Cisplatin With or Without WEE1 Inhibitor MK-1775 in Treating Patients With Recurrent or Metastatic Head and Neck Cancer

Study Overview
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Brief Summary
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This randomized phase II trial studies how well cisplatin with or without WEE1 inhibitor MK-1775 works in treating patients with head and neck cancer that has come back or has spread to other parts of the body. Drugs used in chemotherapy, such as cisplatin, may prevent tumor cells from multiplying by damaging their deoxyribonucleic acid (DNA), which in turn stops the tumor from growing. WEE1 inhibitor MK-1775 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. It is not yet known whether cisplatin is more effective with or without WEE1 inhibitor MK-1775 in treating patients with head and neck cancer.

Detailed Description
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PRIMARY OBJECTIVES: I. To compare the overall response rate assess the efficacy of MK-1775 (WEE1 inhibitor MK-1775) in combination with cisplatin to cisplatin alone in patients with recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN) as per overall response rate (using Response Evaluation Criteria in Solid Tumors [RECIST] criteria version [v]1.1). SECONDARY OBJECTIVES: I. Assess secondary measures of efficacy (progression free survival at 6 months and 12 months, overall survival rate at 12 months). II. Assess measures of efficacy by tumor protein (p)53 status. III. Evaluate safety and tolerability. IV. Explore predictive and pharmacodynamic biomarkers. OUTLINE: SAFETY RUN-IN: Patients receive WEE1 inhibitor MK-1775 orally (PO) twice daily (BID) for 5 doses beginning on day 1 and cisplatin intravenously (IV) over 1 hour on day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients are randomized to 1 of 2 treatment arms. ARM I: Patients receive WEE1 inhibitor MK-1775 PO BID for 5 doses beginning on day 1 and cisplatin IV over 1 hour on day 1. ARM II: Patients receive placebo PO BID for 5 doses beginning on day 1 and cisplatin IV over 2 hour on day 1. In both arms, courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up at 30 days and then every 3 months for up to 1 year.

Official Title
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A Randomized Phase II Trial of Cisplatin With or Without Wee1 Kinase Inhibitor AZD1775 (MK-1775) for First-line Treatment of Recurrent or Metastatic Squamous Cell Cancer of the Head and Neck (RM-SCCHN)

Conditions
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Recurrent Hypopharyngeal Squamous Cell Carcinoma, Recurrent Laryngeal Squamous Cell Carcinoma, Recurrent Laryngeal Verrucous Carcinoma, Recurrent Lip and Oral Cavity Squamous Cell Carcinoma, Recurrent Metastatic Squamous Cell Carcinoma in the Neck With Occult Primary, Recurrent Nasal Cavity and Paranasal Sinus Squamous Cell Carcinoma, Recurrent Oral Cavity Verrucous Carcinoma, Recurrent Oropharyngeal Squamous Cell Carcinoma, Squamous Cell Carcinoma Metastatic in the Neck With Occult Primary, Stage IV Hypopharyngeal Squamous Cell Carcinoma, Stage IVA Laryngeal Squamous Cell Carcinoma, Stage IVA Laryngeal Verrucous Carcinoma, Stage IVA Lip and Oral Cavity Squamous Cell Carcinoma, Stage IVA Nasal Cavity and Paranasal Sinus Squamous Cell Carcinoma, Stage IVA Oral Cavity Verrucous Carcinoma, Stage IVA Oropharyngeal Squamous Cell Carcinoma, Stage IVB Laryngeal Squamous Cell Carcinoma, Stage IVB Laryngeal Verrucous Carcinoma, Stage IVB Lip and Oral Cavity Squamous Cell Carcinoma, Stage IVB Nasal Cavity and Paranasal Sinus Squamous Cell Carcinoma, Stage IVB Oral Cavity Verrucous Carcinoma, Stage IVB Oropharyngeal Squamous Cell Carcinoma, Stage IVC Laryngeal Squamous Cell Carcinoma, Stage IVC Laryngeal Verrucous Carcinoma, Stage IVC Lip and Oral Cavity Squamous Cell Carcinoma, Stage IVC Nasal Cavity and Paranasal Sinus Squamous Cell Carcinoma, Stage IVC Oral Cavity Verrucous Carcinoma, Stage IVC Oropharyngeal Squamous Cell Carcinoma, Tongue Carcinoma

