Clinical Stage I HPV-Mediated (p16-Positive) Oropharyngeal Carcinoma AJCC v8, Clinical Stage II HPV-Mediated (p16-Positive) Oropharyngeal Carcinoma AJCC v8, Human Papillomavirus Positive Oropharyngeal Squamous Cell Carcinoma, Oropharyngeal Basaloid Carcinoma, Pathologic Stage I HPV-Mediated (p16-Positive) Oropharyngeal Carcinoma AJCC v8, Pathologic Stage II HPV-Mediated (p16-Positive) Oropharyngeal Carcinoma AJCC v8, Posterior Tongue Squamous Cell Carcinoma, Soft Palate Squamous Cell Carcinoma, Stage III Oropharyngeal Squamous Cell Carcinoma AJCC v7, Stage IVA Oropharyngeal Squamous Cell Carcinoma AJCC v7, Tonsillar Squamous Cell Carcinoma
Conditions
Brief summary
This phase II trial studies the side effects and best dose of ipilimumab, nivolumab, and radiation therapy and how well they work in treating patients with advanced human papillomavirus (HPV) positive oropharyngeal squamous cell carcinoma. Immunotherapy with monoclonal antibodies, such as ipilimumab and nivolumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Radiation therapy uses high energy x-rays to kill tumor cells and shrink tumors. Giving ipilimumab, nivolumab, and radiation therapy may work better in treating patients with HPV positive oropharyngeal squamous cell carcinoma.
Detailed description
PRIMARY OBJECTIVES: I. To evaluate the safety, tolerability and feasibility of ipilimumab and nivolumab when administered concurrently with reduced-field radiotherapy (intensity-modulated radiation therapy \[IMRT\]). II. To evaluate the clinical complete response rate to ipilimumab, nivolumab and IMRT with reduced field at six months as indicated by fluorodeoxyglucose - positron emission tomography/computed tomography (FDG-PET/CT) post completion of radiation therapy (RT). III. To evaluate the 2-year progression-free survival (PFS) rate of subjects with low-intermediate volume, local-regionally advanced, human papilloma virus (HPV)-positive squamous cell carcinoma of the head and neck (SCCHN) treated with ipilimumab, nivolumab and reduced-field IMRT. SECONDARY OBJECTIVES: I. To evaluate overall response rate to six weeks of induction immunotherapy (IO). II. To evaluate the frequency of pharyngeal dysphasia as measured by Dynamic Imaging (Dynamic Imaging Grade of Swallowing Toxicity \[DIGEST\]) grade on modified barium swallow (MBS) and patient-reported symptoms (MD Anderson Dysphagia Inventory \[MDADI\]) at 6 month, 1 and 2 years after radiotherapy (\[IMRT\]. III. To measure acute and chronic toxicities per Patient-Reported Outcomes Common Terminology Criteria for Adverse Events (CTCAE PRO). IV. To measure acute toxicity profiles at the end of radiation therapy and IO and at 6 months. V. To measure late toxicity profiles at 1 and 2 years. VI. To determine local and regional control at 6 and 12 months. VII. To determine patterns of failure (local-regional relapse vs. distant) at 1 and 2 years. VIII. To determine overall survival (OS) at 1 and 2 years. CORRELATIVE OBJECTIVES: I. To evaluate associations between total mutational load, interferon (INF) gamma score, T cell clonality at diagnosis with clinical response to induction, combination CTLA-4 PD-1 checkpoint blockade. II. To evaluate changes in the tumor immune microenvironment (CD8 + INF gamma score, T cell clonality, in tumor biopsy specimens pre and post induction immunotherapy (IO). III. To evaluate dynamic changes in and clearance of oral HPV and cell-free deoxyribonucleic acid (cfDNA) viral load during therapy and to investigate associations with PFS and OS. EXPLORATORY OBJECTIVES: I. To evaluate changes in peripheral blood lymphocyte phenotypes and serum cytokine profiles before and after induction IO. II. To evaluate changes in the T cell receptor repertoire in tumor-infiltrating lymphocyte (TIL) and the peripheral blood in tumor biopsy specimens pre and post induction IO. III. To determine the negative and positive predictive values (NPV and PPV) of FDG-PET/CT 12-14 weeks after end of RT for 1 year and 2 year PFS and OS. OUTLINE: Patients receive nivolumab intravenously (IV) over 30 minutes on days 1, 15, and 29 and ipilimumab IV over 30 minutes on day 1. Treatment repeats every for 6 weeks for 2 cycles in the absence of disease progression or unacceptable toxicity. Beginning on day 1 of cycle 2, patients also undergo IMRT 5 days a week (Monday-Friday) for 6 weeks in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up at 2 weeks, every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter.
