Ruxolitinib in Operable Head and Neck Cancer

Study Overview
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Brief Summary
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The purpose of this study is to assess the safety and efficacy of ruxolitinib in patients with operable Head and neck squamous cell carcinoma (HNSCC) who are planned for definitive surgery.

Detailed Description
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PRIMARY OBJECTIVES: I. To identify baseline and/or pharmacodynamic biomarkers of response to ruxolitinib, based upon association with quantitative change in tumor size following 14-21 days of neoadjuvant ruxolitinib in patients with operable HNSCC as determined by quantitative change in Tumor size. SECONDARY OBJECTIVES: I. To describe the tolerability of brief neoadjuvant exposure to ruxolitinib II. To assess the effect of ruxolitinib on the tumoral Ki-67 proliferation index III. To evaluate additional candidate biomarkers of ruxolitinib response or resistance in HNSCC patients as determined by quantitative change in Tumor size, including: Baseline activation and/or modulation of additional JAK/STAT3 signaling pathway proteins Baseline SHP-2 overexpression Reverse-phase protein array (RPPA) will be conducted on paired pre- and post-treatment tissue as a source of unbiased biomarker discovery. OUTLINE: Participants will be assigned neoadjuvant ruxolitinib based on participant platelet counts at baseline. Participants with a platelet count of 200,000 or greater will take 20 mg twice daily and participants with a platelet count between 150,000 and 200,000 will take 15 mg twice daily. Participants may continue treatment for up to 4 weeks from the time of study entry to time of planned standard of care surgery for cancer. Participants will be followed up for 12-weeks post-operation.

Official Title
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Pharmacodynamic Effects and Predictive Biomarkers of Janus Kinases (JAK)/Signal Transducer and Activator of Transcription (STAT) Inhibition With Ruxolitinib in Operable Head and Neck Cancer: a Window Trial

Conditions
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Head and Neck Squamous Cell Carcinoma

Intervention / Treatment
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* Drug: Ruxolitinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically or cytologically confirmed, primary or recurrent, head and neck squamous cell carcinoma, including variants. Patients must have at least one measureable lesion in accordance with RECIST 1.1 (tumor diameter ≥ 1 cm; short-axis lymph node diameter ≥ 1.5 cm) OR by caliper measurement (tumor diameter ≥ 1 cm). Any diagnostic pretreatment biopsy sample is acceptable including fine needle aspiration (FNA). Primary tumors of any head and neck (oral cavity, oropharynx, hypopharynx, or larynx) site will be included. Surgical resection of head and neck must be planned, either as primary treatment or salvage. Patients must have submitted adequate pretreatment archival or fresh tissue. Age ≥ 18 years. Eastern Cooperative Oncology Group (ECOG) performance status 0-2 (See Appendix 1). Women of childbearing potential (WOCBP) must have a negative serum pregnancy test (sensitivity ≤ 25 human chorionic gonadotropin (HCG) IU/L) within 4 weeks prior to registration and will be repeated within 72 hours prior to the start of study drug administration. Persons of reproductive potential must agree to use and utilize an adequate method of contraception throughout treatment and for at least 12 weeks after study drug is stopped. Prior to study enrollment, women of childbearing potential must be advised of the importance of avoiding pregnancy during trial participation and the potential risk factors for an unintentional pregnancy. Adequate hematologic, renal and hepatic function, as defined by: Absolute neutrophil count (ANC) ≥ 1,500/ul, platelets ≥ 150,000/ul. Creatinine ≤ 1.5 x institutional upper limit of normal (ULN). Bilirubin ≤ 1.5 x ULN, aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≤ 2.5 x ULN. Have signed written informed consent Exclusion Criteria: Subjects who fail to meet the above criteria. Prior therapy for head and neck cancer is allowed, and the number of treatments is not limited. However, any systemic therapy should have been completed at least 30 days prior to study enrollment. Any radiation to the head and neck should have been completed at least 30 days prior to study enrollment. Palliative radiation outside of the head and neck does not require a washout. Pregnancy or breastfeeding. Women (patients or partners of male patients) of childbearing potential (WOCBP) must practice acceptable methods of birth control to prevent pregnancy. All WOCBP must have a negative pregnancy test within 4 weeks prior to registration, and this must be repeated within 72 hours prior to first receiving ruxolitinib. If the pregnancy test is positive, the patient must not receive ruxolitinib and must not be enrolled in the study. Any unresolved chronic toxicity ≥ grade 2 from previous anticancer therapy (except alopecia and anemia), according to Common Terminology Criteria for Adverse Events v4.0 (CTCAE). Current active infection requiring systemic antibiotic or antifungal therapy. Acute hepatitis or known HIV. Treatment with a non-approved or investigational drug within 30 days prior to Day 1 of study treatment. New York Heart Association (NYHA) Class III or IV heart disease. History of thromboembolic event or other condition currently requiring anticoagulation with warfarin (coumadin). Patients who are treated with low molecular weight heparin or fondaparinux are eligible. History of significant bleeding disorder unrelated to cancer, including: diagnosed congenital bleeding disorders (e.g., von Willebrand's disease, diagnosed acquired bleeding disorder within one year (e.g., acquired anti-factor VIII antibodies, or ongoing or recent (≤ 3 months) significant gastrointestinal bleeding Concomitant Medications, any of the following should be considered for exclusion: Strong CYP3A4 inhibitors: (Patients must discontinue drug 7 days prior to starting ruxolitinib), including but not limited to boceprevir, clarithromycin, conivaptan, indinavir, itraconazole, ketoconazole, lopinavir, mibefradil, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, or voriconazole. In addition, patients will be instructed to avoid grapefruit or grapefruit juice, starfruit, or seville oranges. Prisoners or subjects who are compulsorily detained (involuntarily incarcerated) for treatment of either a psychiatric or physical (e.g., infectious) illness.