Intervention / Treatment
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* Drug: Cisplatin
* Other: Laboratory Biomarker Analysis
* Other: Pharmacological Study
* Other: Placebo
* Drug: WEE1 Inhibitor AZD1775


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must have histologically or cytologically confirmed SCCHN that is recurrent and/or metastatic and not amendable to curative therapy by surgery or radiation; SCCHN originating from the following sites are eligible: oral cavity, oropharynx, larynx, hypopharynx and paranasal sinus; for patients with a diagnosis of SCCHN of unknown origin, their eligibility must be reviewed and approved by the principal investigator No prior systemic chemotherapy or WEE1 kinase inhibitor therapy for metastatic or recurrent disease will be allowed; patients are permitted to have received prior systemic chemotherapy as a part of the initial multimodality treatment for locally advanced disease if this treatment was completed more than 6 months prior to enrollment Patients must have disease amenable to biopsy and must be medically fit to undergo a biopsy Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded) as > 10 mm with computed tomography (CT) scan; indicator lesions must not have been previously treated with surgery, radiation therapy or radiofrequency ablation unless there is documented progression after therapy Patients must have completed any previous surgery or radiotherapy >= 4 weeks prior to enrollment Eastern Cooperative Oncology Group (ECOG) performance status 0-2 (Karnofsky > 60%) Life expectancy of greater than 12 weeks Leukocytes >= 3,000/mcL Absolute neutrophil count >= 1,500/mcL Platelets >= 100,000/mcL Hemoglobin >= 9 g/dL Total bilirubin within normal institutional limits Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 × institutional upper limit of normal Prothrombin time (PT)/partial thromboplastin time (PTT)/international normalized ratio (INR) =< 1.5 upper limit of normal (ULN) Creatinine within normal institutional limits OR calculated creatinine clearance >= 60 mL/min/1.73 m^2 for patients with levels above institutional normal using modified Cockcroft-Gault Cardiac function: 12-lead electrocardiogram (ECG) with normal tracing, or non-clinically significant changes that do not require medical intervention; corrected QT (QTc) interval is to be < 470 msec Women of childbearing potential and men must be surgically sterilized, practicing abstinence, or agree to use 2 birth control methods prior to study entry and for the duration of study participation including up to 30 days after the last dose of MK-1775; the 2 methods of birth control can be either 2 barrier methods or a barrier method plus a hormonal method to prevent pregnancy; the following are considered adequate barrier methods of contraception: diaphragm or sponge, and condom; other methods of contraception such as copper intrauterine device or spermicide may be used; appropriate hormonal contraceptives will include any registered and marketed contraceptive agent that contains an estrogen and/or a progestational agent (including oral, subcutaneous, intrauterine, or intramuscular agents); should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately Ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: Past or current malignancy other than SCCHN, except for: Cervical carcinoma stage 1B or less Non-invasive basal cell and squamous cell skin carcinoma Malignant melanoma with a complete response of a duration of > 10 years Radically treated prostate cancer (prostatectomy or radiotherapy) with normal prostate specific antigen (PSA), and not requiring ongoing anti-androgen hormonal therapy Other cancer diagnosis with a complete response of duration of > 5 years Patients may not be receiving any other investigational agents Patients with known brain metastases should be excluded from this clinical trial History of allergic reactions attributed to compounds of similar chemical or biologic composition to MK-1775 or cisplatin Patients who are unable to take oral medications and/or who have a clinical or radiological diagnosis of bowel obstruction are ineligible Uncontrolled intercurrent illness including, but not limited to ongoing or active infection, active peptic ulcer disease, myocardial infarction within 6 months prior to entry, congestive heart failure, symptomatic congestive heart failure, active cardiomyopathy, unstable angina pectoris, cardiac arrhythmia, uncontrolled hypertension or psychiatric illness/social situations that would limit compliance with study requirements Pregnant women are excluded from this study; breastfeeding should be discontinued if the mother is treated with MK-1775 Human immunodeficiency virus (HIV)-positive patients are ineligible Patients taking the following prescription or non-prescription drugs or other products (i.e. grapefruit juice) are ineligible: sensitive cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4) substrates, CYP3A4 substrates with a narrow therapeutic index, moderate to potent inhibitors/inducers of CYP3A4; patients would be eligible if the medications can be discontinued two weeks prior to day 1 of dosing and withheld throughout the study until 2 weeks after the last dose of study medication

