WEE1 Inhibitor MK-1775, Docetaxel, and Cisplatin Before Surgery in Treating Patients With Borderline Resectable Stage III-IVB Squamous Cell Carcinoma of the Head and Neck

PRIMARY OBJECTIVES:

I. To evaluate the safety profile and determine a maximum tolerated dose (MTD) dose of
AZD1775 (WEE1 inhibitor MK-1775) in combination with weekly cisplatin and docetaxel as a
neoadjuvant approach in locally advanced borderline resectable and/or surgically unresectable
with high nodal burden (e.g., >= N2b disease) and judged appropriate for non-surgical
definitive therapy.

II. To determine the pharmacokinetics (PK) of the combination of single doses of AZD1775 with
fixed weekly dosing of docetaxel and cisplatin given on a three out of four week cycle.

III. To evaluate pharmacodynamic (PD) biomarkers of AZD1775 drug effect in head and neck
squamous cell carcinoma (HNSCC) cancers, and in particular p53 mutated HNSCC patients.

SECONDARY OBJECTIVES;

I. To evaluate the preliminary activity and efficacy of the combination in terms of objective
response rate in patients with borderline resectable and unresectable HNSCC and in
particular, in p53 mutated HNSCC patients.

II. The rate of resectability for borderline unresectable patients will be noted post
neoadjuvant therapy.

III. The rate of unresectable patients who underwent definitive therapy via chemoradiation.

IV. Progression-free survival will be noted as part of the preliminary efficacy determination
of this study.

VI. During all parts of the study, patients will be monitored carefully for the development
of adverse experiences and will be monitored for clinical and/or radiographic evidence of
disease progression according to usual standards of clinical practice.

TERTIARY OBJECTIVES:

I. To gain mechanistic understanding of the link between p53 mutation status and disruption
of immunoglobulin heavy constant gamma 2 (G2M) regulation deregulation.

II. To confirm kinase inhibition in tumor primary cultures as well as in patient
tumor-derived xenografted (PDX) mice extracts, downstream signaling consequences (WEE1 G2
checkpoint kinase [WEE1]; WEE1's target, cyclin-dependent kinase 1 [CDC2]), and mechanisms of
p53 synthetic lethality which sensitize cancer cells to genotoxic therapy.

OUTLINE: This is a dose-escalation study of WEE1 inhibitor MK-1775.

Patients receive WEE1 inhibitor MK-1775 orally (PO) twice daily (BID) on days 2-4, 9-11, and
16-18, and day -7 prior to course 1, day 1 for PD assessment. Patients also receive cisplatin
intravenously (IV) on days 1 (or up to two days after last dose of WEE1 inhibitor MK-1775
lead-in is completed), 8 (or 7 days after first chemotherapy dose), and 15, and docetaxel IV
on days 1, 8, and 15. Patients experiencing progressive disease undergo surgical resection.
Patients not deemed surgically resectable proceed to chemoradiation as clinically indicated.
Patients experiencing stable disease or partial response may receive 2 additional courses of
treatment every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 1 year and
then every 6 months for 4 years.

Inclusion Criteria:

- Provision of informed consent prior to any study specific procedures

- Current diagnosis of histological or cytopathological HNSCC malignancy borderline
resectable stage III up to stage IVb (T1-4, N0-2, M0) or unresectable stage IV with
high nodal status defined as >= N2b (by the American Joint Committee on Cancer [AJCC]
7th Edition Staging) that is amenable or appropriate for curative treatment;
borderline resectability is assessed; NOTE: surgical unresectability will be defined
as the combination of the treating surgeon's judgment of unresectability plus one of
the following objective criteria:

- Encasement of tumor or nodes to the carotid artery or 3/4 encasement of the
carotid artery

- Involvement of prevertebral musculature

- Need for glossectomy or extensive glossal resection where functional outcome is
considered unacceptable to surgeon or patient

- Involvement of the cervical spine

- Severe, unacceptable functional deficit that would result from any proposed
definitive surgical resection

