Decitabine and Nivolumab in Participants With Recurrent/Metastatic Squamous Cell Carcinoma of the Head and Neck

NCT07216833 | Not Yet Recruiting Phase 1 DMC FDA Drug

• 1 other identifier: CASE7324
• Study Type: interventional
• Target: 15
• Locations: 1 country
• Sites: 1

Brief Summary

This research study is for people who have recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) that has been confirmed by tissue or cell analysis and is considered incurable with local treatments. People who are eligible to receive anti-PD-L1 therapy as a first line treatment and whose primary tumor is located in the oral cavity, oropharynx, hypopharynx, or larynx, may be eligible to participate. The purpose of this study is to evaluate the immunogenicity of decitabine in combination with nivolumab, and to evaluate the safety and tolerability of decitabine in combination with nivolumab and to determine the maximum tolerated dose. Decitabine is a drug that is currently approved by the Food and Drug Administration (FDA) for the treatment of myelodysplastic syndrome (MDS). Decitabine is considered an investigational (experimental) drug in this study because it is not approved by the FDA for the treatment of HNSCC. Decitabine is a chemotherapy drug that works by targeting DNA methylation, a process that can restore normal function to genes that are involved in cell growth and differentiation. This can help reduce the growth of cancer cells. Nivolumab is a drug that is approved by the FDA for the treatment of HNSCC, as well as other types of cancer. Nivolumab is an immunotherapy drug that works by helping the body's immune system recognize and attack cancer cells.

Conditions

Head and Neck Cancer; Head and Neck Neoplasms; Head and Neck Squamous Cell Carcinoma

Keywords

Decitabine and Nivolumab

Outcome Measures

Primary Outcomes (4)

• Pharmacodynamics data on the effects of decitabine, as measured by change in global DNA methylation status

  DNA methylation will be measured pre- and post-decitabine administration and will be compared using Wilcoxon signed-rank test. Methylation analysis requires 500ng of isolated DNA and will be performed on the Illumina Infinium EPIC array.

  Day 1, Day 8

• Immunogenicity of decitabine in combination with nivolumab, as measured by change in immunologic biomarkers

  Changes in immunologic biomarkers will be correlated with changes in DNA methylation, measured pre- and post-decitabine administration. Immunologic biomarkers include PD-L1 expression (IHC), HLA Class I protein expression (IHC), TIL (tumor infiltrating lymphocytes, IHC and multiplex IF).

  Day 1, Day 8

• Safety and tolerability of decitabine in combination with nivolumab, as measured by number of adverse events

  Participants will be evaluated for safety with a follow up visit approximately 28 (+/- 7) days after treatment discontinuation. The National Cancer Institute Common Terminology Criteria for Advanced events (NCI CTCAE) version 5 will be used for adverse event grading. Safety evaluation will be measured by reviewing the adverse event (AE) profile, clinical laboratory safety tests, vital signs, and ECG monitoring.

  Up to 35 days post-treatment discontinuation (treatment may last up to 2 years)

• Maximum tolerated dose (MTD)

  MTD is defined as the dose level at which safety can be confirmed. If 2 or more out of 3 participants experienced a dose limiting toxicity (DLT), the dose will be de-escalated and evaluated for safety. MTD will be evaluated through the treatment period. Participants will receive treatment of up to 35 treatment cycles until disease progression or other adverse event(s).

  Through treatment period, up to 35 cycles (each cycle is 28 days) or up to 2 years

Secondary Outcomes (2)

• Objective response rate (ORR)

  End (week 4) of every 3 cycles, up to 35 total cycles (each cycle is 28 days) or up to 2 years

• Overall survival (OS)

  Until death, up to 2 years

Study Arms (1)

Decitabine + Nivolumab

EXPERIMENTAL

Participants will receive 28-day cycles of decitabine followed by nivolumab for up to 35 cycles (up to 2 years) or until disease progression or other adverse event(s).

Drug: Decitabine; Drug: Nivolumab

Interventions

Decitabine DRUG

Participants will receive dose level 1 (DL1). If 2 of 3 participants experience dose limiting toxicity (DLT) on DL1, then the dose will be de-escalated to DL1-1. If 2 of 3 participants experience DLT on DL1-1, then no further de-escalation will occur and no additional participants will be enrolled. DL1: Intravenous (IV) administration of decitabine 20 mg/m2 from Days 1-5 DL1-1: Intravenous (IV) administration of decitabine 20 mg/m2 from Days 1-4

Decitabine + Nivolumab

Nivolumab DRUG

Nivolumab will be used as a fixed dose in combination with de-escalating dose levels (DL1, DL1-1) of decitabine. Participants will receive 480 mg of nivolumab on Day 8 every 4-week cycle.

