Party: Assuntina G. Sacco, Assistant Professor of Internal Medicine, University of California, San Diego
ClinicalTrials.gov Identifier: NCT03082534     History of Changes
Other Study ID Numbers: 160621
MISP 52211 ( Other Identifier: MERCK SHARP & DOHME CORP )
First Posted: March 17, 2017    Key Record Dates
Last Update Posted: May 23, 2018
Last Verified: May 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No

Keywords provided by Assuntina G. Sacco, University of California, San Diego:
Head and Neck Cancer
Pembrolizumab
Keytruda®
Cetuximab
Erbitux®
Recurrent
Metastatic
PD-1
PD-L1
non-EBV related Nasopharynx

Additional relevant MeSH terms:
Carcinoma
Carcinoma, Squamous Cell
Head and Neck Neoplasms
Mouth Neoplasms
Oropharyngeal Neoplasms
Laryngeal Neoplasms
Nasopharyngeal Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Squamous Cell
Neoplasms by Site
Mouth Diseases
Stomatognathic Diseases
Pharyngeal Neoplasms
Otorhinolaryngologic Neoplasms
Pharyngeal Diseases
Otorhinolaryngologic Diseases
Laryngeal Diseases
Respiratory Tract Diseases
Respiratory Tract Neoplasms
Nasopharyngeal Diseases
Pembrolizumab
Cetuximab
Antineoplastic Agents