- NOTE: the principal investigator (PI) of the study, Dr. Mendez, is a
surgical ear, nose and throat (ENT) (head and neck) oncologist and all HNSCC
cases will be discussed at the University of Washington/Seattle Cancer Care
Alliance weekly tumor conference where two other ENT surgical oncologists,
and co-investigators in this study, will help assess resectability; as
surgical unresectability may vary from patient to patient based on
individual anatomy, treating physicians may, with the approval of the
surgical team, declare a tumor not meeting the above criteria to be
unresectable; in this case, the reason for unresectability should be
documented in the medical record; medical co-morbidity and poor performance
status may not be used to declare a patient unresectable

- Patients must all have available tumor tissue for biopsy and not have any bleeding
diathesis and/or chronic anticoagulation that cannot be stopped for the biopsy

- Eastern Cooperative Oncology Group (ECOG) 0-2

- Absolute neutrophil count (ANC) > 1500/uL

- Hemoglobin > 9 g/dL

- Platelets > 100,000/uL

- Total bilirubin within 1.5 times the institutional upper limit of normal (ULN)

- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 times ULN

- Creatinine must be < 1.5 ULN or creatinine clearance must be > 50 mL/min (calculated
by Cockcroft and Gault equation)

- International normalized ratio (INR) < 1.5 times ULN

- The expanded cohort will consist of predominantly (> 50%) p53 mutated HNSCC patients
at the MTD

- Willingness to use a medically acceptable method of contraception throughout the study
period and for 4 weeks after the final administration of AZD1775 or longer if needed
as per chemotherapies' product information (all subjects)

- For female subjects with reproductive potential: a negative serum pregnancy test

Exclusion Criteria:

- Non-squamous cell carcinomas of the head and neck region i.e. nasopharyngeal carcinoma
(World Health Organization [WHO] type II and III) and salivary gland carcinomas

- Severe uncontrolled intercurrent illness including, but not limited to, ongoing or
active infection, symptomatic congestive heart failure, unstable angina pectoris,
unstable cardiac arrhythmia, uncontrollable hypertension or any other condition or
circumstance that could interfere with adherence to the study's procedures or
requirements, or otherwise compromise the study's objectives

- Prior treatment with any of the chemotherapy medications (cisplatin or docetaxel) for
HNSCC or with AZD1775

- Prior bone marrow transplant or history of organ transplant requiring the need for any
chronic immunosuppressive medications

- Prior radiation to any of the field required to treat the tumor

- Any distant metastatic disease

- Major psychiatric disorders which would limit compliance

- Neuropathy grade 2 or higher

- History of prolonged QT syndrome or electrocardiogram (ECG) at screening QT interval
corrected for heart rate (QTc) of > 470 ms with Bazett's or Fridericia's formula

- Active infection requiring systemic antibiotic therapy or causing fever (temp > 100.5
degrees Fahrenheit [F] or 38.1 degrees Celsius [C]) within 1 week prior to dosing with
AZD1775

- Pregnant or breast-feeding females

- Second primary malignancy within 3 years (not including in situ carcinoma of the
cervix, non-melanoma skin cancer or low-grade [Gleason score =< 6] localized prostate
cancer) at the time of consideration for study enrollment

- Known prior severe allergic/hypersensitivity to the chemotherapy or any of the
components of the study treatment

- Refractory nausea and vomiting, chronic gastrointestinal diseases, inability to
swallow and retain the formulated oral product or previous significant bowel resection
that would preclude adequate absorption of AZD1775

- Inability or unwillingness to abstain from taking any medications or herbal
supplements that are moderate or strong inducers of cytochrome P450 family 3,
subfamily A, polypeptide 4 (CYP3A4) at least 1 week prior dosing with AZD1775 and
while on study treatment

- Pre-existing hearing impairment (patients who are willing to accept risk of further
impairment will be considered after audiologic testing)

- Patients taking live vaccines including yellow fever vaccinations