Clinical trial NCT02508246 (phase 1, status: completed)
Conditions: head and neck squamous cell carcinoma
ICD codes: C22.0, C4A.9, C7B.1, C4A.0, C4A.31, C4A.51, C4A.8
Drugs: cisplatin, docetaxel, wee1 inhibitor azd1775
SMILES: [H][C@@]12N(C)C3=CC(OC)=C(C=C3[C@@]11CCN3CC=C[C@](CC)([C@@]13[H])[C@@]([H])(OC(C)=O)[C@]2(O)C(=O)OC)[C@]1(C[C@@]2([H])CN(CC(CC)=C2)CC2=C1NC1=CC=CC=C21)C(=O)OC, [H][N]1([H])[C@@H]2CCCC[C@H]2[N]([H])([H])[Pt]11OC(=O)C(=O)O1, CN1CCN(CC1)C1=CC=C(NC2=NC=C3C(=O)N(CC=C)N(C3=N2)C2=NC(=CC=C2)C(C)(C)O)C=C1
Eligibility criteria:

        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