Pembrolizumab, Cisplatin, and Intensity Modulated Radiation Therapy in Treating Patients with Previously Untreated Stage III-IVb Head and Neck Cancer
This randomized phase II trial studies how well pembrolizumab works when given during or after cisplatin and intensity modulated radiation therapy in treating patients with previously untreated stage III-IVb head and neck cancer. Monoclonal antibodies, such as pembrolizumab, may block tumor growth in different ways by targeting certain cells. Drugs used in chemotherapy, such as cisplatin, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Radiation therapy uses high-energy x-rays to kill tumor cells and shrink tumors. It is not yet known whether giving pembrolizumab during or after cisplatin and intensity modulated radiation therapy will kill more tumor cells.
- Patients must have histologically-confirmed head and neck squamous cell carcinoma with no evidence of distant metastasis; the primary site may be the oral cavity, oropharynx, larynx, or hypopharynx; patients with squamous cell carcinoma of unknown primary, metastatic to cervical lymph nodes, are permitted to enroll
- Patients must have high risk or intermediate risk disease, defined below; staging evaluation should be determined by imaging studies and complete head and neck exam in accordance with the American Joint Committee on Cancer Staging Manual, 7th edition * High risk patient must meet one of the following criteria: ** Surgically unresectable oral cavity; patients who are technically resectable but refuse surgery due to morbidity (eg. total glossectomy) are also eligible; medically inoperable patients are not eligible ** Larynx: T4 any N; T2-3 and >= N2a ** Hypopharynx: T1-2N1-3 or T3-4N0-3 ** Oropharynx: p16(-) AND T3-4 or >= N2a ** Unknown primary: p16(-) AND >= N2a * Intermediate risk patients must meet one of the following criteria: ** Oropharynx: p16(+) AND one of the following *** T3 or >= N2a AND >= 10 pack-years tobacco exposure *** T4 or N3 disease irrespective of tobacco exposure ** Unknown primary: p16(+) AND one of the following: *** >= N2a AND >= 10 pack-years tobacco exposure *** N3 disease irrespective of tobacco exposure Note: for patients with oropharyngeal or unknown primary tumors, p16 status must be known, and can be performed at the local site; p16-positive disease is defined as >= 70% of tumor cells demonstrating diffuse nuclear and cytoplasmic staining by p16 immunohistochemistry (IHC); a positive test for human papilloma virus (HPV) -16 by in-situ hybridization (ISH), if this is the local site preference for assessing HPV status, may substitute for p16 IHC testing; p16 staining is not required for non-oropharyngeal sites
- Patients must be untreated with curative-intent surgery for current diagnosis of stage III, IVa, or IVb disease; diagnostic biopsy of primary tumor and/or nodal sites is permitted * Diagnostic simple tonsillectomy is permitted, provided patient has Response Evaluation Criteria in Solid Tumors (RECIST)-measurable nodal disease * Patients with a second HNSCC primary tumor are eligible for this study, provided more than 2 years have elapsed since the first diagnosis of HNSCC, the original tumor was managed with surgery only (no adjuvant chemotherapy or radiotherapy), and has not recurred
- Patients with simultaneous primaries or bilateral tumors are excluded, with the exception of patients with bilateral tonsil cancers or patients with T1-2, N0, M0 differentiated thyroid carcinoma (resected or management deferred), who are eligible
- No prior systemic (chemotherapy or biologic/molecular targeted therapy) or radiation treatment for head and neck cancer * Patients may have received chemotherapy or radiation for a previous, curatively treated non-HNSCC malignancy, provided at least 2 years have elapsed * Patients must be untreated with radiation above the clavicles
- Patients with a history of curatively-treated non-HNSCC malignancy must be disease-free for at least 2 years except for excised and cured: carcinoma-in-situ of breast or cervix; non-melanomatous skin cancer; T1-2, N0, M0 resected differentiated thyroid carcinoma; superficial bladder cancer; T1a or T1b prostate cancer comprising < 5% of resected tissue with normal prostate specific antigen (PSA) since resection
