PI3K Inhibitor BKM120 and Cetuximab in Treating Patients With Recurrent or Metastatic Head and Neck Cancer

Inclusion Criteria:

* Histologically / cytologically confirmed diagnosis of squamous cell carcinoma of head and neck origin not amenable to curative intent therapy; both human papillomavirus (HPV)(+) and HPV(-) tumors are eligible; tumors (squamous histology) of unknown primary that are clearly related to the head and neck area are eligible
* Presence of measurable lesions (RECIST V1.1)
* Mandatory tumor biopsy/biopsies in accessible tumors; for inaccessible tumors availability of tissue is required: \>= 10 tumor containing formalin-fixed paraffin-embedded (FFPE) slides/sections
* Progressive disease after exposure to a platinating agent (e.g. cisplatin or carboplatin) in a prior line of therapy, or documented intolerance to such an agent
* Eastern Cooperative Oncology Group (ECOG) performance status =\< 2
* No more than two lines of prior cytotoxic chemotherapy in the recurrent/metastatic (palliative intent) treatment setting
* Prior use of cetuximab or another epidermal growth factor receptor (EGFR) inhibitor is allowable and if used as a single agent should not be considered as a cytotoxic chemotherapy
* Patients must have at least one site of measurable disease (if applicable) (per RECIST 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
* Magnesium \>= the lower limit of normal for the institution
* Potassium within normal limits for the institution
* Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) within 1.5 x normal range (or =\< 3.0 x upper limit of normal \[ULN\] if liver metastases are present)
* 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)
* Negative serum pregnancy test within 72 hours before starting study treatment in women with childbearing potential
* Signed informed consent
* International normalized ratio (INR) =\< 2.5

Exclusion Criteria:

* Patients who have received prior treatment with a P13K inhibitor
* No available tumor material for correlative studies
* Patients with a known hypersensitivity to BKM120 or to its excipients, or hypersensitivity to cetuximab
* More than two prior lines of cytotoxic chemotherapy in the recurrent/metastatic disease setting (palliative treatment intent)(excluding single agent use of an EGFR inhibitor)
* Patients with untreated brain metastases are excluded; however, patients with treated brain metastases are eligible if they are \> 4 weeks from therapy completion (including radiation and/or surgery), are clinically stable at the time of study entry and are not receiving corticosteroid therapy at the time of study entry
* 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 (treating physician to decide on whether to administer 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)
  * \>= Common Terminology Criteria for Adverse Events (CTCAE) version 4 (v4) grade 3 anxiety
  * Meets the cut-off score of \>= 10 in the Patient Health Questionnaire 9 (PHQ-9) or a cut-off of \>= 15 in the Generalized Anxiety Disorder 7 (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 v4 grade 2
* Patient has active cardiac disease including any of the following:

  * History of clinically significant heart failure (previously assessed) with a left ventricular ejection fraction (LVEF) of \< 50% as determined by multiple grated acquisition (MUGA) scan or echocardiogram (ECHO)
  * Corrected QT (QTc) \> 480 msec on screening electrocardiogram (ECG) (using the Fridericia QT correction \[QTcF\] 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 infraction 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 (hemoglobin A1C \[HbA1C\] \> 7.5%)
* Patients with any history of hyperglycemia (elevated blood glucose level on blood chemistries) should be considered for initiation of Metformin treatment (500mg, PO, twice daily) prior to starting BKM120
* 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 have been treated with any hematopoietic colony-stimulating growth factors (e.g., filgrastim \[G-CSF\], sargramostim \[GM-CSF\]) =\< 2 weeks prior to starting study drug; erythropoietin or darbepoetin therapy, if initiated at least 2 weeks prior to enrollment, may be continued
* 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 other than specified in exclusion criterion #4

  * 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 (eg. 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
* Patients who have received chemotherapy or targeted anticancer therapy =\< 4 weeks (6 weeks for nitrosourea, antibodies or mitomycin-C) prior to starting study drug must recover to a grade 1 before starting the trial
* Patients who have received any continuous or intermittent small molecule therapeutics (excluding monoclonal antibodies) =\< 5 effective half lives prior to starting study drug or who have not recovered from side effects of such therapy; typically a \>= 2 week interval since completion of prior therapy is recommended and 4 weeks for monoclonal antibodies
* Patients who have received wide field radiotherapy =\< 4 weeks or limited field radiation for palliation =\< 2 weeks prior to starting study drug or who have not recovered from side effects of such therapy
* 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 may be affected by cytochrome P450 interactions, and are therefore 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
* Known diagnosis of human immunodeficiency virus (HIV) infection unless patient is fully immunocompetent (cluster of differentiation 4 \[CD4\] \> 200) and patient is not taking antiretroviral therapy
* History of another malignancy within 3 years, except cured basal cell carcinoma of the skin or excised carcinoma in situ of the cervix, or any tumor that is after clearing with the principal investigator (PI) clearly not considered to have impact on prognosis
* Patient is unable or unwilling to abide by the study protocol or cooperate fully with the investigator