Ages Eligible for Study
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Minimum Age: 18 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Neoadjuvant Ruxolitinib<br>Participants will take 15 mg or 20 mg of ruxolitinib by mouth twice daily for up to 4 weeks during the pre-operative window for 14-21 days, or up to 28 days for delays in planned surgery. Dose will be assigned based on participant platelet count at baseline. The last dose will be taken the morning of planned surgery. Ruxolitinib will be dispensed in 5 mg tablets. Participants will either take three tables (15 mg) in the morning and evening, or four tablets in the morning and evening (20 mg). Participants will be asked to fill out a drug diary indicating when doses of study drug are taken and any side effects they experience. | Drug: Ruxolitinib<br>* Given orally<br>* Other names: Jakafi;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Median change in Tumor Size | Measured as a proportional percent (range -100% to +100%) from baseline to day of final dose of ruxolitinib. The size of the tumor will be determined and net change in Tumor measurements used to determine the response. | Up to 4 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of participants with treatment-related adverse events | The proportion of participants with treatment-related adverse events, classified according to NCI CTCAE version 4 will be reported. | Up to 12 weeks | 
| Proportion of participants with surgical complications | The proportion of participants with documented surgical complications will be reported. | Up to 12 weeks. | 
| Median length of hospital stay | The median length of hospital stay following the standard of care, surgical procedure be reported. | Up to 12 weeks | 
| Change in Ki-67 proliferative index value | The Ki-67 proliferative index will be measured in baseline and post-treatment tumor tissue as described, and will serve as a secondary endpoint (pharmacodynamic efficacy) | Up to 12 weeks | 
| Identification of biomarkers | Biomarkers of ruxolitinib response or resistance will be analyzed for correlations with change in tumor size and change in Ki-67. Biomarkers to be analyzed included baseline activation and/or modulation of additional JAK/STAT3 signaling pathway proteins, baseline Src homology 2 domain-containing protein tyrosine phosphatase 2 (SHP-2) overexpression, and Reverse-phase protein array (RPPA). | Up to 12 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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JAK/STAT inhibition, Biomarkers