Interventions
RADIATIONIntensity-Modulated Radiation Therapy
Undergo IMRT
BIOLOGICALIpilimumab
Given IV
BIOLOGICALNivolumab
Given IV
OTHERQuality-of-Life Assessment
Ancillary studies
OTHERQuestionnaire Administration
Ancillary studies
Sponsors
M.D. Anderson Cancer Center
National Cancer Institute (NCI)
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Histologically or cytologically newly confirmed diagnosis of squamous cell carcinoma (including the histological variants of papillary or basaloid) of the oropharynx (tonsil, base of tongue, soft palate, or oropharyngeal walls) * Clinical American Joint Committee on Cancer (AJCC) 7th edition stage T1N2a-N2CM0, T2N1-N2CM0, T3N0-N2CM0, equivalent to AJCC 8th edition stage 1 and 2 (T1 N2, T2 N1-N2, T3 N0-N2) excluding T1N0-N1 and T2N0 (Brian O'Sullivan et al. 2016) * Tumor positive for p16 immunohistochemistry (IHC) (defined as greater than 70% strong nuclear or nuclear and cytoplasmic staining of tumor cells) and HPV DNA in situ hybridization or HPV messenger ribonucleic acid (mRNA) RNAScope. Repeat samples may be required if adequate diagnostic tissue is unavailable for testing * Zubrod Performance Status of 0-1 * Patients must have radiographically evident measurable disease at the primary site or at nodal stations per response evaluation criteria in solid tumors (Response Evaluation Criteria in Solid Tumors \[RECIST\]) 1.1 documented by diagnostic quality CT or magnetic resonance imaging (MRI) of the neck with contrast within 28 days prior to registration; a FDG-PET/CT of the neck performed for the purposes of radiation planning is acceptable as a substitute if the CT is of diagnostic quality * Diagnostic quality cross sectional imaging of the thorax within 28 days prior to registration. A 18-FDG-PET/CT or conventional CT are acceptable * FDG-PET/CT of the neck is required within 28 days prior to registration for comparison to post treatment FDG-PET/CT. Note: Repeat imaging for variability within 96 hours of this time frame should be allowed to avoid unnecessary re-imaging and its financial and potential physical consequences for patients * History and physical exam within 1 month prior to registration * Fiberoptic exam with laryngopharyngoscopy (mirror and/or fiberoptic and/or direct procedure) by radiation oncologist, medical oncologist or ear, nose, throat (ENT)/head and neck surgeons within 28 days prior to registration * Absolute neutrophil count (ANC) \>= 1,500 cells/mm\^3 (within 2 weeks prior to registration) * Platelets \>= 100,000 cells/mm\^3 (within 2 weeks prior to registration) * Hemoglobin \>= 8.0 g/dl (within 2 weeks prior to registration); Note: The use of transfusion or other intervention to achieve Hgb \>= 8.0 g/dl is acceptable * Serum creatinine \< 1.5 mg/dl or creatinine clearance (CC) \>= 50 ml/min determined by 24-hour collection or estimated by Cockcroft-Gault formula (within 2 weeks prior to registration) * Bilirubin \< 2 mg/dl (within 2 weeks prior to registration) * Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) \< 3 x the upper limit of normal (within 2 weeks prior to registration) * Sodium (Na), potassium (K), chloride (Cl), glucose, calcium (Ca), magnesium (Mg), albumin, amylase, lipase, thyroid stimulating hormone (TSH) within 2 weeks prior to registration * Negative serum pregnancy test within 2 weeks prior to registration for women of childbearing potential * Seronegative for active hepatitis-B or hepatitis-C infection and seronegative for human immunodeficiency virus (HIV) * Mandatory submission of hematoxylin and eosin (H\&E) and paraffin-embedded tumor block or unstained slides
Exclusion criteria
* Cancers of the oral cavity (oral tongue, floor mouth, alveolar ridge, buccal or lip), or the nasopharynx, hypopharynx, or larynx, even if p16 positive * Carcinoma of the neck of unknown primary site origin (even if p16 positive) * Definitive clinical or radiologic evidence of metastatic disease or adenopathy below the clavicles * Gross total excision of both primary and nodal disease with curative intent; this includes tonsillectomy, local excision of primary site, and nodal excision that removes all clinically and radiographically evident disease * Simultaneous primary cancers or separate bilateral primary tumor sites * Prior invasive malignancy (except non-melanomatous skin cancer) unless disease free for a minimum of 1095 days (3 years) (for example, carcinoma in situ of the breast, oral cavity, or cervix are all permissible) * Prior systemic chemotherapy for the study cancer; note that prior chemotherapy for a different cancer is allowable; patients who have received PD-1/PD-L1 or CTLA4 therapy for a previous malignancy are not eligible * Prior RT to the region of the study cancer that would result in overlap of radiation therapy fields * Severe, active co-morbidity defined as any of the following: Unstable angina and/or congestive heart failure requiring hospitalization within the last 6 months; acute bacterial or fungal infection requiring intravenous antibiotics at the time of registration; chronic obstructive pulmonary disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy within 30 days of registration; hepatic insufficiency resulting in clinical jaundice and/or coagulation defects; a diagnosis of immunodeficiency or use of any form of systemic immunosuppressive therapy. The use of physiologic doses of corticosteroids may be approved after consultation with the sponsor * Active autoimmune disease that has required systemic treatment in past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). 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. Steroid premedications for contrast allergy allowed * Has evidence of active, non-infectious pneumonitis * Has received a live vaccine within 30 days of planned start of study therapy * Pregnancy or breast-feeding; this exclusion is necessary because the treatment involved in this study may be significantly teratogenic * History of severe hypersensitivity or contraindication to CT or PET contrast material uncontrolled with pre-medications (steroids, antihistamines)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Radiographic (RECIST) Response | 6 months post completion of radiation therapy (approximately 9 months post start of treatment) | Per Response Evaluation Criteria in Solid Tumors Criteria (RECIST v.1.1) for target lesions and assessed by CT or MRI: Complete Response (CR), disappearance of all target lesions; Partial Response (PR), \>= 30% decrease in the sum of the longest diameter of target lesions; Stable Disease (SD), neither sufficient shrinkage to qualify for PR nor sufficient growth to qualify for PD; Progressive Disease (PD), \>= 20% increase in the sum of the longest diameter with an absolute increase of at least 5 mm or the appearance of new lesions |
| Pathologic Response -- Percent Viable Tumor Change | From first registration on trial (baseline biopsy) to post Cycle 1 of IO (6 weeks after start of treatment) | Pathologic response refers to the evaluation of how much a tumor has shrunk after treatment by the pathologist on trial examining tissue samples under a microscope. Tissue samples from baseline and at follow up were evaluated for tumor response. Percent viable tumor change is calculated using viable tumor data collected at the biopsy to the biopsy at the end of Cycle 1 of treatment. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Toxicity (Number of Adverse Events) | time of first drug administration to 30 days after last drug administration | Adverse events (AEs) are categorized as follows: Treatment-Emergent Adverse Events (TEAEs), which refer to any AEs that arise or worsen in severity after the initiation of treatment with the study product; and Treatment-Related Adverse Events (TRAEs), defined as TEAEs that are considered possibly, probably, or definitely related to the treatment. Adverse Events were graded 1 to 5 via CTAE 4.0 guidelines. All AEs, whether serious or non-serious, will be captured from the time of the first administration of the investigational agent until 30 days following the last dose of study drug or until the initiation of alternative anticancer therapy |
| Survival Analysis -- Progression Free Survival | 12 month post treatment follow up (15 months post treatment start), 18 month post treatment follow up (21 months post treatment start), 24 month post treatment follow up (27 months post treatment start) | Analyses of overall survival (OS) and progression-free survival (PFS) were performed. PFS was defined as from treatment initiation to progression or death, whichever occurred first, or last follow-up. The distribution was estimated by Kaplan-Meier method. |
| Survival Analysis -- Overall Survival (Percentage of Participants Alive at 12 Months, 18 Months, and 24 Months) | 12 month post treatment follow up (15 months post treatment start), 18 month post treatment follow up (21 months post treatment start), 24 month post treatment follow up (27 months post treatment start) | Analyses of overall survival (OS) and progression-free survival (PFS) were performed. OS was defined as from treatment initiation to death or last follow-up time. The distribution was estimated by Kaplan-Meier method. No death was observed. |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORRenata Ferrarotto, MD
M.D. Anderson Cancer Center
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 15 Participants |
| Age, Categorical Between 18 and 65 years | 20 Participants |
| Distribution of categorical clinical characteristics among evaluable participants ECOG PS: 0 | 32 Participants |
| Distribution of categorical clinical characteristics among evaluable participants ECOG PS: 1 | 3 Participants |
| Distribution of categorical clinical characteristics among evaluable participants Overall Stage: Stage I | 33 Participants |
| Distribution of categorical clinical characteristics among evaluable participants Overall Stage: Stage II | 2 Participants |
| Distribution of categorical clinical characteristics among evaluable participants Primary Site: Base of tongue | 22 Participants |
| Distribution of categorical clinical characteristics among evaluable participants Primary Site: Oropharynx, NOS | 1 Participants |
| Distribution of categorical clinical characteristics among evaluable participants Primary Site: Tonsil | 12 Participants |
| Distribution of categorical clinical characteristics among evaluable participants Smoking history: Current | 9 Participants |
| Distribution of categorical clinical characteristics among evaluable participants Smoking history: Former | 11 Participants |
| Distribution of categorical clinical characteristics among evaluable participants Smoking history: Never | 15 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 4 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 31 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Race (NIH/OMB) White | 33 Participants |
| Region of Enrollment United States | 35 participants |
| Sex: Female, Male Female | 1 Participants |
| Sex: Female, Male Male | 34 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 35 |
| other Total, other adverse events | 35 / 35 |
| serious Total, serious adverse events | 9 / 35 |
Outcome results
None listed