Carboplatin, Nab-Paclitaxel, Durvalumab Before Surgery and Adjuvant Therapy in Head and Neck Squamous Cell Carcinoma

STUDY OBJECTIVES

Primary Objective:

Estimate the pathologic complete response rate (pCRR) after induction chemotherapy with
carboplatin, nab-paclitaxel, and durvalumab in previously untreated stage III and IV SCCHN
amenable to surgical resection

Secondary Objectives:

- Report the clinical complete response rate (cCRR) and clinical response rate (cRR)
following induction chemotherapy

- Estimate the percent of patients who have a change in estimated risk level. Prior to
induction, this will be assessed clinically (by imagining and physical exam). Post
induction, this will be assessed by surgical pathology report

- Estimate the overall survival (OS) and progression free survival (PFS) associated with 3
part therapy consisting of induction chemotherapy, surgery and risk-adapted use of
chemoradiation

- Characterize the toxicity profile associated with both induction therapy and total 3
part therapy consisting of induction chemotherapy, surgery and risk-adapted use of
chemoradiation

Translational/Exploratory Objectives:

- Correlative studies will evaluate cellular correlates of response and changes in the
tumor microenvironment across therapy

- Explore correlation between measures of clinical response to induction chemotherapy and
long term outcomes (PFS and OS) and compare them to pathologic measures of response
(pCRR)

PROCEDURES This is a single-arm, nonrandomized phase II trial consisting of 3 parts. After
informed consent and screening, pre-induction, risk levels will be assessed clinically, by a
combination of physical exam and imaging.

Part 1: All patients will then receive 6 weeks of induction chemotherapy in Part 1 comprised
of weekly cycles of carboplatin and nab-paclitaxel for 6 cycles in combination with
durvalumab administered once every two weeks for 5 cycles (Day 1 of the weeks 1, 3, 5, 7, and
9).

Part 2: Within a 1-4 the week window post induction, tumor imaging will be followed by
surgical resection.

Part 3: After surgery, patients will be stratified into one of 3 risk categories based on
their disease pathology, assigned a treatment group based on their risk. Low risk patients
with receive durvalumab once every two weeks for 3 cycles, while medium risk or high risks
groups will receive concurrent chemoradiation therapy followed by durvalumab once every two
weeks for 3 cycles.

Follow up After completion of study therapy (which will vary by study arm) patients will be
evaluated every three months during follow up for progression over a period of 18 months.
Each follow up visit will include physical examination, CT or MRI imaging of the neck. Chest
imaging will be obtained (or not) as indicated by standard of care. After the first 18
months, patients will be followed-up per standard of care, with documentation in the case
report form (CRF) limited to progression and survival noted at their standard of care visits.
If a patient should move away or otherwise be lost to in-person follow up but is amenable to
telephone follow up, this will be permitted during the standard of care follow up period.

Inclusion Criteria:

- Previously untreated, histologically proven, surgically resectable primary squamous
cell carinoma of the head and neck, stage III or IV (HPV positive or negative
non-metastatic disease). SCCHN of unknown primary is excluded. SCCHN of the oral
cavity is allowed*. Unambiguously squamous Epstein-Barr virus (EBV)-negative
nasopharynx cancer will be excluded nor will unambiguously squamous cancers of the
skull base that are clearly surgically resectable and clearly squamous. Squamous skin
cancer occurring in the head/neck region will not be eligible nor will EBV+positive
nasopharynx cancer. (*Note: Induction chemotherapy is not considered standard therapy
for SCCHN of the oral cavity and participation on this trial will lead to a delay in
time to definitive, potentially curative therapy i.e., surgery).

- Eastern Cooperative Oncology Group (ECOG) performance status of 0-1

- Measurable disease as per RECIST 1.1

- Age greater than or equal to 18 at time of study entry

- Adequate bone marrow function as demonstrated by:

- Absolute neutrophil count (ANC) ≥ 1,500 cells/mm3

- Hgb > 10 g/dL (use of transfusion to reach this threshold prior to study
initiation is acceptable)

- Platelet count ≥ 100,000/mm3

- Adequate hepatic and renal function as demonstrated by:

- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x upper
limit of normal (ULN);

- Total serum bilirubin ≤1.5 x ULN

- Creatinine clearance (CrCL) > 40 mL/min as measured via Cockcroft-Gault

- 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))/(72 x serum
creatinine (mg/dL)) x 0.85

- Negative serum β human chorionic gonadotropin (β-hCG) pregnancy test within 72 hours
of day 1 of induction chemotherapy in women of child-bearing potential.

- All males and females of childbearing potential must agree to use adequate
contraception during the study. Adequate contraception is defined as any medically
recommended method (or combination of methods) as per standard of care. Females of
non-childbearing potential are those who are postmenopausal greater than 1 year or who
have had a bilateral tubal ligation or hysterectomy or bilateral oophorectomy. See
section 4.13 for list of acceptable methods of contraception.

- Signed an institutional review board (IRB)-approved informed consent and HIPAA
authorization.

- Subject 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.

- Subjects must agree to allow use of any pre-treatment tissue remaining after
definitive diagnosis is made (ie, archival and or fresh tissue) for research purposes.
In addition, subjects must consent to allow use of their residual post-operative
tissue for research purposes.

