Radiotherapy With Durvalumab Prior to Surgical Resection for HPV Negative Squamous Cell Carcinoma

Head and neck cancer is a disease that is known to have poor survival outcomes and response
to combination chemoradiation. This study will feature a dose escalation of Gy fractions and
dose expansion phases of durvalumab. It will also feature surgical resection 3-6 weeks after
radiation as recommended by the ENT surgeon.

Inclusion Criteria:

1. Histologically or cytologically confirmed stage III or IV HNSCC oral cavity,
hypopharynx, oropharynx, or larynx

2. Measurable disease defined as lesions that can be accurately measured in at least one
dimension (longest diameter to be recorded) as >10 mm with CT scan or >10 mm with
calipers by clinical exam by RECIST 1.1

3. Patients who are deemed resectable by ENT surgeon without pre-existing medical
conditions that could inhibit surgery following neoadjuvant therapy, and do not refuse
surgery

4. Written informed consent and HIPAA authorization obtained from the patient prior to
performing any protocol-related procedures, including screening evaluations

5. Age > 18 years at time of study entry

6. ECOG performance status ≤ 1

7. Life expectancy ≥ 24 weeks

8. Body weight >30kg

9. Adequate normal organ and marrow function as defined below:

- Hemoglobin ≥9.0 g/dL

- Absolute neutrophil count (ANC) 1.0 x 109/L (> 1000 per mm3)

- Platelet count ≥75 x 109/L (>75,000 per mm3)

- Serum bilirubin ≤1.5 x institutional upper limit of normal (ULN). This will not
apply to patients with confirmed Gilbert's syndrome (persistent or recurrent
hyperbilirubinemia that is predominantly unconjugated in the absence of hemolysis
or hepatic pathology), who will be allowed only in consultation with their
physician.

- AST (SGOT)/ALT (SGPT) ≤2.5 x institutional upper limit of normal

- Measured creatinine clearance (CL) >40 mL/min or Calculated creatinine CL>40
mL/min by the Cockcroft-Gault formula (Cockcroft and Gault 1976) or by 24-hour
urine collection for determination of creatinine clearance:

Males:

Creatinine CL (mL/min) = Weight (kg) x (140 - Age) 72 x serum creatinine (mg/dL)

Females:

Creatinine CL (mL/min) = Weight (kg) x (140 - Age) x 0.85

72 x serum creatinine (mg/dL)

10. Evidence of post-menopausal status or negative urinary or serum pregnancy test for
female pre-menopausal patients. Women will be considered post-menopausal if they have been
amenorrheic for 12 months without an alternative medical cause. The following age-specific
requirements apply:

- Women <50 years of age would be considered post-menopausal if they have been
amenorrheic for 12 months or more following cessation of exogenous hormonal treatments
and if they have luteinizing hormone and follicle-stimulating hormone levels in the
post-menopausal range for the institution or underwent surgical sterilization
(bilateral oophorectomy or hysterectomy)

- Women ≥50 years of age would be considered post-menopausal if they have been
amenorrheic for 12 months or more following cessation of all exogenous hormonal
treatments, had radiation-induced menopause with last menses >1 year ago, had
chemotherapy-induced menopause with last menses >1 year ago, or underwent surgical
sterilization (bilateral oophorectomy, bilateral salpingectomy or hysterectomy).

11. Patient is willing and able to comply with the protocol for the duration of the
study including undergoing treatment and scheduled visits and examinations including
follow up.

Exclusion Criteria:

1. Participation in another clinical study with an investigational product during the
last 3 months

2. Patients with active ILD / pneumonitis or with a history of ILD/ pneumonitis requiring
steroids

3. Concurrent enrollment in another clinical study, unless it is an observational
(non-interventional) clinical study or during the follow-up period of an
interventional study

4. Any previous treatment with a PD1 or PD-L1 inhibitor, including durvalumab,
anti-PD-L2, anti-CD137, or anti-cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4)
antibody (including ipilimumab or any other antibody or drug specifically targeting
T-cell co-stimulation or checkpoint pathways)

5. Receipt of the last dose of anticancer therapy (chemotherapy, immunotherapy, endocrine
therapy, targeted therapy, biologic therapy, tumor embolization, monoclonal
antibodies, other investigational agent) 30 days prior to the first dose of study drug
for patients who have received prior TKIs [e.g., erlotinib, gefitinib and crizotinib]
and within 6 weeks for nitrosourea or mitomycin C. (If sufficient wash-out time has
not occurred due to the schedule or PK properties of an agent, a longer wash-out
period may be required.)

6. Patients with QTc interval > 470 msec during screening

7. Current or prior use of immunosuppressive medication within 14 days before the first
dose of durvalumab, with the exceptions of intranasal and inhaled corticosteroids or
systemic corticosteroids at physiological doses, which are not to exceed 10 mg/day of
prednisone, or an equivalent corticosteroid. The following are exceptions to this
criterion:

- Intranasal, inhaled, topical steroids, 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)

8. Any concurrent chemotherapy, IP, biologic, or hormonal therapy that is not part of
standard NCCN indicated HNSCC adjuvant concurrent CRT. Concurrent use of hormonal
therapy for non-cancer-related conditions (e.g., hormone replacement therapy) is
acceptable.

9. History of allogenic organ or bone marrow transplantation

10. 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 5 years may be included but only
after consultation with the study physician

- Patients with celiac disease controlled by diet alone

11. 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

12. History of another primary malignancy except for:

- Malignancy treated with curative intent and with no known active disease ≥3 years
before the first dose of IP and of low potential risk for recurrence

- Adequately treated non-melanoma skin cancer or lentigo maligna without evidence
of disease

- Adequately treated carcinoma in situ without evidence of disease

13. History of leptomeningeal carcinomatosis

14. History of active primary immunodeficiency

15. Active infection including tuberculosis (clinical evaluation that includes clinical
history, physical examination and radiographic findings, and 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.

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

17. Female patients who are pregnant or breastfeeding or male or female patients of
reproductive potential who are not willing to employ highly effective birth control
from screening to 90 days after the last dose of durvalumab monotherapy. Patient must
have a negative serum or urine pregnancy test within 72 hours of study entry.

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

19. Prior randomisation or treatment in a previous durvalumab clinical study

20. Prior treatment for head and neck cancer. Note: patients with synchronous head and
neck cancer primaries are an exception to this criterion and may qualify for the
study.

21. Patients with HPV-positive or p16-positive oropharyngeal SCCA

22. Patients with sinonasal SCCAs

23. Patients with metastatic SCCA neck disease with an unknown primary tumor site

24. Patients with distant metastatic disease on initial screening imaging

25. Judgment by the investigator that the patient is unsuitable to participate in the
study and the patient is unlikely to comply with study procedures, restrictions and
requirements