Safety Testing of Adding Nivolumab to Chemotherapy in Patients With Intermediate and High-Risk Local-Regionally Advanced Head and Neck Cancer

Safety Evaluations of Nivolumab (Anti-PD-1) Added To Chemotherapy (CRT) Platforms In Patients With Intermediate And High-Risk Local-Regionally Advanced Head and Neck Squamous Cell Carcinoma

This study will evaluate the safety of adding nivolumab to several chemotherapy platforms with weekly cisplatin, high-dose cisplatin, cetuximab or radiation therapy alone.

Study Overview

• Status: Completed
• Conditions: Head and Neck Squamous Cell Carcinoma (HNSCC)
• Intervention / Treatment: Drug: Nivolumab; Drug: Cisplatin; Radiation: IMRT; Drug: Cetuximab

• Study Type: Interventional
• Enrollment (Actual): 40
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • Palo Alto, California, United States, 94304
      • Stanford Cancer Institute
  • Florida
    • Orlando, Florida, United States, 32806
      • University of Florida Cancer Center at Orlando Health
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Emory University/Winship Cancer Institute
  • Kentucky
    • Louisville, Kentucky, United States, 40202
      • University of Louisville
  • Ohio
    • Cleveland, Ohio, United States, 44106
      • University Hospitals Cleveland Medical Center
    • Columbus, Ohio, United States, 43210
      • Ohio State University
  • Oregon
    • Portland, Oregon, United States, 97213
      • Providence Portland Medical Center
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15232
      • UPMC - Shadyside Hospital
  • Texas
    • Houston, Texas, United States, 77030
      • MD Anderson Cancer Center
  • Virginia
    • Falls Church, Virginia, United States, 22042
      • Inova Fairfax Hospital
  • Wisconsin
    • Madison, Wisconsin, United States, 53792
      • University of Wisconsin Hospital and Clinics

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Histologically or cytologically-confirmed diagnosis of HNSCC of the oral cavity, oropharynx, larynx, or hypopharynx.
• Intermediate-risk group: Oropharynx cancer that is p16-positive by immunohistochemistry with smoking status > 10 Pack-years, stage T1-2N2b-N3 OR ≤ 10 pack-years, stage T4N0-N3 or T1-3N3.

• High-risk group: Oral cavity, larynx, hypopharynx, or p16-negative oropharynx cancer, stage T1-2N2a-N3 or T3-4-N0-3 based on the following diagnostic workup:

  • Mandatory submission of H&E and p16 stained slides for central review of p16 staining is required for oropharyngeal patients and H&E stained slide block (or punch biopsy of paraffin block) for PD-L1 expression analysis for all patients
  • History/physical examination within 28 days prior to registration
  • Examination by Radiation Oncologist, Medical Oncologist, and Ear, Nose, Throat (ENT) or Head & Neck Surgeon within 28 days prior to registration
  • Fiberoptic exam with laryngopharyngoscopy within 28 days prior to registration
  • Diagnostic quality, cross sectional imaging of the thorax within 28 days prior to registration; 18-F-FDG-PET/CT or conventional CT are acceptable.
  • Diagnostic quality CT or MRI of neck, with contrast, within 28 days prior to registration; a 18-F-FDG-PET/CT of the neck only is acceptable as a substitute if the CT is of diagnostic quality and with IV contrast.
• Age ≥ 18 years
• The trial is open to both genders

Exclusion Criteria:

