Buparlisib, Cisplatin, and Radiation Therapy in Treating Patients with Stage III/IV Head and Neck Cancer

Inclusion Criteria

• Patients with stage III/IV per tumor/nodes/metastasis (TNM) guidelines for head and neck sites (American Joint Committee on Cancer [AJCC] 7th Edition), locally advanced, biopsy proven squamous cell cancer of the head and neck that undergo chemoradiation as their primary treatment with curative intent; patients with oropharynx (human papillomavirus [HPV] positive and HPV negative), hypopharynx, larynx primaries, nasopharynx as well as those with documented squamous cell cancer (SCC) of the cervical lymph nodes, with unknown primaries, are eligible
• > 10 pack years of tobacco use or more
• Eastern Cooperative Oncology Group (ECOG) performance status =< 2
• Patients must have at least one site of measurable disease (if applicable) (per Response Evaluation Criteria in Solid Tumors [RECIST] 1.1 for solid tumors or the appropriate disease classification/criteria for the target population)
• Absolute neutrophil count (ANC) > 1.5 x 10^9/L
• Platelets > 100 x 10^9/L
• Hemoglobin (Hb) > 9 g/dL
• Total calcium (corrected for serum albumin) within normal limits (bisphosphonate use for malignant hypercalcemia control is not allowed)
• 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 upper limit normal [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
• International normalized ratio (INR) =< 2

Exclusion Criteria

• Presence of distant metastatic disease
• Less than or equal to 10 pack years of tobacco history
• Patients who have received prior chemotherapy
• Patients who have received prior radiation to the head and neck or adjacent anatomical site (e.g., upper lobe lung, brain)
• Patients who have received prior treatment with a phosphoinositide 3-kinase (P13K) inhibitor
• Patients with a known hypersensitivity to BKM120 or to its excipients
• Patients with acute or chronic liver, renal disease or pancreatitis
• Patients with the following mood disorders as judged by the investigator or a psychiatrist, or as a result of patient’s mood assessment questionnaire: * Medically documented history of or active major depressive episode, bipolar disorder (I or II), obsessive-compulsive disorder, schizophrenia, a history of suicidal attempt or ideation, or homicidal ideation (immediate risk of doing harm to others) or patients with active severe personality disorders (defined according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition [DSM- IV]) are not eligible; Note: for patients with psychotropic treatments ongoing at baseline, the dose and the schedule should not be modified within the previous 6 weeks prior to start of study drug * >= Common Terminology Criteria for Adverse Events (CTCAE) grade 3 anxiety * Meets the cut-off score of >= 12 in the Patient Health Questionnaire (PHQ)-9 or a cut-off of >= 15 in the Generalized Anxiety Disorder (GAD)-7 mood scale, respectively, or selects a positive response of "1, 2, or 3" to question number 9 regarding potential for suicidal thoughts in the PHQ-9 (independent of the total score of the PHQ-9)
• Patients with diarrhea >= CTCAE grade 2
• Patient has active cardiac disease including any of the following: * Left ventricular ejection fraction (LVEF) < 50% as determined by multiple gated acquisition (MUGA) scan or echocardiogram (ECHO) * Corrected QT (QTc) interval > 480 msec on screening electrocardiogram (ECG) (using the QTc Fridericia [F] formula) * Angina pectoris that requires the use of anti-anginal medication * Ventricular arrhythmias except for benign premature ventricular contractions * Supraventricular and nodal arrhythmias requiring a pacemaker or not controlled with medication * Conduction abnormality requiring a pacemaker * Valvular disease with document compromise in cardiac function * Symptomatic pericarditis
• Patient has a history of cardiac dysfunction including any of the following: * Myocardial infarction within the last 6 months, documented by persistent elevated cardiac enzymes or persistent regional wall abnormalities on assessment of LVEF function * History of documented congestive heart failure (New York Heart Association functional classification III-IV) * Documented cardiomyopathy
• Patient has poorly controlled diabetes mellitus or steroid-induced diabetes mellitus
• Other concurrent severe and/or uncontrolled concomitant medical conditions (e.g., active or uncontrolled infection) that could cause unacceptable safety risks or compromise compliance with the protocol * Significant symptomatic deterioration of lung function; if clinically indicated, pulmonary function tests including measures of predicted lung volumes, diffusing capacity of the lung for carbon monoxide (DLco), oxygen (O2) saturation at rest on room air should be considered to exclude pneumonitis or pulmonary infiltrates
• Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of BKM120 (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection); patients with unresolved diarrhea will be excluded as previously indicated
• Patients who are 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
• Patients receiving chronic treatment with steroids or another immunosuppressive agent * Note: Topical applications (e.g. rash), inhaled sprays (e.g. obstructive airways diseases), eye drops or local injections (e.g. intra-articular) are allowed; patients with previously treated brain metastases, who are on stable low dose corticosteroids treatment (e.g. dexamethasone 2 mg/day, prednisolone 10 mg/day) for at least 14 days before start of study treatment are eligible
• Patients who have taken herbal medications and certain fruits within 7 days prior to starting study drug; herbal medications include, but are not limited to St. John’s wort, Kava, ephedra (ma huang), Gingko biloba, dehydroepiandrosterone (DHEA), yohimbe, saw palmetto, and ginseng; fruits include the cytochrome P450, family 3, subfamily A (CYP3A) inhibitors Seville oranges, grapefruit, pummelos, or exotic citrus fruits
• Patients who are 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 note that co-treatment with weak inhibitors of CYP3A is allowed)
• Patients who have undergone major surgery =< 2 weeks prior to starting study drug or who have not recovered from side effects of such therapy
• Patients who are 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; double barrier contraceptives must be used through the trial by both sexes; oral, implantable, or injectable contraceptives are not considered effective for this study; women of child-bearing potential, defined as sexually mature women who have not undergone a hysterectomy or who have not been naturally postmenopausal for at least 12 consecutive months (i.e., who has had menses any time in the preceding 12 consecutive months), must have a negative serum pregnancy test =< 72 hours prior to initiating treatment * Women are considered post-menopausal and not of child bearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age appropriate, history of vasomotor symptoms) or six months of spontaneous amenorrhea with serum follicle stimulating hormone (FSH) levels > 40 mIU/mL (for United States [US] only: and estradiol < 20 pg/mL) or have had surgical bilateral oophorectomy (with or without hysterectomy) at least six weeks ago; in the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment is she considered not of child bearing potential * Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, must use highly effective contraception during treatment and for 4 weeks after stopping treatment * The highly effective contraception is defined as either: ** True abstinence: when this is in line with the preferred and usual lifestyle of the subject; periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception ** Sterilization: have had surgical bilateral oophorectomy (with or without hysterectomy) or tubal ligation at least six weeks ago; in case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment ** Male partner sterilization (with the appropriate post-vasectomy documentation of the absence of sperm in the ejaculate); for female subjects on the study, the vasectomized male partner should be the sole partner for that patient ** Use of a combination of any two of the following (a+b): a) Placement of an intrauterine device (IUD) or intrauterine system (IUS) b) Barrier methods of contraception: condom or occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository ** Oral contraception, injected or implanted hormonal methods are not allowed ** Fertile males, defined as all males physiologically capable of conceiving offspring must use condom during treatment, for 4 weeks after stopping treatment and for additional 12 weeks (16 weeks in total after study drug discontinuation) and should not father a child in this period ** Female partner of male study subject should use highly effective contraception during dosing of any study agent and for 16 weeks after final dose of study therapy
• 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
• Patient is unable or unwilling to abide by the study protocol or cooperate fully with the investigator