Exclusion Criteria:

- Involvement in the planning and/or conduct of the study (applies to staff at the study
site) or previous enrollment in the present study.

- Any metastatic disease.

- Known history of previous clinical diagnosis of tuberculosis.

- History and/or confirmed pneumonitis.

- Low-risk HPV+ disease of the oropharynx, defined as meeting all of the following
criteria:

- Patients with known HPV+ by fluorescence in situ hybridization (FISH) and/or p16

- Smoking history ≤ 10 pack years

- Stage T1-2N0-2b, T3N0

- Not considered eligible for any of the chemotherapy agents included in the induction
regimen.

- Current active hepatic or biliary disease (with exception of patients with Gilbert's
syndrome, asymptomatic gallstones, or stable chronic liver disease per investigator
assessment).

- Major surgery within 28 days prior to day 1 of study treatment from which the patient
has not completely recovered.

- Receiving any investigational agent currently or within 28 days or 5 half-lives of Day
1 of treatment on this study, whichever is shorter.

- Active, serious infection, medical, or psychiatric condition that would represent an
inappropriate risk to the patient or would likely compromise achievement of the
primary study objective, including unstable angina, serious uncontrolled cardiac
arrhythmia, uncontrolled infection, or myocardial infarction ≤ 6 months prior to study
entry.

- Active or prior documented autoimmune or inflammatory disorders (including
inflammatory bowel disease [eg, colitis, Crohn's disease], diverticulitis with the
exception of a prior episode that has resolved or diverticulosis, celiac disease,
irritable bowel disease, or other serious gastrointestinal chronic conditions
associated with diarrhea; systemic lupus erythematosus; Wegener's syndrome
[granulomatosis with polyangiitis]; myasthenia gravis;; rheumatoid arthritis;
hypophysitis, uveitis; etc) within the past 2 years prior to the start of treatment.
[Note: Subjects with vitiligo, Grave's disease, or psoriasis not requiring systemic
treatment (within the past 2 years) are not excluded]

- Known mean QT interval corrected for heart rate (QTc) ≥470 ms calculated from 3
electrocardiograms (ECGs) using Frediricia's Correction. (Note that ECG is not
required for study entry and is not part of study procedures).

- Other prior or concomitant malignancies with the exception of:

- Non-melanoma skin cancer

- In-situ malignancy

- Low-risk prostate cancer after curative therapy

- Other cancer for which the patient has been disease free for ≥ 5 years before the
first dose of study drug and of low potential risk for recurrence.

- Any concurrent chemotherapy, investigational product, biologic or hormonal therapy for
cancer treatment. Concurrent use of hormonal therapy for non-cancer-related conditions
(e.g. hormone replacement therapy) is acceptable.

- Current or prior use of immunosuppressive medication within 14 days prior to the first
dose of durvalumab. The following are exceptions to this criterion: intranasal,
inhaled, topical or local steroid injections (eg. intra-articular injection); steroids
as premedication for hypersensitivity reactions; systemic corticosteroid at
physiologic doses not to exceed 10mg/day of prednisone or equivalent.[Note: If
systemic corticosteroids are part of the treatment regimen for the indication under
study, the systemic corticosteroid is permitted].

- Known human immunodeficiency virus (HIV), hepatitis C virus (HCV) or evidence of
active hepatitis B virus (HBV).

- History of hypersensitivity to durvalumab or any excipient.

- Receipt of live attenuated vaccination within 30 days prior the first dose of
durvalumab [Note: If a vaccine is part of the treatment regimen for the indication
under study, the vaccine is permitted].

- Female subjects who are pregnant, breast-feeding or female patients of reproductive
potential who are not employing an effective method of birth control from starting
dose of study medications (Cycle 1 Day 1), including dosing interruptions through 90
days after receipt of the last dose of durvalumab. Refrain from egg cell donation
while taking durvalumab and for at least 90 days after the last dose of durvalumab.

- Male subjects who are not employing an effective method of birth control from starting
dose of study medications (Cycle 1 Day 1), including dosing interruptions through 6
months after receipt of study treatment. Male subjects should agree to refrain from
sperm donation while taking study treatment and for at least 6 months after the last
dose of nab-paclitaxel and at least 90 days after the last dose of durvalumab. Should
a female partner of a male patient become pregnant or suspect she is pregnant while
participating in the study, he should inform his treating physician and the female
partner should call her physician immediately.

- Any previous treatment with a programmed cell death protein 1 (PD-1) or programmed
death-ligand 1 (PD-L1) inhibitor, including durvalumab.

- History of primary immunodeficiency.

- History of organ transplant.

- Any condition that, in the opinion of the investigator, would interfere with
evaluation of study treatment or interpretation of patient safety or study results
(eg, uncontrolled intercurrent illness including, but not limited to, ongoing or
active infection, symptomatic congestive heart failure, uncontrolled hypertension,
unstable angina pectoris, cardiac arrhythmia, active peptic ulcer disease or
gastritis, active bleeding diatheses or psychiatric illness/social situations that
would limit compliance with study requirements or compromise the ability of the
subject to give written informed consent).

- Patients with known contraindications to radiotherapy including inherited syndromes
associated with hypersensitivity to ionizing radiation (e.g., Ataxia Telangiectasia,
Nijmegen Breakage Syndrome).