A Phase 2 Trial of PD-L1 t-haNK, N-803 IL-15 superagonist (Anktiva), and Cetuximab for immunotherapy-treated patients with advanced HNSCC (QUILT-505)

The purpose of this research study is to test the safety and efficacy of the combination
of PD-L1 t-haNK (modified immune cells), N-803 (a manufactured protein that stimulates
the immune system), and cetuximab (a targeted antibody) in treating advanced head and
neck cancer.

The names of the therapies involved in this study are:

- PD-L1 t-haNK cell therapy (a NK cell therapy infusion)

- N-803 (a type of recombinant human superagonist)

- Cetuximab (a type of antibody)

Inclusion Criteria:

- Participants must have an existing histologically confirmed diagnosis of head and
neck squamous cell carcinoma (HNSCC) with evidence of recurrent, metastatic (R/M) or
locoregionally advanced, incurable or unresectable disease from any mucosal subsite
including oral cavity, oropharynx, larynx, hypopharynx, nasal cavity, and the
paranasal sinuses.

- Participants must have at least one RECIST v1.1 measurable lesion, as defined as at
least one lesion that can be accurately measured in at least one dimension (longest
diameter to be recorded for non-nodal lesions and short axis for nodal lesions) ≥ 1
cm with CT scans or MR imaging.

- Must have had at least 1, but no more than 2, prior lines of prior systemic therapy
for R/M HNSCC; one of these lines should have included anti-PD-1/L1 therapy.

- a.Platinum-based therapy as part of definitive/adjuvant or curative-intent
treatment can count as 1 prior line of therapy if the subject progressed within
6 months of receiving therapy.

- b. At least 2 weeks must have elapsed since the end of prior chemotherapy,
biological agents (2 weeks for anti-cancer monoclonal antibody containing
regimens) or any investigational drug product, with adequate recovery of
treatment-related toxicity to NCI CTCAE v5 grade ≤1 (or tolerable grade 2) or
back to baseline (except for alopecia or peripheral neuropathy).

- Be ≥18 years of age on the day of signing informed consent.

- Must provide prior documentation on tumor PD-L1 expression status and HPV status
(for oropharyngeal cancer cases), if available from the medical record.

- Have a performance status of 0 or 1 on the ECOG Performance Scale (see Appendix A).

- Participants must have adequate organ and marrow function as defined below (within
14 days prior to study registration):

- a. ANC ≥1,000/mcL

- b. ALC ≥ 600/mcl

- c. Hemoglobin ≥9 g/dL

- d. Platelets ≥100,000/mcL

- e. Total bilirubin ≤ upper limit of normal (ULN)

- f. AST(SGOT)/ALT(SGPT) ≤2.5x institutional ULN (or ≤1.5x institutional ULN if
concomitant with alkaline phosphatase >2.5x institutional ULN) or ≤5x ULN for
those with liver metastases

- g. Serum creatinine ≤1.5x ULN or creatinine clearance ≥60 mL/min/1.73 m2 for
participants with creatinine levels above 1.5x ULN

- Baseline tumor measurements must be documented from imaging within 28 days prior to
study registration.

- Female subjects of childbearing potential should have a negative urine or serum
pregnancy test within 7 days of study registration. Female subjects should not
become pregnant or nurse a baby during the study and through 120 days after the last
dose of study drugs. Male subjects should use a condom as a contraceptive during the
study and through 120 days after the last dose of study drugs.

Sperm donation is discouraged for up to 6 months after the last dose of study drug.

-Be willing and able to provide written informed consent for the trial.

Exclusion Criteria

- Have been previously treated with 3 or more lines of systemic therapy for R/M HNSCC.

- Have received radiation therapy (RT) within 10 days of starting protocol therapy.

- Solid organ transplant (allograft) recipients.

- Participant has known active central nervous system (CNS) metastases and/or
carcinomatous meningitis. Subjects with previously treated brain metastases may
participate provided they are stable (without evidence of progression by imaging and
off systemic steroids for at least 3 weeks prior to study registration) and have no
evidence of new or enlarging brain metastases.

- A history of significant autoimmune disease as judged by the treating investigator
and on active therapy including prednisone ≥10 mg daily dose equivalent of
corticosteroids.

- Uncontrolled intercurrent illness including but not limited to ongoing or active
infection; evidence of symptomatic congestive heart failure, unstable angina
pectoris, stroke, or ventricular arrhythmia within 6 months of enrollment.

- Has a known additional malignancy that is progressing or requires active treatment.
Exceptions might 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.

- Any known positive test result for hepatitis B virus or hepatitis C virus indicating
presence of virus, e.g., hepatitis B surface antigen (HBsAg, Australia antigen)
positive, or hepatitis C antibody (anti-HCV) positive (except if HCV-RNA negative).
Patients with HIV are eligible if their plasma HIV viral load is undetectable at
baseline on antiretroviral therapy.

- Subjects who are pregnant, or breastfeeding, or expecting to conceive or father
children within the projected duration of the trial, starting with the pre-screening
or screening visit through 120 days after the last dose of trial treatment.
Breastfeeding should be discontinued if the mother is treated on this protocol.
Women who could potentially become pregnant while undergoing treatment on this
protocol must be willing to use 2 methods of contraception.