IRX-2 Regimen, Durvalumab, Tremelimumab for Incurable Head and Neck Squamous Cell Carcinoma

Study Population:

Patients with histologically or cytologically confirmed recurrent or metastatic squamous cell
carcinoma of oral cavity, oropharynx, paranasal sinuses, hypopharynx, or larynx that is not
amenable to local therapy with curative intent. Squamous cell carcinoma of unknown primary in
cervical lymph node can be included only if p16 status is positive.

Inclusion Criteria:

- Participants must have histologically or cytologically confirmed squamous cell
carcinoma of oral cavity, oropharynx, paranasal sinuses, hypopharynx, or larynx.
Squamous cell carcinoma of unknown primary in cervical lymph node can be included only
if p16 status is positive.

- Must have recurrent or metastatic HNSCC stage III/IV that is not amenable to local
therapy with curative intent (surgery or radiation therapy with or without
chemotherapy).

- Willing and able to give informed consent and adhere to protocol therapy; written
informed consent and any locally required authorization must be obtained from the
patient prior to performing any protocol-related procedures, including screening
evaluations

- At least 18 years of age

- Up to three prior systemic therapy regimens for recurrent and/or metastatic disease.
Prior exposure to PD-1/PD-L1 inhibitor monotherapy, prior exposure to CTLA-4 inhibitor
monotherapy, or prior exposure to IRX-2 monotherapy is allowed.

- Eastern Cooperative Oncology Group (ECOG) 0-2

- Adequate normal organ and marrow function as outlined in protocol documentation

- Must have measurable disease, defined as at least one lesion that can be accurately
measured in at least one dimension (longest diameter to be recorded) as outlined in
Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.

- Life expectancy of greater than 3 months.

- Female participants of childbearing potential must have a negative serum pregnancy
test within 7 days prior to enrollment.

- Body weight must be > 30 Kg.

Exclusion Criteria:

- Prior exposure to a combination of PD-1/PD-L1 inhibitors and CTLA-4 inhibitors.

- Prior exposure to a combination of IRX-2 regimen, PD-1/PD-L1 inhibitors and CTLA-4
inhibitors.

- Radiation therapy with a curable intent within 30 days of first dose of study
treatment is excluded. However, radiation therapy with a palliative intent is allowed
to treat after 14 days from the last dose of radiation.

- Any medical contraindications or previous therapy that would preclude treatment with
the IRX-2 Regimen, durvalumab, or tremelimumab.

- Any unresolved toxicity NCI Common Terminology Criteria for Adverse Events (CTCAE)
Grade ≥ 2 from previous anticancer therapy with the exception of alopecia, vitiligo,
and the laboratory values defined in the inclusion criteria, and except toxicities the
investigator deems irreversible.

- Grade ≥ 2 neuropathy will be evaluated on a case-by-case basis after consultation with
the study physician

- Patients with irreversible toxicity not reasonably expected to be exacerbated by
treatment with IRX-2, durvalumab or tremelimumab may be included only after
consultation with the study physician.

- Active or prior documented autoimmune or inflammatory disorders (including
inflammatory bowel disease [e.g., colitis or Crohn's disease], diverticulitis [with
the exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome,
or Wegener syndrome [granulomatosis with polyangiitis, Graves' disease, rheumatoid
arthritis, hypophysitis, uveitis, etc]). The following are exceptions to this
criterion: Patients with vitiligo or alopecia; Patients with hypothyroidism (e.g.,
following Hashimoto syndrome) stable on hormone replacement. Any chronic skin
condition that does not require systemic therapy; Patients without active disease in
the last 2 years may be included but only after consultation with the study physician;
Patients with celiac disease controlled by diet alone.

- Current or prior use of immunosuppressive medication within 14 days before the first
dose of durvalumab or tremelimumab. The following are exceptions to this criterion:
Intranasal, inhaled, topical steroid, or local steroid injections (e.g., intra
articular injection); Systemic corticosteroids at physiologic doses not to exceed 10
mg/day of prednisone or its equivalent; Steroids as premedication for hypersensitivity
reactions (e.g., CT scan premedication).

- Major surgical procedure (as defined by the Investigator) within 28 days prior to the
first dose of durvalumab and tremelimumab. Note: Local surgery of isolated lesions for
palliative intent is acceptable.

- History of allogenic organ transplantation.

- Symptomatic cardiopulmonary disease (including congestive heart failure and
hypertension), coronary artery disease, serious arrhythmia or chronic lung disease.
Patients with these conditions who are stable with relatively minor symptoms and who
are appropriate candidates for systemic treatments need not be excluded.

- Myocardial infarction within the last 3 months.

- Known infection with hepatitis B, hepatitis C, or HIV.

- Signs or symptoms of systemic bacterial infection (use of antibiotics to treat
superficial infection or contamination of tumor shall not, by itself, be considered
evidence of infection).

- Clinically significant gastritis or peptic ulcer disease.

- Stroke or other symptoms of cerebral vascular insufficiency within the last 3 months.

- Allergy to ciprofloxacin (or other quinolones).

- Previous diagnosis of invasive cancer from which the individual is not disease-free
AND that has required treatment within the past 3 years, except for superficial skin,
cervical cancer in-situ, or early stage prostate or bladder cancer (i.e. treatment
with curative intent and long term disease-free expectations).

- History of leptomeningeal carcinomatosis

- Known allergy or hypersensitivity to any of the study drugs or any of the study drug
excipients.

- Females who are pregnant or breastfeeding; males or females of reproductive potential
who are not willing to employ effective birth control from screening to 180 days after
the last dose of durvalumab + tremelimumab combination therapy or 90 days after the
last dose of durvalumab monotherapy or 1 year after last dose of cyclophosphamide,
whichever is the longer time period.

- Uncontrolled intercurrent illness, including but not limited to, ongoing or active
infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable
angina pectoris, cardiac arrhythmia, interstitial lung disease, serious chronic
gastrointestinal conditions associated with diarrhea, or psychiatric illness/social
situations that would limit compliance with study requirement, substantially increase
risk of incurring AEs or compromise the ability of the patient to give written
informed consent.

- Mean QT interval corrected for heart rate using Fridericia's formula (QTcF) ≥470 ms
calculated from 3 ECGs (within 15 minutes at 5 minutes apart).

- History of active primary immunodeficiency

- Active infection including tuberculosis (clinical evaluation that includes clinical
history, physical examination and radiographic findings, and tuberculosis (TB) testing
in line with local practice), hepatitis B (known positive HBV surface antigen (HBsAg)
result), hepatitis C, or human immunodeficiency virus (positive HIV 1/2 antibodies).
Patients with a past or resolved HBV infection (defined as the presence of hepatitis B
core antibody [anti-HBc] and absence of HBsAg) are eligible. Patients positive for
hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative
for HCV RNA.

- Receipt of live attenuated vaccine within 30 days prior to the first dose of
investigational produce (IP). Note: Patients, if enrolled, should not receive live
vaccine whilst receiving IP and up to 30 days after the last dose of IP.