De-Escalation Therapy for Human Papillomavirus Negative Disease

NCT ID: NCT03944915

Last Updated: 2025-05-11

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 35 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2019-08-26
• Study Completion Date: 2023-11-01

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.

Conditions

Human Papilloma Virus; Squamous Cell Carcinoma; Squamous Cell Carcinoma of the Head and Neck; HPV-Related Squamous Cell Carcinoma; HNSCC

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Standard Chemotherapy

Induction Therapy

Group Type: EXPERIMENTAL

Carboplatin

Intervention Type: DRUG

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.

Paclitaxel

Intervention Type: DRUG

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.

Nivolumab

Intervention Type: DRUG

Nivolumab will be given through IV infusions at 360 mg on day 1 every 21 days for 3 cycles.

De-escalated Chemotherapy

Radiation therapy with chemotherapy

Group Type: EXPERIMENTAL

Paclitaxel

Intervention Type: DRUG

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.

Radiation

Intervention Type: RADIATION

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

Hydroxyurea Pill

Intervention Type: DRUG

One dose of hydroxyurea pill by mouth at start of 5-FU infusion during radiotherapy cycle

5-fluorouracil

Intervention Type: DRUG

5-FU will be given by IV infusion continuously for 5 days during radiotherapy cycles

Filgrastim Injection

Intervention Type: DRUG

Filgrastim shot will be given if patient has certain side effects during radiotherapy cycle on days 6-12.

Cisplatin

Intervention Type: DRUG

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.

Interventions

Carboplatin

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.

Intervention Type: DRUG

Paclitaxel

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.

Intervention Type: DRUG

Nivolumab

Nivolumab will be given through IV infusions at 360 mg on day 1 every 21 days for 3 cycles.

Intervention Type: DRUG

Radiation

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

Intervention Type: RADIATION

Hydroxyurea Pill

One dose of hydroxyurea pill by mouth at start of 5-FU infusion during radiotherapy cycle

Intervention Type: DRUG

5-fluorouracil

5-FU will be given by IV infusion continuously for 5 days during radiotherapy cycles

Intervention Type: DRUG

Filgrastim Injection

Filgrastim shot will be given if patient has certain side effects during radiotherapy cycle on days 6-12.

Intervention Type: DRUG

Cisplatin

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.

Intervention Type: DRUG

Other Intervention Names

5-FU; Filgrastim shot

Eligibility Criteria

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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

University of Chicago

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Everett Vokes, MD

Role: PRINCIPAL_INVESTIGATOR

University of Chicago

Locations

University Of Chicago Medicine Comprehensive Cancer Center

Chicago, Illinois, United States

Countries

United States

References

Rosenberg AJ, Juloori A, Jelinek MJ, Agrawal N, Cursio JF, Cipriani N, Lingen MW, Izumchenko E, Katipally R, Chin J, Ginat D, Pasternak-Wise O, Gooi Z, Blair E, Pearson AT, Haraf DJ, Vokes EE. Neoadjuvant Nivolumab Plus Chemotherapy Followed by Response-Stratified Chemoradiation Therapy in HPV-Negative Head and Neck Cancer: The DEPEND Phase 2 Nonrandomized Clinical Trial. JAMA Oncol. 2025 May 1;11(5):492-501. doi: 10.1001/jamaoncol.2025.0081.

Reference Type: DERIVED

PMID: 40048190 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

IRB19-0162

Identifier Type: -

Identifier Source: org_study_id