Anti-PD-L1/TGF-beta Trap (M7824) Alone and in Combination With TriAd Vaccine and N-803 for Resectable Head and Neck Squamous Cell Carcinoma Not Associated With Human Papillomavirus Infection
Anti-PD-L1/TGF-beta Trap (M7824) Alone and in Combination With TriAd Vaccine and N-803 for Resectable Head and Neck Squamous Cell Carcinoma Not Associated With Human Papillomavirus Infection
Background:

 Some people who get head and neck cancer will need surgery to treat their cancer. Research
 suggests that immunotherapy drugs may help fight head and neck cancer if given before
 surgery. In most cases, there is enough time between cancer diagnosis and surgery to test
 immunotherapy drugs. In this study, researchers are testing the safety and anti-cancer
 abilities of 3 drugs given before surgery for head and neck cancer.

 Objective:

 To learn if giving M7824 alone, or with the TriAd vaccine, or with TriAd vaccine plus N-803
 can shrink previously untreated head and neck tumors before surgery or stop the tumors from
 coming back after all treatment.

 Eligibility:

 People age 18 and older who have a head and neck cancer that has not been treated before, and
 the tumor must be removed with surgery.

 Design:

 Participants will be screened in a separate protocol.

 Participants will have the following tests:

 -  medical history and physical exams

 -  computed tomography or magnetic resonance imaging scans

 -  tumor, mucosa, and skin biopsies

 -  electrocardiograms to monitor heart activity

 -  endoscopies (a tube is inserted through the nose to see the upper airway)

 -  blood and urine tests.

 All participants will get M7824 through an intravenous infusion. For this, a small plastic
 tube is put into an arm vein. Some may also get the TriAd vaccine. It is injected under the
 skin on the arms or legs. Some may also get N-803. It is injected under the skin on the
 stomach.

 Participants will have clinic visits while they are getting treatment and after treatment
 ends.

 After treatment ends, participants will have their scheduled surgery. There will be two
 follow up visits at the NIH after your surgery. They will be contacted by phone or email
 every 2 weeks for 3 months. Then they will be contacted every 3 months for 2 years.

 ...
Background:

 -  Approximately 50% of patients with advanced p16-negative head and neck squamous cell
 carcinoma (HNSCC) will develop locoregional or distant relapse within two years of
 completing definitive standard-of-care treatment.

 -  Two ongoing clinical trials investigating neoadjuvant PD-1 blockade before surgical
 resection of HNSCC suggest that immunotherapy can both cytoreduce existing disease
 before surgery and reduce the risk of locoregional or distant disease relapse after
 surgery.

 -  Preliminary data from these studies suggest neoadjuvant treatments can be administered
 without delaying planned surgical intervention.

 -  Experiments conducted by the Laboratory of Tumor Immunology and Biology (LTIB)
 demonstrated synergistic activity with tumor-targeted adenoviral vaccine plus M7824 plus
 N-803 in humanized mice bearing human carcinomas and in vitro studies.

 -  M7824 is a bifunctional fusion protein consisting of an anti-programmed death ligand
 1(PD-L1) antibody and the extracellular domain of transforming growth factor beta
 (TGF-beta) receptor type 2, a TGF-beta trap.

 -  Adenoviral vaccines targeting known shared tumor antigens can generate antigen-specific
 T cells.

 -  N-803 is an IL-15/IL-15R alpha super agonist complex that can enhance both NK cell and T
 cell anti-tumor activity via expansion and activation.

 -  Activity observed with neoadjuvant anti-PD-1 agents alone provides rationale for testing
 of M7824 alone and in combination with other immune oncologic agents that have been
 shown to work in concert with M7824 in preclinical studies.

 -  Analysis of pre- and post-treatment tissues from HNSCC patients presents a unique
 opportunity to interrogate the effects the above treatment(s) on tumor.

 -  A dose escalation of N-803 in combination with a flat dose of M7824 was conducted at the
 National Cancer Institute. Thirteen patients have been treated with the combination. No
 DLTs were observed.

