Clinical Trials /

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

NCT02508246

Description:

This phase I trial studies the side effects and the best dose of WEE1 inhibitor MK-1775 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.

Related Conditions:
  • Head and Neck Squamous Cell Carcinoma
Recruiting Status:

Completed

Phase:

Phase 1

Trial Eligibility

Document

AZD1775, <span class="go-doc-concept go-doc-intervention">Docetaxel</span>, and <span class="go-doc-concept go-doc-intervention">Cisplatin</span> Before Surgery in Treating Patients With Borderline Resectable Stage III-IVB Squamous Cell Carcinoma of the Head and Neck

Title

  • Brief Title: AZD1775, Docetaxel, and Cisplatin Before Surgery in Treating Patients With Borderline Resectable Stage III-IVB Squamous Cell Carcinoma of the Head and Neck
  • Official Title: A Phase I Clinical Trial of AZD1775 in Combination With Neoadjuvant Weekly Docetaxel and Cisplatin Prior to Surgery in Squamous Cell Carcinoma of the Head and Neck (HNSCC)
  • Clinical Trial IDs

    NCT ID: NCT02508246

    ORG ID: 9168

    NCI ID: NCI-2015-01064

    Trial Conditions

    Stage III Laryngeal Squamous Cell Carcinoma

    Stage III Oral Cavity Squamous Cell Carcinoma

    Stage III Oropharyngeal Squamous Cell Carcinoma

    Stage IVA Laryngeal Squamous Cell Carcinoma

    Stage IVA Oral Cavity Squamous Cell Carcinoma

    Stage IVA Oropharyngeal Squamous Cell Carcinoma

    Stage IVB Laryngeal Squamous Cell Carcinoma

    Stage IVB Oral Cavity Squamous Cell Carcinoma

    Stage IVB Oropharyngeal Squamous Cell Carcinoma

    Trial Interventions

    Drug Synonyms Arms
    Cisplatin Abiplatin, Blastolem, Briplatin, CDDP, Cis-diammine-dichloroplatinum, Cis-diamminedichloridoplatinum, Cis-diamminedichloro Platinum (II), Cis-diamminedichloroplatinum, Cis-dichloroammine Platinum (II), Cis-platinous Diamine Dichloride, Cis-platinum, Cis-platinum II, Cis-platinum II Diamine Dichloride, Cismaplat, Cisplatina, Cisplatinum, Cisplatyl, Citoplatino, Citosin, Cysplatyna, DDP, Lederplatin, Metaplatin, Neoplatin, Peyrone's Chloride, Peyrone's Salt, Placis, Plastistil, Platamine, Platiblastin, Platiblastin-S, Platinex, Platinol, Platinol- AQ, Platinol-AQ, Platinol-AQ VHA Plus, Platinoxan, Platinum, Platinum Diamminodichloride, Platiran, Platistin, Platosin Treatment (WEE1 inhibitor MK-1, cisplatin, docetaxel, surgery)
    Docetaxel RP56976, Taxotere, Taxotere Injection Concentrate Treatment (WEE1 inhibitor MK-1, cisplatin, docetaxel, surgery)
    WEE1 Inhibitor MK-1775 MK-1775 Treatment (WEE1 inhibitor MK-1, cisplatin, docetaxel, surgery)

    Trial Purpose

    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.

    Detailed Description

    PRIMARY OBJECTIVES:

    I. To evaluate the safety profile and determine a maximum tolerated dose (MTD) dose of
    AZD1775 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.

    V. 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) 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.

    Trial Arms

    Name Type Description Interventions
    Treatment (WEE1 inhibitor MK-1, cisplatin, docetaxel, surgery) Experimental Patients receive WEE1 inhibitor MK-1775 PO 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 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. Cisplatin, Docetaxel, WEE1 Inhibitor MK-1775

    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. Mndez, 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

    Minimum Eligible Age: 18 Years

    Maximum Eligible Age: N/A

    Eligible Gender: Both

    Primary Outcome Measures

    Incidence of adverse events graded according to the NCI CTCAE version 4.03

    MTD of AZD1775, based on the incidence of dose limiting toxicity (DLT), graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.03

    Secondary Outcome Measures

    Objective response (complete response, partial response, stable disease or progressive disease) according to Response Evaluation Criteria In Solid Tumors

    Pharmacodynamic profile of AZD1775

    PK profile of WEE1 inhibitor MK-1775 with docetaxel and cisplatin

    Progression-free survival (PFS) duration

    Trial Keywords