- The patient must consent to a research biopsy at baseline, and during week 2 of cisplatin-IMRT; all patients will be evaluated for the feasibility of research biopsy at the time of enrollment, as a condition of eligibility; the performing physician must agree that a cup forceps biopsy or an 18 to 14 gauge core needle biopsy can be safely performed; every effort will be made to couple the baseline research biopsy to a standard of care diagnostic or staging procedure; NOTE: patients who have had research tissue procured under an omnibus tissue consent, who are determined to have sufficient fresh, fresh-frozen, and paraffin tissue for analysis of immune-inflammatory biomarkers per the translational science co-chair, may substitute the archived tissue and do not need to undergo baseline research biopsy; such tissue must have been obtained within the prior 24 weeks and no interval anti-cancer therapy administered
- Eastern Cooperative Oncology Group (ECOG) performance status 0-1
- Patients must have measurable disease according to RECIST 1.1
- Absolute neutrophil count (ANC) >= 1,500/mm^3
- Platelets >= 100,000/mm^3
- Serum creatinine =< 1.5 X upper limit of normal (ULN) OR measured or calculated creatinine clearance (glomerular filtration rate [GFR] can also be used in place of creatinine or calculated creatinine clearance [CrCl]) creatinine clearance >= 60 mL/min (for subject with creatinine levels > 1.5 X institutional ULN) determined by 24-hour collection or estimated by Cockcroft-Gault formula
- Serum total bilirubin =< 1.5 X ULN OR direct bilirubin =< ULN for subjects with total bilirubin levels > 1.5 ULN
- Aspartate transaminase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) and alanine transferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 X ULN
- International normalized ratio (INR) or prothrombin time (PT) =< 1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or partial thromboplastin time (PTT) is within therapeutic range of intended use of anticoagulants
- Activated partial thromboplastin time (aPTT) =< 1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants
- Written informed consent must be obtained from all patients prior to study registration; patients should have the ability to understand and the willingness to sign a written informed consent document
- If a woman of childbearing potential, documentation of negative pregnancy within 14 days prior to first dose; sexually active patients must agree to use adequate contraceptive measures, while on study and for 30 days after the last dose of study drug; all fertile female subjects (and their partners) must agree to use a highly effective method of contraception; effective birth control includes (a) intrauterine device (IUD) plus one barrier method; or (b) 2 barrier methods; effective barrier methods are male or female condoms, diaphragms, and spermicides (creams or gels that contain a chemical to kill sperm); should a woman become pregnant or suspect she is pregnant while in this study, she should inform her treating physician immediately
- Nasopharyngeal primary site
- Current participation in or previous participation in a study of an investigational agent or using an investigational device within 4 weeks of the first dose of study treatment
- History of severe allergic or anaphylactic reactions or hypersensitivity to recombinant proteins or excipients in the investigational agent
- Distant metastatic disease including central nervous system (CNS) or leptomeningeal metastases is not allowed
- History of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment
- Received prior monoclonal antibody within 4 weeks prior to study day 1 or who has not recovered (i.e. =< grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier
- History of second malignancy within 2 years prior to study day 1 (except for excised and cured non-melanoma skin cancer, carcinoma in situ of breast or cervix, superficial bladder cancer, or T1a or T1b prostate cancer comprising < 5% of resected tissue with normal prostate specific antigen [PSA] since resection)
- Active autoimmune disease requiring systemic treatment within the past 3 months or a documented history of clinically severe autoimmune disease, or a syndrome that requires systemic steroids or immunosuppressive agents; subjects with vitiligo or resolved childhood asthma/atopy would be an exception to this rule; subjects that require intermittent use of bronchodilators or local steroid injections would not be excluded from the study; subjects with hypothyroidism stable on hormone replacement or Sjogren’s syndrome will not be excluded from the study
- Known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies)
