Radiotherapy With Durvalumab Prior to Surgical Resection for HPV Negative Squamous Cell Carcinoma
Radiotherapy With Durvalumab Prior to Surgical Resection for HPV Negative Squamous Cell Carcinoma
This is a multi-center, prospective, single-arm phase I/Ib safety trial. Patients eligible
 for treatment must be diagnosed with non-metastatic, biopsy-proven stage II-IVB oral cavity,
 stage III-IVB larynx and hypopharynx, or stage III-IVB HPV/p16 negative intermediate-high
 risk oropharynx head and neck cancer, and must be eligible and amenable to surgical
 resection.
This study will be enrolled using a 3+3 model. Patients will receive one dose of neoadjuvant
 durvalumab 1500 mg approximately 3-6 weeks prior to standard of care surgery. It will be
 given concurrently with the first dose of radiation (RT). The starting RT dose level will be
 given as 6 Gy for 2 fractions (12 Gy total) every other day over approximately one week to
 sites of gross disease (Table 1) only to minimize exposure to normal tissue. If toxicity
 develops and surgery is delayed by more than 8 weeks (qualifying as a DLT), the radiation
 dose will be dropped per protocol for the next set of patients. If this dose is tolerated,
 the dose will be increased to 6 Gy for 3 fractions (18 Gy total) for the next 3 patients.
 Patients will proceed to surgical resection approximately 3-6 weeks after radiation as
 recommended by the ENT surgeon.
Inclusion Criteria:

 1. Histologically or cytologically confirmed: stage II-IVB oral cavity, stage III-IVB
 larynx, stage III-IVB hypopharynx, or stage III-IVB HPV and/or p16 negative
 intermediate-high risk oropharynx head and neck cancer (AJCC 8th edition)

 2. Measurable disease defined as lesions that can be accurately measured in at least one
 dimension (longest diameter to be recorded) as >10 mm by CT, PET/CT or MRI or >10 mm
 on visual inspection by clinical exam

 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. Patients with p16-positive oropharyngeal SCCA. No verification of p16 status is needed
 for laryngeal cancer or oral cavity cancer.

 21. Patients with sinonasal SCCAs

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

 23. Patients with distant metastatic disease on initial screening imaging

 24. 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