Phase Ib Study of BKM120 With Cisplatin and XRT in High Risk Locally Advanced Squamous Cell Cancer of Head and Neck

Study Overview
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Brief Summary
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This research study is evaluating a drug called buparlisib (BKM120) as a possible treatment for locally advanced head and neck squamous cell cancer.

Detailed Description
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This phase Ib study is combining standard chemoradiotherapy with weekly cisplatin and BKM120 to assess tolerability of this combination in high risk patients with locally advanced Squamous Cell Carcinoma of the Head and Neck (SCCHN). The investigators will also obtain preliminary information about the efficacy of this treatment. The participant will receive the study drug buparlisib once daily, by mouth, for 45 days. The participant will be given a study drug-dosing diary for each cycle. It will include special instructions for taking the study drug at home. The investigators are looking for the highest dose of the study drug that can be administered safely without severe or unmanageable side effects, not everyone who participates in this research study will receive the same dose of the study drug. The dose given will depend on the number of participants who have been enrolled in the study before and how well they have tolerated their doses. All participants will receive weekly cisplatin injection. Cisplatin will be given intra-venously (IV) on days: (1, 8, 15, 22, 29, 36 and 43) at DFCI. All participants will receive daily radiotherapy with intensity-modulated radiotherapy (IMRT) for 7 weeks, delivered at DFCI. IMRT is a type of 3-dimensional radiation therapy that uses computer-generated images to show the size and shape of the tumor. Thin beams of radiation of different intensities are aimed at the tumor from many angles. This type of radiation therapy reduces the damage to healthy tissue near the tumor. The investigators would like to keep track of the participant's medical condition. Follow-up will continue every 4 to 12 weeks after the end of treatment for the first year and at the investigator's discretion thereafter.

Official Title
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A Phase Ib Study of BKM120 With Weekly Cisplatin and Radiotherapy in High Risk Locally Advanced Squamous Cell Cancer of the Head and Neck

Conditions
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Hypopharyngeal Cancer, Carcinoma, Squamous Cell of Head and Neck, HPV Positive Oropharyngeal Squamous Cell Carcinoma, Early Invasive Cervical Squamous Cell Carcinoma, Carcinoma of Larynx, Cancer of Nasopharynx

Intervention / Treatment
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* Drug: BKM120
* Drug: Cisplatin
* Radiation: Intensity-modulated radiotherapy (IMRT)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Stage III/IV, locally advanced, biopsy proven squamous cell cancer of the head and neck that undergo chemoradiation as their primary treatment with curative intent. Oropharynx (HPV positive and HPV negative), hypopharynx, larynx primaries, nasopharynx as well as those with documented SCC of the cervical lymph nodes, with unknown primaries. >10 pack years of tobacco use Age ≥ 18 years ECOG performance status ≤ 2 At least one site of measurable disease Adequate bone marrow function as shown by: ANC > 1.5 x 109/L, Platelets >100 x 109/L, Hb >9 g/dL Total calcium (corrected for serum albumin) within normal limits Magnesium ≥ the lower limit of normal Potassium within normal limits for the institution. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) within normal range Serum bilirubin within normal range (or ≤ 1.5 x ULN if liver metastases are present; or total bilirubin ≤ 3.0 x ULN with direct bilirubin within normal range in patients with well documented Gilbert Syndrome) Serum creatinine ≤ 1.5 x ULN or 24-hour clearance ≥ 50 mL/min Serum amylase ≤ ULN Serum lipase ≤ ULN Fasting plasma glucose ≤ 120 mg/dL (6.7 mmol/L) Signed informed consent INR ≤ 2 Exclusion Criteria: Distant metastatic disease Less than or equal to 10 pack years of tobacco history Received prior chemotherapy Received prior radiation to the head and neck or adjacent anatomical site Received prior treatment with a P13K inhibitor. Known hypersensitivity to BKM120 or to its excipients Acute or chronic liver, renal disease or pancreatitis Mood disorders ≥ CTCAE grade 3 Diarrhea ≥ CTCAE grade 2 Active cardiac disease History of cardiac dysfunction including any of the following: Patient has poorly Impairment of gastrointestinal (GI) function Currently receiving treatment with medication with a known risk to prolong the QT interval or inducing Torsades de Pointes and the treatment cannot either be discontinued or switched to a different medication prior to starting study drug. Chronic treatment with steroids or another immunosuppressive agent. Herbal medications and certain fruits within 7 days prior to starting study drug. Currently treated with drugs known to be moderate and strong inhibitors or inducers of isoenzyme CYP3A, and the treatment cannot be discontinued or switched to a different medication prior to starting study drug. Please refer to Appendix B for a list of prohibited inhibitors and inducers of CYP3A (Please note that co-treatment with weak inhibitors of CYP3A is allowed). Undergone major surgery ≤ 2 weeks prior to starting study drug or who have not recovered from side effects of such therapy. Currently taking therapeutic doses of warfarin sodium or any other coumadin-derivative anticoagulant. Women who are pregnant or breast feeding or adults of reproductive potential not employing an effective method of birth control. Known diagnosis of human immunodeficiency virus (HIV) infection History of another malignancy within 3 years, except cured basal cell carcinoma of the skin or excised carcinoma in situ of the cervix

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: BKM120<br>Participants will be enrolled in cohorts of 3- 6 per dose level. Once the MTD is reached, an additional 10 patients will be treated at that dose level and an amendment will be submitted to declare the dose. BKM120 will start 2 weeks prior to first dose of cisplatin and radiation start. During the study, BKM120 will be administered orally daily for 45 days. Starting dose 40 mg. Cisplatin: Starting Dose 30 mg/m2, given IV, weekly on days: (1, 8, 15, 22, 29, 36 and 43). Radiotherapy: All participants will receive daily radiotherapy with intensity-modulated radiotherapy (IMRT) for 7 weeks. | Drug: BKM120<br>* BKM120 is a potent and highly specific oral pan-class I PI3K inhibitor.<br>* Other names: Buparlisib;Drug: Cisplatin<br>* Cisplatin is a chemotherapy drug<br>* Other names: Platinol;Radiation: Intensity-modulated radiotherapy (IMRT)<br>* IMRT is the medical use of ionizing radiation, generally as part of cancer treatment to control or kill malignant cells<br>* Other names: IMRT;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Determine Maximum Tolerated Dose (MTD) of BKM120/cisplatin combination with radiation therapy | Determine Maximum Tolerated Dose (MTD) of BKM120/cisplatin in combination with radiation therapy in patients with locally advanced squamous cell cancer of the head and neck. | 2 Years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate |  | 2 Years | 
| Time to Progression |  | 2 Years | 
| Survival |  | 2 years | 
| Mood alteration from BKM120 |  | 2 Years | 
| Activity of BKM120 as single agent in sequential biopsies |  | 2 Years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hypopharyngeal Cancer, Early Invasive Cervical Squamous Cell Carcinoma, Carcinoma of Larynx, Carcinoma, Squamous Cell of Head and Neck, Human Papillomavirus Positive Oropharyngeal Carcinoma, Cancer of Nasopharynx