This phase I trial studies the side effects and the best dose of WEE1 inhibitor MK-1775
(AZD1775) when given together with docetaxel and cisplatin in treating patients with stage
III-IVB squamous cell carcinoma of the head and neck that may or may not be able to be
removed by surgery (borderline resectable). WEE1 inhibitor MK-1775 may block the growth of
tumor cells by blocking some of enzymes that are needed for tumor growth and may also help
docetaxel and cisplatin work better by making tumor cells more sensitive to the drug. Drugs
used in chemotherapy, such as docetaxel and cisplatin, work in different ways to stop the
growth of tumor cells, either by killing the cells, by stopping them from dividing, or by
stopping them from spreading. Giving WEE1 inhibitor MK-1775 with docetaxel and cisplatin
before surgery may kill more tumor cells and shrink the tumor, allowing patients to undergo
surgery to remove it.
16-18, and day - 7 prior to course 1, day 1 for PD assessment. Patients also receive
cisplatin intravenously (IV) 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.
Minimum age: 18 Years.
Maximum age: N/A.
Gender(s): Both.
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. Méndez, 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 ration (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