Decitabine + Nivolumab

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Participants must have histologically or cytologically confirmed recurrent or metastatic HNSCC considered incurable by local therapies and eligible to receive anti-PD-L1 as first-line treatment (PD-L1 positive with combined positive score (CPS) 1 as evaluated in pre-screening).
• Participants must have primary tumor locations in following; oral cavity, oropharynx, hypopharynx, or larynx (nasopharynx is not allowed).
• No systemic therapy administered in the recurrent or metastatic setting (except for systemic therapy completed within 6 months or \> 6 months if given as part of multimodal treatment for locally advanced disease).
• Participants must not have received prior treatment with immune checkpoint inhibitors.
• For primary site locally recurrent HNSCC, participants can provide archival tumor tissue not older than 3 months from a core or excisional biopsy for PD-L1 pre-screening using the PD-L1 IHC 22C3 pharmDx assay.
• For metastatic cancer patients, archival tumor tissue of distant metastatic lesion should not be older than 3 months from a core biopsy for PD-L1 pre-screening using the PD-L1 IHC 22C3 pharmDx assay.
• For primary site locally recurrent HNSCC, participants must have lesions amenable to obtain pre-treatment tumor biopsies in screening period after eligibility confirmation and before start of treatment and on-treatment tumor biopsies on C1D8 \& C3D21 after start of treatment if lesions are still present at that time. If a recent archival biopsy is obtained within 3 months prior to start of treatment, this biopsy can be used as a pre-treatment biopsy.
• Participants should be ≥ 18 years of age
• Participants should have ECOG Performance status ≤ 2
• Participants must have normal organ and marrow function as defined below:
• Hemoglobin ≥ 9.0 g/dl
• Leukocytes ≥ 3,000/mcL
• Absolute neutrophil count ≥ 1,500/mcL
• Platelet count ≥ 100,000/mcL
• Total bilirubin within normal institutional limits (Gilbert's syndrome related elevated bilirubin is accepted as long as levels have been stable within last 3 months).

You may not qualify if:

• Participants with progressive disease within six months of completion of curatively intended systemic treatment for locoregionally advanced HNSCC.
• Participants with history of severe immune related adverse effects from prior immunotherapy, except hypothyroidism clinically stable on hormone replacement treatment and controlled type 1 diabetes. All other endocrinopathies are excluded even if controlled with medications.
• Participants with Grade ≥ 3 infections within 4 weeks before the first study drug administration. Clinically active infections \> Grade 1 within 2 weeks before the first study drug administration.
• Participants with previous or active myocarditis/myositis in history (independent of cause).
• Participants with pneumonitis, idiopathic pulmonary fibrosis, organizing, interstitial lung disease active or history of autoimmune disease. Autoimmune thyroid disease as well as other non-life-threatening autoimmune diseases such as vitiligo or autoimmune alopecia that don't require systemic immunosuppression are not excluded.
• Participants with known human immunodeficiency virus (HIV) infection, uncontrolled active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection.
• Participants with treatment with systemic immunosuppressant medications within 2 weeks before the first study drug administration. However, low-dose steroid use (prednisone equivalent \<=10 mg daily) for other reasons is allowed.
• Participants receiving any other investigational agents.
• Participants with untreated brain metastases/CNS disease will be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events.
• Participants with uncontrolled intercurrent illness including, but not limited to ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
• Participants with confirmed COVID-19. Participants with confirmed COVID-19 within 7 days prior to starting treatment will be excluded, however upon recovery with confirmation of negative COVID test, participant can be reconsidered for the study.
• Participants with a history of hypersensitivity to active or inactive excipients of decitabine or nivolumab or drugs with a similar chemical structure or class to either agent.
• Participants with any other condition which in the Investigator's opinion would not make the patient a good candidate for the clinical trial.

Sponsors & Collaborators

• Kyunghee Burkitt, DO, PhD: lead

Study Sites (1)

Case Comprehensive Cancer Center, Cleveland Clinic Foundation Taussig Cancer Institute

Cleveland, Ohio, 44195, United States

Location

Related Publications (7)

• Siegel RL, Miller KD, Jemal A. Cancer statistics, 2020. CA Cancer J Clin. 2020 Jan;70(1):7-30. doi: 10.3322/caac.21590. Epub 2020 Jan 8.