• Definitive clinical or radiologic evidence of distant (beyond cervical lymph node and neck tissue) metastatic disease.
• Patients with oral cavity cancer are excluded from participation if resection of the primary tumor is considered technically feasible by an oral or head and neck cancers surgical subspecialist.
• Carcinoma of the neck of unknown primary site origin (even if p16-positive).
• Absence of RECIST, v. 1.1 defined measurable disease.
• Gross total excision of both primary and nodal disease; this includes tonsillectomy, local excision of primary site, and nodal excision that removes all clinically and radiographically evident disease. Patients with RECIST, v. 1.1 evaluable remaining cancer either in the neck or primary site remain eligible.
• Simultaneous primary cancers or separate bilateral primary tumor sites.
• Prior invasive malignancy (except non-melanomatous skin cancer) unless disease free for a minimum of 3 years; (for example, carcinoma in situ of the breast, oral cavity, or cervix are all permissible).
• Prior systemic chemotherapy for the study cancer.
• Prior radiotherapy to the region of the study cancer that would result in overlap of radiation therapy fields.
• Patients with active autoimmune disease, with exceptions of vitiligo, type I diabetes mellitus, hypothyroidism and psoriasis.
• Use of systemic corticosteroids (> 10 mg daily prednisone or equivalent) or other immunosuppressive medications within 14 days of study drug administration, with exception of inhaled or topical steroids.
• Known immunosuppressive disease, for example HIV infection or history of bone marrow transplant or chronic lymphocytic leukemia (CLL).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm 1 (Nivolumab + Cisplatin); Patients will receive Nivolumab via IV administration every 14 days for 10 doses starting 14 days prior to IMRT. Cisplatin will be given weekly. IMRT will be given at 5 fractions per week for 7 weeks for a dose of 70 Gy. Adjuvant nivolumab every 28 days for 7 doses will be administered starting 3 months after end of chemoradiation. Adjuvant administration of nivolumab may be discontinued if more than 4 of first 8 patients receive less than 7 doses.	Drug: Nivolumab; Anti-PD-1 targeted immunotherapy; Other Names: Opdivo; Drug: Cisplatin; Anti-cancer alkylating agent; Other Names: Platinol; Radiation: IMRT; High-precision radiotherapy; Other Names: Intensity Modulated Radiation Therapy
Experimental: Arm 2 (Nivolumab + High-dose Cisplatin); Patients will receive Nivolumab via IV administration starting 14 days prior to IMRT, then Day 1 of IMRT and then every 21 days for 6 doses. Cisplatin will be given every 21 days for 3 doses. IMRT will be given at 5 fractions per week for 7 weeks for a dose of 70 Gy. Adjuvant nivolumab every 28 days for 7 doses will be administered starting 3 months after end of chemoradiation. Adjuvant administration of nivolumab may be discontinued if more than 4 of first 8 patients receive less than 7 doses.	Drug: Nivolumab; Anti-PD-1 targeted immunotherapy; Other Names: Opdivo; Drug: Cisplatin; Anti-cancer alkylating agent; Other Names: Platinol; Radiation: IMRT; High-precision radiotherapy; Other Names: Intensity Modulated Radiation Therapy
Experimental: Arm 3 (Nivolumab + Cetuximab); Patients will receive Nivolumab via IV administration every 14 days for 10 doses starting 14 days prior to IMRT. Cetuximab will be given for 7 doses. IMRT will be given at 5 fractions per week for 7 weeks for a dose of 70 Gy. Adjuvant nivolumab every 28 days for 7 doses will be administered starting 3 months after end of chemoradiation. Adjuvant administration of nivolumab may be discontinued if more than 4 of first 8 patients receive less than 7 doses.	Drug: Nivolumab; Anti-PD-1 targeted immunotherapy; Other Names: Opdivo; Radiation: IMRT; High-precision radiotherapy; Other Names: Intensity Modulated Radiation Therapy; Drug: Cetuximab; Epidermal Growth Factor Receptor (EGFR) antagonist; Other Names: Erbitux
Experimental: Arm 4 (Nivolumab + IMRT); Patients will receive Nivolumab via IV administration every 14 days for 10 doses starting 14 days prior to IMRT. IMRT will be given at 5 fractions per week for 7 weeks for a dose of 70 Gy. Adjuvant nivolumab every 28 days for 7 doses will be administered starting 3 months after end of chemoradiation. Adjuvant administration of nivolumab may be discontinued if more than 4 of first 8 patients receive less than 7 doses.	Drug: Nivolumab; Anti-PD-1 targeted immunotherapy; Other Names: Opdivo; Radiation: IMRT; High-precision radiotherapy; Other Names: Intensity Modulated Radiation Therapy

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Dose Limiting Toxicity (DLT)	A nivolumab attributable, dose-limiting toxicity (DLT) will be defined as follows: 1) Any ≥ grade 3 adverse event (CTCAE, v. 4) that is related to nivolumab that does not resolve to grade 1 or less within 28 days; 2) A delay in radiotherapy of > 2 weeks due to toxicity related to nivolumab; 3) Inability to complete radiotherapy due to toxicity related to nivolumab; 4) Inability to receive an adequate dose (≥ 70%) of cisplatin (Arm 1 and 2) or cetuximab (Arm 3) due to toxicity definitely related to nivolumab.	From the first dose of nivolumab to 28 days after the completion of radiation therapy.

Collaborators and Investigators

• Sponsor: RTOG Foundation, Inc.
• Collaborators: Bristol-Myers Squibb
• Investigators: Principal Investigator: Maura Gillison, MD, PhD, RTOG Foundation; Principal Investigator: Robert Ferris, MD, PhD, RTOG Foundation

Publications and helpful links

General Publications

• Gillison ML, Ferris RL, Harris J, Colevas AD, Mell LK, Kong C, Jordan RC, Moore KL, Truong MT, Kirsch C, Chakravarti A, Blakaj DM, Clump DA, Ohr JP, Deeken JF, Gensheimer MF, Saba NF, Dorth JA, Rosenthal DI, Leidner RS, Kimple RJ, Machtay M, Curran WJ Jr, Torres-Saavedra P, Le QT. Safety of Nivolumab Added to Chemoradiation Therapy Platforms for Intermediate and High-Risk Locoregionally Advanced Head and Neck Squamous Cell Carcinoma: Radiation Therapy Oncology Group Foundation 3504. Int J Radiat Oncol Biol Phys. 2022 Oct 11:S0360-3016(22)03434-4. doi: 10.1016/j.ijrobp.2022.10.008. Online ahead of print.

Study record dates

Study Major Dates

• Study Start: June 1, 2016
• Primary Completion (Actual): September 25, 2018
• Study Completion (Actual): February 21, 2022

Study Registration Dates

• First Submitted: May 4, 2016
• First Submitted That Met QC Criteria: May 4, 2016
• First Posted (Estimate): May 6, 2016

Study Record Updates

• Last Update Posted (Actual): November 29, 2022
• Last Update Submitted That Met QC Criteria: November 22, 2022
• Last Verified: November 1, 2022

More Information

Terms related to this study

• Keywords: Nivolumab; HNSCC; Head and Neck Squamous Cell Carcinoma
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Neoplasms, Glandular and Epithelial; Head and Neck Neoplasms; Neoplasms, Squamous Cell; Carcinoma; Carcinoma, Squamous Cell; Squamous Cell Carcinoma of Head and Neck; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Antineoplastic Agents, Immunological; Immune Checkpoint Inhibitors; Nivolumab; Cetuximab
• Other Study ID Numbers: RTOG 3504; RF 3504 (Other Identifier: RTOG Foundation); CA209-410 (Other Identifier: Bristol-Myers Squibb)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No