- Known active hepatitis B (e.g., hepatitis B surface antigen [HBsAg] reactive) or hepatitis C (e.g., hepatitis C virus [HCV] ribonucleic acid [RNA] [qualitative] is detected)
- Received a live vaccine within 30 days prior to the first dose of trial treatment
- Received prior therapy with an anti-programmed cell death 1 (PD-1), anti-PD-L1, anti-programmed cell death 1 ligand 2 (PD-L2), anti-CD137, or anti-cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody (including ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways)
- Significant pulmonary disease, including pulmonary hypertension, interstitial lung disease, or active, non-infectious pneumonitis
- History or current evidence of any other medical or psychiatric 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
- Peripheral neuropathy >= grade 2
- Significant cardiovascular disease, including: * Cardiac failure New York Heart Association (NYHA) class III or IV * Myocardial infarction, severe or unstable angina within 6 months prior to study day 1 * History of serious arrhythmia (i.e., ventricular tachycardia, or ventricular fibrillation) * Ventricular cardiac arrhythmias requiring anti-arrhythmic medications * Known left ventricular ejection fraction (LVEF) =< 50%
- Significant thrombotic or embolic events within 3 months prior to study day 1; significant thrombotic or embolic events include but are not limited to stroke or transient ischemic attack (TIA); catheter-related thrombosis is not a cause for exclusion; diagnosis of deep vein thrombosis or pulmonary embolism is allowed if the patient is clinically stable and has completed or is on stable anti-coagulation therapy
- Major surgery within 6 weeks prior to study day 1 (subjects must have completely recovered from any previous surgery prior to study day 1); biopsy, diagnostic tonsillectomy, airway tumor debulking or excisional lymph node biopsy do not constitute major surgery
- Active infection requiring antibiotics or antifungals within 7 days prior to first dose of study drug
- Significant electrolyte imbalance prior to enrollment (note that patients may be supplemented to achieve acceptable electrolyte values): * Hypomagnesemia < 1.2 mg/dL or 0.5 mmol/L * Hypokalemia < 3.0 mmol/L
- Women must not be pregnant or breastfeeding; pregnant women are excluded from this study
Locations & Contacts
Contact: Julie E. Bauman
Trial Objectives and Outline
I. To evaluate two schedules of fixed-dose pembrolizumab (concurrent vs. sequential) added to the standard, concurrent cisplatin- intensity modulated radiotherapy (IMRT) in patients with previously untreated locally advanced (PULA) head and neck squamous cell carcinoma (HNSCC) in order to recommend the schedule to be tested in a subsequent definitive randomized trial as determined by the composite endpoint of dose limiting toxicity (DLT) rate, 1-year failure rate, and 1-year progression free survival (PFS) rate.
I. To evaluate the toxicity of two sequences of the combination of pembrolizumab and concurrent cisplatin-IMRT in patients with PULA HNSCC.
II. To evaluate the relationship of baseline programmed cell death 1 ligand 1 (PD-L1) expression by tumor and tumor-infiltrating lymphocytes (TILs) to preliminary efficacy.
III. To evaluate the dynamics of PD-L1 expression in the tumor and TILs via a repeat biopsy after two weeks in patients with accessible tumor.
IV. To evaluate the tumor microenvironment, activation, and proliferation markers on TIL and natural killer (NK) cells in pre- and post-treatment specimens, including cluster of differentiation (CD)3, CD8, CD45RO, CD4/ forkhead box P3 (FOXP3), PD-L1, and Ki-67.
V. To evaluate the dynamic expression of tumor antigens (TA)-specific T cells in serial peripheral blood mononuclear cells (PBMCs) by flow cytometry.
OUTLINE: Patients are randomized to 1 of 2 arms.
ARM I (SEQUENTIAL): Patients receive cisplatin intravenously (IV) over 60 minutes and undergo IMRT once weekly in weeks 1-7. Beginning 3 weeks after cisplatin and IMRT, patients receive pembrolizumab IV over 30 minutes every 3 weeks in weeks 10, 13, 16, 19, 22, 25, 28, and 31.
ARM II (CONCURRENT): Patients receive pembrolizumab IV over 30 minutes in weeks -1, 3, 6, 10, 13, 16, 19, and 22. Patients receive cisplatin over 60 minutes IV and undergo IMRT as in Arm 1.
After completion of study treatment, every 3 months for 2 years, every 6 months for 1 year, and then annually for2 years.
Trial Phase & Type
University of Pittsburgh Cancer Institute (UPCI)
Julie E. Bauman
Secondary IDs NCI-2016-00793
Clinicaltrials.gov ID NCT02777385