  PMID: 31912902 BACKGROUND

• Ang KK, Harris J, Wheeler R, Weber R, Rosenthal DI, Nguyen-Tan PF, Westra WH, Chung CH, Jordan RC, Lu C, Kim H, Axelrod R, Silverman CC, Redmond KP, Gillison ML. Human papillomavirus and survival of patients with oropharyngeal cancer. N Engl J Med. 2010 Jul 1;363(1):24-35. doi: 10.1056/NEJMoa0912217. Epub 2010 Jun 7.

  PMID: 20530316 BACKGROUND

• Vermorken JB, Mesia R, Rivera F, Remenar E, Kawecki A, Rottey S, Erfan J, Zabolotnyy D, Kienzer HR, Cupissol D, Peyrade F, Benasso M, Vynnychenko I, De Raucourt D, Bokemeyer C, Schueler A, Amellal N, Hitt R. Platinum-based chemotherapy plus cetuximab in head and neck cancer. N Engl J Med. 2008 Sep 11;359(11):1116-27. doi: 10.1056/NEJMoa0802656.

  PMID: 18784101 BACKGROUND

• Burtness B, Harrington KJ, Greil R, Soulieres D, Tahara M, de Castro G Jr, Psyrri A, Baste N, Neupane P, Bratland A, Fuereder T, Hughes BGM, Mesia R, Ngamphaiboon N, Rordorf T, Wan Ishak WZ, Hong RL, Gonzalez Mendoza R, Roy A, Zhang Y, Gumuscu B, Cheng JD, Jin F, Rischin D; KEYNOTE-048 Investigators. Pembrolizumab alone or with chemotherapy versus cetuximab with chemotherapy for recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-048): a randomised, open-label, phase 3 study. Lancet. 2019 Nov 23;394(10212):1915-1928. doi: 10.1016/S0140-6736(19)32591-7. Epub 2019 Nov 1.

  PMID: 31679945 BACKGROUND

• Ferris RL, Blumenschein G Jr, Fayette J, Guigay J, Colevas AD, Licitra L, Harrington K, Kasper S, Vokes EE, Even C, Worden F, Saba NF, Iglesias Docampo LC, Haddad R, Rordorf T, Kiyota N, Tahara M, Monga M, Lynch M, Geese WJ, Kopit J, Shaw JW, Gillison ML. Nivolumab for Recurrent Squamous-Cell Carcinoma of the Head and Neck. N Engl J Med. 2016 Nov 10;375(19):1856-1867. doi: 10.1056/NEJMoa1602252. Epub 2016 Oct 8.

  PMID: 27718784 BACKGROUND

• Ghoneim HE, Fan Y, Moustaki A, Abdelsamed HA, Dash P, Dogra P, Carter R, Awad W, Neale G, Thomas PG, Youngblood B. De Novo Epigenetic Programs Inhibit PD-1 Blockade-Mediated T Cell Rejuvenation. Cell. 2017 Jun 29;170(1):142-157.e19. doi: 10.1016/j.cell.2017.06.007. Epub 2017 Jun 22.

  PMID: 28648661 BACKGROUND

• Pauken KE, Sammons MA, Odorizzi PM, Manne S, Godec J, Khan O, Drake AM, Chen Z, Sen DR, Kurachi M, Barnitz RA, Bartman C, Bengsch B, Huang AC, Schenkel JM, Vahedi G, Haining WN, Berger SL, Wherry EJ. Epigenetic stability of exhausted T cells limits durability of reinvigoration by PD-1 blockade. Science. 2016 Dec 2;354(6316):1160-1165. doi: 10.1126/science.aaf2807. Epub 2016 Oct 27.

  PMID: 27789795 BACKGROUND

MeSH Terms

Conditions

Head and Neck Neoplasms; Squamous Cell Carcinoma of Head and Neck

Interventions

Decitabine; Nivolumab

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Carcinoma, Squamous Cell; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type

Intervention Hierarchy (Ancestors)

Azacitidine; Aza Compounds; Organic Chemicals; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Ribonucleosides; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Study Officials

• Kyunghee Burkitt, DO, PhD, MS

  Case Comprehensive Cancer Center, Cleveland Clinic

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Kyunghee Burkitt, DO, PhD, MS

CONTACT

216-445-6013; burkitk@ccf.org

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: October 8, 2025
• First Posted: October 15, 2025
• Study Start: January 1, 2026
• Primary Completion (Estimated): July 31, 2027
• Study Completion (Estimated): December 31, 2027
• Last Updated: October 15, 2025

Record last verified: 2025-10

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR
• Time Frame: Data included in the peer reviewed publication will be publicly available indefinitely. No raw data will be shared.
• Access Criteria: A peer-reviewed publication will be made available according to the publishing journal's specifications. CCF personnel will not share study data apart from that which has been published publicly.

Locations

US (1)