Inclusion Criteria:

          -  Participants must have histologically or cytologically confirmed squamous cell
             carcinoma of oral cavity, oropharynx, paranasal sinuses, nasal cavity, 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 that is not amenable to local therapy with
             curative intent (surgery or radiation therapy with or without chemotherapy).
             Participants with persistent disease following radiation therapy administered with or
             without a chemotherapy sensitizer may also be included.

          -  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

          -  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.

          -  Participants must have a mass that is accessible and safe for repeat biopsy Note: if a
             participant is considered to be amendable to biopsy at the time of enrollment but is
             then unable to undergo a post-treatment biopsy this will not be considered an
             ineligible subject, although the missed biopsy will still constitute a protocol
             deviation.

        Exclusion Criteria:

          -  Prior exposure to a combination of IRX-2 regimen, and PD-1/PD-L1 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 and durvalumab

          -  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 the IRX- regiemtn or durvalumab 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. 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).

          -  Concomitant anticoagulation with oral anticoagulants (such as warfarin, direct
             thrombin and Factor Xa inhibitors) or platelet inhibitors (such as clopidogrel) that
             cannot be safely stopped.

          -  Major surgical procedure (as defined by the Investigator) within 28 days prior to the
             first dose of durvalumab. 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 or known untreated or symptomatic brain
             metastases. Treated, asymptomatic brain metastasis can be included.

          -  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 90 days after
             the last dose of durvalumab 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.