Pilot Study of Sonidegib and Buparlisib in Treating Patients With Advanced or Metastatic Basal Cell Carcinoma

INCLUSION CRITERIA:

   - Able to understand and sign informed consent

   - Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2

   - Metastatic BCC, histologic confirmation of distant BCC metastasis

   - Metastatic disease, target lesion must be measurable using computed tomography (CT) or
   magnetic resonance imaging (MRI)

   - Locally advanced BCC are required to have disease that is considered inoperable due to
   significant functional compromise or to have a medical contraindication to surgery

   - Nevoid BCC syndrome (Gorlin syndrome) may enroll in this study but must meet the
   criteria for locally advanced or metastatic disease listed above

   - COHORT 2 ONLY: A Smoothened inhibitor must have been previously administered as
   monotherapy

   - Absolute neutrophil count (ANC) ≥ 1.5 x 10^9/L

   - Platelets ≥ 80 x10^9/L

   - Hemoglobin (Hb) > 9 g/dL or values ≥ lower limit of normal (LLN) for site-specific lab

   - Total calcium (corrected for serum albumin) within normal limits (biphosphonate 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 [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

   - International normalized ratio (INR) ≤ 2

EXCLUSION CRITERIA:

   - Prior treatment with a P13K inhibitor

   - Known hypersensitivity to buparlisib or to its excipients

   - Untreated brain metastases are excluded; however, patients with metastatic central
   nervous system (CNS) tumors may participate in this trial, if the patient is > 4 weeks
   from therapy completion (including radiation and/or surgery), is clinically stable at
   the time of study entry and is not receiving corticosteroid therapy

   - Acute or chronic liver, renal disease or pancreatitis

   - Baseline creatinine kinase (CK) > ULN

   - 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)

      - ≥ 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 7-item (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)

   - Diarrhea ≥ CTCAE grade 2

   - 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)

      - QTc > 450 msec on screening electrocardiogram (ECG) (using the 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 3-4)

      - Documented cardiomyopathy

   - Patient has poorly controlled diabetes mellitus [defined as hemoglobin A1C (HgA1c) >
   ULN], steroid-induced diabetes mellitus, or insulin dependent diabetes mellitus

   - Other concurrent severe and/or uncontrolled concomitant medical conditions (eg, 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 buparlisib (eg, 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 (eg, filgrastim (granulocyte-colony stimulating factor, G-CSF), sargramostim
   (granulocyte-macrophage colony-stimulating factor, 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

      - