HNSCC, HPV-Related Squamous Cell Carcinoma, Human Papilloma Virus, Squamous Cell Carcinoma, Squamous Cell Carcinoma of the Head and Neck
Conditions
Brief summary
This study is looking to see if nivolumab, an immunotherapy drug, given with carboplatin and paclitaxel (2 chemotherapy agents) during induction therapy in advanced stage HPV negative patients can significantly shrink the subject's cancer.
Interventions
DRUGCarboplatin
Carboplatin will be given through IV infusions for 30-60 minutes on day 1 of each cycle. Each cycle will last 21 days. There will be 3 cycles.
DRUGPaclitaxel
During Induction Therapy Paclitaxel (100 mg) will be given through IV infusions on days 1, 8 and 15 of each 21 day cycle. There will be 3 cycles. During Radiotherapy, paclitaxel will be given after a dose of radiation by IV infusion for 60 minutes after day 1 of radiotherapy.
DRUGNivolumab
Nivolumab will be given through IV infusions at 360 mg on day 1 every 21 days for 3 cycles.
RADIATIONRadiation
Patients will receive 4.5-5 cycles of radiation depending on response. Those with a positive response will receive radiation for 4.5 cycles with a total radiation dose of 66 Gy. Patients with a moderate or no response will receive 5 cycles with a total radiation dose of 70-75 Gy. 2 times a day for days 1-5 followed by a rest period for days 6-13
DRUGHydroxyurea Pill
One dose of hydroxyurea pill by mouth at start of 5-FU infusion during radiotherapy cycle
DRUG5-fluorouracil
5-FU will be given by IV infusion continuously for 5 days during radiotherapy cycles
Filgrastim shot will be given if patient has certain side effects during radiotherapy cycle on days 6-12.
DRUGCisplatin
Radiotherapy may also be given with a different chemotherapy agent called cisplatin. This is the traditional standard of care chemotherapy regimen. In this case, the radiotherapy will be given once daily for 5 days per week. Cisplatin will be administered via IV once every 21 days for 2 or 3 cycles.
Sponsors
University of Chicago
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Patients must have pathologically confirmed locally advanced, non-metastatic, HPV-negative head and neck squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx, nasopharynx, larynx, or sinuses. 2. Stage IV disease with the exception of nasopharyngeal tumor-3, node-2 (stage III) based of American Joint Committee on Cancer staging 8th edition 3. If a primary oropharyngeal squamous cell carcinoma is diagnosed, HPV must be ruled out by immunohistochemistry. 4. Availability of ≥10 unstained 5 micron slides. Patients who cannot fulfill this requirement will need to undergo a new biopsy prior to enrollment on study. 5. Patients must be at least 18 years of age. 6. Measurable disease (either primary site and/or nodal disease) by RECIST criteria. 7. No previous radiation or chemotherapy for a head and neck cancer. 8. No complete surgical resection for a head and neck cancer within 8 weeks of enrollment (although lymph node biopsy including excision of an individual node with presence of residual nodal disease, or surgical biopsy/excision of the tumor with residual measurable disease is acceptable.) No surgical procedures or biopsies will occur after baseline scans are performed and measurable lesions are identified. 9. Eastern Cooperative Oncology Group performance status 0-1 10. Normal Organ Function 1. Leukocytes ≥ 3000/mm3 2. Platelets ≥ 100,000/mm3 3. Absolute neutrophil count ≥ 1,500 4. Hemoglobin ≥ 9.0 gm/dL 5. Aspartate Aminotransferase (AST) and Alanine Aminotransferase (ALT) ≤ 2.5x upper limit of normal 6. Alkaline phosphatase ≤ 2.5x upper limit of normal 7. Albumin \> 2.9 gm/dL 8. Total bilirubin ≤ 1.5 mg/dL 9. Creatinine clearance \> 45 mL/min, normal within 2 weeks prior to start of treatment (Of note, the standard Cockcroft and Gault formula must be used to calculate creatinine clearance (CrCl) for enrollment or dosing) 11. Patients must sign a study-specific informed consent form prior to study entry. Patients should have the ability to understand and the willingness to sign a written informed consent document. 12. Women of childbearing potential must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior to the start of study drug 13. Women must not be breastfeeding 14. Women of childbearing potential must agree to follow instructions for method(s) of contraception for the duration of treatment with study drug(s) plus 6 months after completing chemoradiation or receiving the last dose of consolidative nivolumab, whichever occurs latest. 15. Men who are sexually active with women of childbearing potential must agree to follow instructions for method(s) of contraception for the duration of treatment with study drug(s) plus 6 months after completing chemoradiation or receiving the last dose of consolidative nivolumab, whichever occurs latest.
Exclusion criteria
1. Unequivocal demonstration of distant metastatic disease (M1 disease). 2. Unidentifiable primary site. 3. Inter-current medical illnesses which would impair patient tolerance to therapy or limit survival. This includes but is not limited to ongoing or active infection, immunodeficiency, symptomatic congestive heart failure, pulmonary dysfunction, cardiomyopathy, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance. Patients with clinically stable and/or chronically managed medical illnesses that are not symptomatic and/or are not expected to impact treatment on protocol are still eligible (conditions to be reviewed by the PI to confirm eligibility) 4. Prior surgical therapy other than incisional/excisional biopsy or organ-sparing procedures such as debulking of airway-compromising tumors. Residual measurable tumor is required for enrollment as discussed above. 5. Patients receiving other investigational agents. 6. Diagnosis of immunodeficiency or is receiving systemic steroid therapy in excess of physiologic dose or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment. 7. Known history of active tuberculosis (Bacillus Tuberculosis infection). 8. Hypersensitivity to nivolumab or any other drug used in this protocol. 9. Prior systemic anti-cancer treatment within the last 8 weeks. 10. 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 or any tumors that are not likely to influence life expectancy in the subsequent 3 years without active treatment. 11. Has active autoimmune disease that has required systemic therapy in the past year (i.e. with steroids or immunosuppressive drugs). Replacement therapy e.g. levothyroxine, insulin, or physiologic corticosteroid doses for adrenal or pituitary insufficiency, etc. are not considered a form of systemic treatment. 12. Has known history of, or any evidence of active, non-infectious pneumonitis. 13. Has a history of HIV. 14. Has known active Hepatitis B or hepatitis C. If eradicated, patient is eligible. 15. Has received a live vaccine within 28 days of planned start of study therapy.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Deep Response Rate (DRR) | 2 years | DRR is 50% or greater response to induction therapy based on RECIST criteria. The objective is to intensify induction chemotherapy with the addition of an immune checkpoint inhibitor aimed at increasing the proportion of patients achieving a deep tumor response in order to subsequently allow risk-adapted definitive chemoradiotherapy in advanced stage HPV negative head and neck squamous cell cancer patients. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival Rate (PFS) | 26 months | Progression free survival at 24 months after completing chemoradiation. PFS will be defined as the time from registration to the date of the first documented disease progression, clinical progression, or death due to any cause, whichever occurs first. |
| Overall Survival Rate (OS) | 26 months | Overall survival will be defined as the time between the date of registration and the date of death. |
| Locoregional Control After Completing Chemoradiation | 26 months | Assess disease control in all patients receiving induction chemoimmunotherapy and compare disease control between radiation arms. |
| Distant Control After Completing Chemoradiation | 26 months | Distant control will be defined as the percent of patients with disease progression below the clavicles. Comparison between the two radiation arms will be made. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Acute and Late Toxicity During Treatment | 1 year | Assess long term and late toxicities in all patients receiving induction therapy and risk-adapted chemoradiotherapy after deep response to induction therapy. Acute and late toxicities will be defined using the National Cancer Institute Common Terminology Criteria for Adverse Events. Comparisons will be made using Fisher's exact test. Acute and late toxicity during treatment and at 1 month, 3 months and 1 year post chemoradiation |
| Enteral Tube Dependency | 1 year | Enteral tube dependency will be defined as continued necessity of any nutrition through enteral tube to maintain weight. The rate of enteral tube dependency will be described within the safety population and among each radiation treatment. Comparisons will be made using Fisher's exact test. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Standard Chemotherapy Standard chemoradiotherapy with paclitaxel, 5-FU, hydroxyurea and hyperfractionated, accelerated radiotherapy to 75 Gy encompassing GTV of primary and nodal disease as well as elective prophylactic nodal irradiation. OR Standard chemoradiotherapy with cisplatin and radiotherapy to 70 Gy encompassing GTV of primary and nodal disease as well as elective prophylactic nodal irradiation | 16 |
| De-escalated Chemotherapy De-escalated chemoradiotherapy with paclitaxel, 5-FU, hydroxyurea and hyperfractionated, accelerated radiotherapy to 66 Gy encompassing GTV of primary and nodal disease without elective prophylactic nodal irradiation. OR De-escalated chemoradiotherapy with cisplatin and radiotherapy to 66 Gy encompassing GTV of primary and nodal disease without elective prophylactic nodal irradiation. | 19 |
| Total | 35 |
Baseline characteristics
| Characteristic | Standard Chemotherapy | De-escalated Chemotherapy | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 5 Participants | 8 Participants | 13 Participants |
| Age, Categorical Between 18 and 65 years | 11 Participants | 11 Participants | 22 Participants |
| Age, Continuous | 57.0 years STANDARD_DEVIATION 11.9 | 60.1 years STANDARD_DEVIATION 12.4 | 58.7 years STANDARD_DEVIATION 12.1 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 0 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 15 Participants | 19 Participants | 34 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 4 Participants | 5 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 2 Participants | 3 Participants |
| Race (NIH/OMB) White | 14 Participants | 13 Participants | 27 Participants |
| Region of Enrollment United States | 16 participants | 19 participants | 35 participants |
| Sex: Female, Male Female | 2 Participants | 6 Participants | 8 Participants |
| Sex: Female, Male Male | 14 Participants | 13 Participants | 27 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 3 / 16 | 2 / 19 |
| other Total, other adverse events | 15 / 16 | 15 / 19 |
| serious Total, serious adverse events | 0 / 16 | 0 / 19 |
Outcome results
Primary
Deep Response Rate (DRR)
DRR is 50% or greater response to induction therapy based on RECIST criteria. The objective is to intensify induction chemotherapy with the addition of an immune checkpoint inhibitor aimed at increasing the proportion of patients achieving a deep tumor response in order to subsequently allow risk-adapted definitive chemoradiotherapy in advanced stage HPV negative head and neck squamous cell cancer patients.
Time frame: 2 years
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Standard Chemotherapy | Deep Response Rate (DRR) | 16 Participants |
| De-escalated Chemotherapy | Deep Response Rate (DRR) | 19 Participants |
Secondary
Distant Control After Completing Chemoradiation
Distant control will be defined as the percent of patients with disease progression below the clavicles. Comparison between the two radiation arms will be made.
Time frame: 26 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Standard Chemotherapy | Distant Control After Completing Chemoradiation | 90 percentage of patients in each arm |
| De-escalated Chemotherapy | Distant Control After Completing Chemoradiation | 94 percentage of patients in each arm |
Secondary
Locoregional Control After Completing Chemoradiation
Assess disease control in all patients receiving induction chemoimmunotherapy and compare disease control between radiation arms.
Time frame: 26 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Standard Chemotherapy | Locoregional Control After Completing Chemoradiation | 93 percentage of patients in each arm |
| De-escalated Chemotherapy | Locoregional Control After Completing Chemoradiation | 89 percentage of patients in each arm |
Secondary
Overall Survival Rate (OS)
Overall survival will be defined as the time between the date of registration and the date of death.
Time frame: 26 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Standard Chemotherapy | Overall Survival Rate (OS) | 79 percentage of patients in each arm |
| De-escalated Chemotherapy | Overall Survival Rate (OS) | 74 percentage of patients in each arm |
Secondary
Progression Free Survival Rate (PFS)
Progression free survival at 24 months after completing chemoradiation. PFS will be defined as the time from registration to the date of the first documented disease progression, clinical progression, or death due to any cause, whichever occurs first.
Time frame: 26 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Standard Chemotherapy | Progression Free Survival Rate (PFS) | 69 percentage of patients in each arm |
| De-escalated Chemotherapy | Progression Free Survival Rate (PFS) | 69 percentage of patients in each arm |
Other Pre-specified
Acute and Late Toxicity During Treatment
Assess long term and late toxicities in all patients receiving induction therapy and risk-adapted chemoradiotherapy after deep response to induction therapy. Acute and late toxicities will be defined using the National Cancer Institute Common Terminology Criteria for Adverse Events. Comparisons will be made using Fisher's exact test. Acute and late toxicity during treatment and at 1 month, 3 months and 1 year post chemoradiation
Time frame: 1 year
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Standard Chemotherapy | Acute and Late Toxicity During Treatment | 0 Participants |
| De-escalated Chemotherapy | Acute and Late Toxicity During Treatment | 0 Participants |
Other Pre-specified
Enteral Tube Dependency
Enteral tube dependency will be defined as continued necessity of any nutrition through enteral tube to maintain weight. The rate of enteral tube dependency will be described within the safety population and among each radiation treatment. Comparisons will be made using Fisher's exact test.
Time frame: 1 year
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Standard Chemotherapy | Enteral Tube Dependency | 3 participants |
| De-escalated Chemotherapy | Enteral Tube Dependency | 3 participants |