 Objectives:

 -Determine the rate of pathologic complete response (pCR) or clinical-to-pathological
 downstaging in patients with previously untreated intermediate/high risk, non-HPV associated,
 squamous cell carcinoma of the head and neck (T1-T4, N0-N3, M0 stage II, III or IV) who
 receive any of the three proposed treatments: M7824 alone, M7824 plus TriAd vaccine, or M7824
 plus TriAd vaccine plus N803 prior to definite surgery.

 Eligibility:

 -  Patients must have histologically or cytologically confirmed, previously untreated
 intermediate/high risk, p16-negative (if oropharyngeal), squamous cell carcinoma of the
 head and neck (T1-T4, N0-N3, M0 stage II, III or IV)

 -  Men or Women; Age greater than or equal to 18 years

 -  ECOG performance status less than or equal to 1

 Design:

 -  This protocol is a sequential window of opportunity trial of Anti-PD-L1/TGF-beta trap
 (M7824) alone and in combination with TriAd Vaccine and N-803 for non-HPV associated
 resectable Head and Neck Squamous Cell Carcinoma (HNSCC).

 -  Patients will be referred to the NIH for this immunotherapy treatment from surrounding
 academic medical centers and private physicians.

 -  Upon referral to the NIH, patients will be rapidly screened, and enrolled on the
 protocol, if appropriate.

 -  This trial will enroll patients in three arms sequentially to permit safety evaluation
 before adding the next agent.

 -  In the first arm of 12 patients, M7824 (1200 mg) will be administered intravenously on
 day 1 and 15.

 -  If no safety concerns, accrual will proceed to the 2nd arm, and 12 patients will enroll
 with M7824 (1200mg; intravenous) treatment on day 1 and 15 and TriAd vaccine (5 x 10
 (11) VP; subcutaneous) treatment on day 1 only.

 -  If no safety concerns, accrual will proceed to the 3rd arm, and 12 patients will enroll
 with M7824 ((1200mg; intravenous) treatment on day 1 and 15 plus TriAd vaccine (5 x
 10(11) VP; subcutaneous injection) and N-803 (15mcg/kg, subcutaneously) treatment on day
 1.

 -  After obtaining pre-treatment biopsies, imaging and blood collection, patients will
 receive the neoadjuvant immunotherapy at the NIH Clinical Center.

 -  Patients will then be sent back to their referring providers for their definitive
 standard of care surgery and adjuvant therapy as indicated based upon pathologic
 analysis of the surgical specimen. NCI investigators will have no role in directing the
 ensuing standard of care surgeries performed at outside institutions.

 -  For consistency in pathologic analysis of resection specimens, tissue blocks and/or
 slides will be obtained from outside institutions and be reviewed by the NCI Laboratory
 of Pathology.

 -  It is expected that up to 20 patients may enroll in one year. Thus, with 3 arms of 12
 patients apiece, up to 36 evaluable patients may enroll. Accrual is expected to be
 completed within 2 years.
-  INCLUSION CRITERIA:

 -  Patients must have histologically or cytologically confirmed, previously untreated
 intermediate/high risk, p16-negative (if oropharyngeal primary tumor), squamous cell
 carcinoma of the head and neck (T1-T4, N0-N3, M0 stage II, III or IV).

 -  Male or female; Age greater than or equal to 18 years.

 -  ECOG performance status less than or equal to 1.

 -  Prothombin time (PT) and partial thromboplastin time (PTT) within normal institutional
 limits. Patients with prolonged PTT determined to be due to lupus anticoagulant will
 not be excluded.

 -  Patients must have adequate organ and marrow function as defined below:

 -  Absolute neutrophil count greater than or equal to 1000/mcL

 -  Platelets greater than or equal to 100,000/mcL

 -  Hemoglobin greater than or equal to 10.0 g/dL

 -  Total bilirubin within normal institutiona l limits; in patients with Gilbert s,
 less than or equal to 3.0 mg/dL

 -  AST (AGOT)/ALT (AGPT) less than or equal to 3X upper limit of normal.