Ages Eligible for Study
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Minimum Age: 19 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I (WEE1 inhibitor MK-1775, cisplatin)<br>Patients receive WEE1 inhibitor MK-1775 PO BID for 5 doses beginning on day 1 and cisplatin IV over 1 hour on day 1. | Drug: Cisplatin<br>* Given IV<br>* Other names: Platosin;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Other: Pharmacological Study<br>* Correlative studies<br>Drug: WEE1 Inhibitor AZD1775<br>* Given PO<br>* Other names: MK1775;|
| Active Comparator: Arm II (placebo, cisplatin)<br>Patients receive placebo PO BID for 5 doses beginning on day 1 and cisplatin IV over 2 hour on day 1. | Drug: Cisplatin<br>* Given IV<br>* Other names: Platosin;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Other: Pharmacological Study<br>* Correlative studies<br>Other: Placebo<br>* Given PO<br>* Other names: sham therapy;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate (Complete Plus Partial Response) Using RECIST Criteria v1.1 | Per Response Evaluation Criteria in solid Tumors (RECIST1.1) Target lesions are assessed as Complete Response(CR), Disappearance of all target lesions; Partial Response (PR),30% decrease in the sum of the diameters of target lesions; Progressive Disease (PD), At least a 20% increase (minimum 5 mm) from smallest sum (nadir); Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. Nontarget lesions are assessed as Complete Response (CR), Disappearance of all non-target lesions; Non-CR/Non-PD, Persistence of one or more non-target lesion(s) and/or maintenance of tumor marker level above the normal limits; Progressive Disease (PD),Appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions; Overall Response(OR); PR=CR+non-CR/non-PD,SD=SD+non-PD; PD=PD+presence of any non-target lesions | Up to 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Adverse Events Using the National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 | Gr 3, Gr 4 and Gr 5 AEs at least possibly related to study drug | Up to 1 year | 
| Levels of Pharmacodynamic Biomarkers | Predictors of clinical outcomes will be investigated using logistic regression, Cox proportional hazards regression and/or generalized estimating equations as appropriate. Descriptive statistics and plotting of data will be used to better understand potential relationships. | Pre-dose, at 4-8 hours on day 3 or 20-24 hours on day 4 | 
| Levels of Predictive Biomarkers | Predictors of clinical outcomes will be investigated using logistic regression, Cox proportional hazards regression and/or generalized estimating equations as appropriate. Descriptive statistics and plotting of data will be used to better understand potential relationships. | Up to day 4 of course 1 | 
| Overall Survival | Estimated in each group by the Kaplan Meier method and differences between groups will be calculated by the log rank test. Hazard ratios for each group will be estimated using the Cox Regression model. | 12 months | 
| Progression Free Survival | Progression-free survival (PFS) is defined as the duration of time from start of treatment to time of progression (20% increase in the sum of the longest diameter of target lesions or a measurable increase in a non-target lesion, or the appearance of new lesions) or death, whichever occurs first. | Time from start of treatment to time of progression or death, whichever occurs first, assessed at 6 months | 
| Progression Free Survival | Estimated in each group by the Kaplan Meier method and differences between groups will be calculated by the log rank test. Hazard ratios for each group will be estimated using the Cox Regression model. | Time from start of treatment to time of progression or death, whichever occurs first, assessed at 12 months |