Ipilimumab, Cetuximab, and Intensity-Modulated Radiation Therapy in Treating Patients With Previously Untreated Stage III-IVB Head and Neck Cancer

Phase 1

Completed

• Conditions: Stage IVB Laryngeal Squamous Cell Carcinoma AJCC v7; Stage IVB Oropharyngeal Squamous Cell Carcinoma AJCC v7; Stage III Oropharyngeal Squamous Cell Carcinoma AJCC v7; Stage IVA Oropharyngeal Squamous Cell Carcinoma AJCC v7; Stage IVB Hypopharyngeal Squamous Cell Carcinoma AJCC v7; Stage III Hypopharyngeal Squamous Cell Carcinoma AJCC v7; Stage III Laryngeal Squamous Cell Carcinoma AJCC v6 and v7; Stage IVA Hypopharyngeal Squamous Cell Carcinoma AJCC v7; Stage IVA Laryngeal Squamous Cell Carcinoma AJCC v7
• Interventions: Biological: Cetuximab; Radiation: Intensity-Modulated Radiation Therapy; Biological: Ipilimumab; Other: Laboratory Biomarker Analysis

• Registration Number: NCT01935921
• Lead Sponsor: National Cancer Institute (NCI)

Brief Summary

This phase Ib trial studies the side effects and best dose of ipilimumab when given together with cetuximab and intensity-modulated radiation therapy (IMRT) in treating patients with previously untreated stage III-IVB head and neck cancer. Monoclonal antibodies, such as ipilimumab and cetuximab, may block tumor growth in different ways by targeting certain cells. Specialized radiation therapy, such as IMRT, that delivers a high dose of radiation directly to the tumor may kill more tumor cells and cause less damage to normal tissue. Giving ipilimumab together with cetuximab and IMRT may kill more tumor cells.

Detailed Description

PRIMARY OBJECTIVES:

I. To identify the starting dose of ipilimumab, in combination with standard cetuximab-IMRT in patients with high- or intermediate-risk, locally advanced head and neck squamous cell carcinoma (HNSCC), for use in a future clinical efficacy trial.

SECONDARY OBJECTIVES:

I. To estimate the clinical response of patients with high- or intermediate-risk, locally advanced HNSCC treated with above regimen using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria.

II. To estimate the 2-year progression-free survival of patients with high- or intermediate-risk, locally advanced HNSCC treated with the above regimen.

III. To investigate serum, lymphocyte and tissue biomarkers as predictors of progression-free survival, toxicity and other outcome parameters in patients with high- or intermediate-risk, locally advanced HNSCC treated with above regimen.

IV. To estimate the association by dose-response modeling between dose of ipilimumab, clinical response and biomarkers.

OUTLINE: This is a dose-escalation study of ipilimumab.

Patients receive cetuximab intravenously (IV) over 60-120 minutes on days 1, 8, 15, and 22. Treatment with cetuximab repeats every 4 weeks for 2 courses. Beginning in week 2 of course 1, patients undergo concurrent IMRT 5 days per week for 7 weeks. Beginning in week 4 (day 1 of course 2) patients also receive ipilimumab IV over 90 minutes once every 21 days for 3 courses. Treatment continues in the absence of disease progression or unacceptable toxicity. Patients achieving disease progression may undergo surgery after completion of therapy.

After completion of study treatment, patients are followed up every 12 weeks for 1 year, every 6 months for 1 year, and then every 12 months for 3 years.

Study Timeline

• Study Start: 2013-04-09
• Study First Submitted: 2013-09-03
• Study First Submitted QC: 2013-09-03
• Study First Posted: 2013-09-05
• Primary Completion: 2016-10-29
• Study Completion: 2018-07-06
• Status Verified: 2023-06
• Last Update Submitted: 2023-06-14
• Last Update Posted: 2023-06-15

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 19

Inclusion Criteria

• American Joint Committee on Cancer (AJCC) stage III/IVB, excluding T1N1, histologically or cytologically confirmed squamous cell carcinoma or undifferentiated carcinoma of the head and neck; patients should not have distant metastasis; primary sites include: oropharynx, hypopharynx, larynx

• Patients must have high or intermediate risk disease, defined as follows:

  • High risk: non-oropharyngeal subsite including larynx or hypopharynx (p16 status not required) or human papilloma virus (HPV)/p16- oropharynx subsite
  • Intermediate risk: HPV/p16+ oropharyngeal squamous cell cancer with: >= 10 pack (pk)-year (yr) smoking history and >= N2 nodal disease, or the presence of T4 tumor or N3 nodal disease, irrespective of smoking status

• Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as >= 20 mm with conventional techniques or as >= 10 mm with spiral computed tomography (CT) scan, magnetic resonance imaging (MRI), or calipers by clinical exam

• Patients should be newly diagnosed HNSCC, with no prior therapy for this disease

• Eastern Cooperative Oncology Group (ECOG) performance status typically =< 1 (Karnofsky >= 70%)

