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Head and Neck Squamous Cell CarcinomaPhase 1NCT02508246

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

A Phase 1 study testing Cisplatin, Docetaxel and Laboratory Biomarker Analysis in people with Head and Neck Squamous Cell Carcinoma, run by University of Washington at 1 site in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial summary

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). Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Head and Neck Squamous Cell Carcinoma
What is being tested?
Cisplatin, Docetaxel and Laboratory Biomarker Analysis
Could I receive a placebo?
No, everyone receives an active treatment
How many people
12 participants
Where
1 siteUnited States
Study dates
22 Jul 2015to 26 Apr 2018
Phase
Phase 1
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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
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  • 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

Who cannot join

  • 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
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  • 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

Trial locations and contacts

1 site in 1 country.

United States1 site
  • Fred Hutch/University of Washington Cancer Consortium

    Seattle, Washington, 98109

Other trials in United States

About this study

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)

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.

Read the detailed description

PRIMARY OBJECTIVES:

  1. 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;

  1. 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:

  1. 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.

Being tested
Cisplatin, Docetaxel, Laboratory Biomarker Analysis, Pharmacological Study, Therapeutic Conventional Surgery
Medical subject headings
Squamous Cell Carcinoma of Head and Neck

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • CisplatinDrug

    Also called Abiplatin, Blastolem, Briplatin, CDDP

    Given IV

  • DocetaxelDrug

    Also called Docecad, RP56976, Taxotere, Taxotere Injection Concentrate

    Given IV

  • Laboratory Biomarker AnalysisOther

    Correlative studies

  • Pharmacological StudyOther

    Correlative studies

  • Therapeutic Conventional SurgeryProcedure or surgery

    Undergo surgery

  • WEE1 Inhibitor AZD1775Drug

    Also called AZD-1775, AZD1775, MK-1775, MK1775

    Given PO

Study groups in NCT02508246
Study groupRoleWhat they receive
Treatment (WEE1 inhibitor MK-1, cisplatin, docetaxel, surgery)ExperimentalPatients 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 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.
Receives: Drug: Cisplatin; Drug: Docetaxel; Other: Laboratory Biomarker Analysis; Other: Pharmacological Study; Procedure: Therapeutic Conventional Surgery; Drug: WEE1 Inhibitor AZD1775

What is being measured

The primary outcome is the main question the study is designed to answer.

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

    Summary tables and graphic displays, as appropriate, will be prepared to examine the distribution of these toxicities per cycle.

    Measured: Up to 2 years post-treatment

  2. 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

    DLT is defined as any adverse event judged by the investigator to be drug-related (i.e., causality rated as possible or greater) that is assessed as grade 3 or worse. Summary tables and graphic displays, as appropriate, will be prepared to examine the distribution of these toxicities per cycle.

    Measured: 28 days

Secondary outcomes (4)
  1. Objective response (complete response, partial response, stable disease or progressive disease) according to Response Evaluation Criteria In Solid Tumors

    Measured: Up to 5 years post-treatment

  2. Pharmacodynamic profile of AZD1775

    Pharmacodynamic parameters will be studied during lead-in monotherapy to determine target engagement, mainly phosphorylated WEE1 and CDC2. Prior to treatment normal tissue in the opposite side of the tumor in the oral mucosa will be used for controls. Biological specificity will be verified by assessing the phosphorylated state of WEE1 and downstream effector molecules: total CDC2, ptyr15 CDC2, for G2/M. Other relevant biomarkers and molecular or genetic analyses may be performed.

    Measured: Time of surgery or up to day 29

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

    Maximum concentration and mean terminal half-life will be focused on during PK analysis.

    Measured: Pre-dose and at 1, 2, 4, 6, and 8-10 hours on days 2 and 4 of course 1, and pre-dose on day 3 of course 1

  4. Progression-free survival (PFS) duration

    PFS will be determined in days or weeks and waterfall plots and graphical data will be provided where suitable.

    Measured: Up to 5 years post-treatment

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted24 Jul 2015 (estimated)
  2. Study start22 Jul 2015
  3. Primary completion26 Apr 2018
  4. Study completion26 Apr 2018

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
12 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT02508246
Sponsor's protocol ID
9168
Other IDs
NCI-2015-01064, 9168, P30CA015704
Status last verified
Mar 2019
First submitted
10 Jul 2015
Last updated
13 Mar 2019
Results posted
No
Data monitoring committee
No

Questions about this trial

What is this clinical trial studying?

A Phase 1 study testing Cisplatin, Docetaxel and Laboratory Biomarker Analysis in people with Head and Neck Squamous Cell Carcinoma, run by University of Washington at 1 site in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 20 inclusion and 17 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 13 Mar 2019. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Incidence of adverse events graded according to the NCI CTCAE version 4.03 (time frame: Up to 2 years post-treatment). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 13 Mar 2019.

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