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

Biomarker Driven Phase 1/1b Trial of Decitabine and Nivolumab in Patients With Recurrent/Metastatic Squamous Cell Carcinoma of the Head and Neck

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.

Head and neck squamous cell carcinoma (HNSCC) is the 6th most common cancer worldwide with approximately 60,000 people diagnosed each year in the United States. People with human papilloma virus (HPV)-positive HNSCC usually have a good prognosis, but HPV-negative people have about a 50% chance that their cancer will come back even after being treated. People who have recurrent or metastatic (R/M) HNSCC who are treated for their cancer tend to have an even worse prognosis, with a median overall survival of about 10 months. An anti-programmed-death-1 (anti-PD1) inhibitor called pembrolizumab was recently approved to treat people with R/M HNSCC. Another type of anti-PD1 inhibitor is a drug called nivolumab, which is also approved to treat people with R/M HNSCC. However, response rates to both pembrolizumab and nivolumab monotherapy are as low as 19% and 13.3% respectively. This shows that there are immune-evasive mechanisms present, meaning that tumor cells can more easily evade being detected and destroyed. Decitabine is a drug that may help anti-PD1 inhibitors like nivolumab better detect and destroy tumor cells. Previous research has shown that using a DNA methyltransferase inhibitor before giving a PD1 inhibitor to treat cancer can help the body's immune system more effectively kill cancer cells. Decitabine is a drug that is a type of DNA methyltransferase inhibitor. The purpose of this study is to evaluate the safety and tolerability of using decitabine in combination with nivolumab to treat HNSCC.

Inclusion Criteria:

• 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).
  • AST (SGOT) ≤ 2.5 X institutional upper limit of normal
  • ALT (SGPT) < 2.5 X institutional upper limit of normal
  • Serum creatinine within normal institutional limits

• Women of child-bearing potential and sexually active men with female partners of child-bearing potential must agree to use a highly effective method of contraception beginning with the first dose of study therapy and for the duration of their participation in the study. This is expected for the entire duration of the study period through 6 months after the last dose. Highly effective methods of contraception include female sterilization (tubal ligation, bilateral oophorectomy, and/or hysterectomy); male sterilization (at least 6 months prior to screening); intrauterine device; and oral, injected, or implanted hormonal contraception AND barrier methods of contraception. Women of child-bearing potential must have documented negative pregnancy test prior to start of investigational treatment regimen. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.

• Participants must have the ability to understand and the willingness to sign a written informed consent document.

Exclusion Criteria:

• 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.