• Leukocytes >= 3,000/mcL

• Absolute neutrophil count >= 1,200/mcL

• Platelets >= 75,000/mcL

• Total bilirubin =< 2 mg/dL (=< 3 mg/dL in case of Gilbert's syndrome)

• Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 2 times institutional upper limit of normal (IULN)

• Creatinine clearance >= 40 mL/min/1.73 m^2

• Patients must have the ability to understand and to sign written informed consent

Exclusion Criteria

• Patients who have had prior chemotherapy, radiotherapy, or surgery with curative intent for HNSCC
• Patients with a history of prior treatment with ipilimumab, anti-programmed cell death 1 (PD 1) antibody, cluster of differentiation 137 (CD137) agonist or other immune activating therapy such as anti-cluster of differentiation 40 (CD 40) antibody
• Patients who are receiving any other investigational agents
• Autoimmune disease: patients with a history of inflammatory bowel disease, including ulcerative colitis and Crohn's disease, are excluded from this study, as are patients with a history of symptomatic non-gastrointestinal autoimmune disease (e.g., rheumatoid arthritis, systemic progressive sclerosis [scleroderma], systemic lupus erythematosus, autoimmune vasculitis [e.g., Wegener's granulomatosis]); central nervous system (CNS) or motor neuropathy considered of autoimmune origin (e.g. Guillain-Barre syndrome and myasthenia gravis, multiple sclerosis)
• Patients with known immunodeficiency disorder, or presumed to be unable to respond to anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA 4) monoclonal antibody (mAb)
• Patients with distant metastatic disease (stage IVC)
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to cetuximab or ipilimumab
• Patient is < 2 years free from a second primary malignancy unless the other malignancy is non-melanomatous skin cancer or an in-situ tumor treated with curative intent
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements; patients with chronic hepatitis B or hepatitis C infections are excluded
• Pregnant women are excluded from this study
• Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Treatment (cetuximab, IMRT, and ipilimumab)	Intensity-Modulated Radiation Therapy	Patients receive cetuximab IV over 60-120 minutes on days 1, 8, 15, and 22. Treatment with cetuximab repeats every 4 weeks for 2 courses. Beginning in week 2 of course 1, patients undergo concurrent IMRT 5 days per week for 7 weeks. Beginning in week 4 (day 1 of course 2) patients also receive ipilimumab IV over 90 minutes once every 21 days for 3 courses. Treatment continues in the absence of disease progression or unacceptable toxicity. Patients achieving disease progression may undergo surgery after completion of therapy.
Treatment (cetuximab, IMRT, and ipilimumab)	Ipilimumab	Patients receive cetuximab IV over 60-120 minutes on days 1, 8, 15, and 22. Treatment with cetuximab repeats every 4 weeks for 2 courses. Beginning in week 2 of course 1, patients undergo concurrent IMRT 5 days per week for 7 weeks. Beginning in week 4 (day 1 of course 2) patients also receive ipilimumab IV over 90 minutes once every 21 days for 3 courses. Treatment continues in the absence of disease progression or unacceptable toxicity. Patients achieving disease progression may undergo surgery after completion of therapy.
Treatment (cetuximab, IMRT, and ipilimumab)	Cetuximab	Patients receive cetuximab IV over 60-120 minutes on days 1, 8, 15, and 22. Treatment with cetuximab repeats every 4 weeks for 2 courses. Beginning in week 2 of course 1, patients undergo concurrent IMRT 5 days per week for 7 weeks. Beginning in week 4 (day 1 of course 2) patients also receive ipilimumab IV over 90 minutes once every 21 days for 3 courses. Treatment continues in the absence of disease progression or unacceptable toxicity. Patients achieving disease progression may undergo surgery after completion of therapy.
Treatment (cetuximab, IMRT, and ipilimumab)	Laboratory Biomarker Analysis	Patients receive cetuximab IV over 60-120 minutes on days 1, 8, 15, and 22. Treatment with cetuximab repeats every 4 weeks for 2 courses. Beginning in week 2 of course 1, patients undergo concurrent IMRT 5 days per week for 7 weeks. Beginning in week 4 (day 1 of course 2) patients also receive ipilimumab IV over 90 minutes once every 21 days for 3 courses. Treatment continues in the absence of disease progression or unacceptable toxicity. Patients achieving disease progression may undergo surgery after completion of therapy.

Primary Outcome Measures

Name	Time	Method
Proportion of dose limiting toxicities at each dose level assessed using National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0	Up to 12 weeks

Secondary Outcome Measures

Name	Time	Method
HPV status	Up to 5 years
Clinical response by Response Evaluation Criteria in Solid Tumors criteria	Up to 5 years	Will be analyzed by generalized linear models with dose-response analysis using logistic regression.
Progression free survival	Up to 5 years	Will be analyzed by generalized linear models.
T cell phenotypes	Up to 5 years
T regulatory cell counts	Up to 5 years
Serum factors and tumor infiltrates	Up to 5 years
Myeloid-derived suppressor cell (MDSC) cell counts	Up to 5 years

Trial Locations

Locations (1)

University of Pittsburgh Cancer Institute (UPCI); 🇺🇸 Pittsburgh, Pennsylvania, United States