 -  Creatinine within 1.5X upper limit of normal institutional limits

 -  The effects of M7824, TriAd vaccines, and N-803 on the developing human fetus are
 unknown. For this reason, men and women of child bearing capacity must agree to use
 highly-effective contraception (hormonal or barrier method of birth control;
 abstinence) prior to study entry, during the study and maintain such contraception
 until 2 months following the last dose of any study agent. Should a woman become
 pregnant or suspect she is pregnant while she or her partner is participating in this
 study, she should inform her treating physician immediately.

 -  Ability of subject to understand and the willingness to sign a written informed
 consent document

 -  Patients with successfully treated hepatitis C virus (HCV) are eligible if HCV viral
 load is undetectable.

 EXCLUSION CRITERIA:

 -  Patients who are immunocompromised as follows:

 -  Human immunodeficiency virus (HIV) positive patients not on or not compliant with
 appropriate anti-retroviral therapy, patients with newly diagnosed (i.e. < 6
 months) HIV, patients with an HIV viral load exceeding 400 copies/mL, HIV+
 patients with a CD4 count < 150 cells/ L, and HIV+ patients on antiretroviral
 therapy < 1 month are excluded. HIV-positive patients will also be excluded if
 the PI determines that there is a clinically significant drug-drug interaction.

 -  Chronic administration (defined as daily or every other day for continued use >14
 days) of systemic corticosteroids or other immune suppressive drugs, within 14
 days before treatment on study. Physiologic daily dosing of steroids is allowed.
 Nasal, or inhaled steroid, topical steroid creams and eye drops for small body
 areas are allowed.

 -  Patients who have undergone allogeneic peripheral stem cell transplantation, or
 solid organ transplantation requiring immunosuppression

 -  Pregnant women are excluded from this study because M7824 is an agent with the
 potential for teratogenic or abortifacient effects. Because there is an unknown but
 potential risk for adverse events in nursing infants secondary to treatment of the
 mother with M7824 breastfeeding should be discontinued if the mother is treated with
 M7824. These potential risks may also apply to other agents used in this study.

 -  Patients with active systemic autoimmune disease, except patients with type 1 diabetes
 mellitus, vitiligo, psoriasis, hypo- or hyperthyroid disease not requiring current
 immunosuppression, or with other endocrine disorders on replacement hormones, are not
 excluded if the condition is well controlled.

 -  History of allergic reactions attributed to compounds of similar chemical or biologic
 composition to study agents to be used in the cohort the subject will be enrolled
 into.

 -  Known allergy to eggs, egg products, aminoglycoside antibiotics (for example,
 gentamicin or tobramycin). Patients enrolling on the M7824 only arm will be exempt
 from this exclusion.

 -  Patients with a history of bleeding diathesis or recent clinically significant
 bleeding events considered by the Investigator as high risk for investigational drug
 treatment are excluded.

 -  Any condition which, in the opinion of the investigator, would prevent full
 participation in this trial (including the long-term follow-up), or would interfere
 with the evaluation of the trial endpoints.

 -  Patients with prior live vaccine, investigational drug, chemotherapy, immunotherapy or
 any prior radiotherapy (except for palliative bone directed therapy) within the past
 28 days prior to enrollment.

 -  Uncontrolled intercurrent acute or chronic illness including, but not limited to,
 ongoing or active infection, symptomatic congestive heart failure (>New York Heart
 Association Class I), hepatic disease, unstable angina pectoris, serious cardiac
 arrhythmia, requiring medication, uncontrolled hypertension (SBP>170/ DBP>105) or
 psychiatric illness/social situations within 12 months that would limit compliance
 with study requirements.

 -  Patients who have undergone major surgery within 4 weeks prior to enrollment. A biopsy
 will not preclude a patient from starting study.

 -  Patients with a history of hepatitis B (HBV) are excluded due to potential risk for
 viral reactivation and resulting liver injury in persons with latent HBV.

 -  Patients with treated or active brain metastases are not eligible because we are
 enrolling non-metastatic head and neck cancer patients in this trial. Standard of care
 treatment is different for head and neck cancer patients with and without metastatic
 disease.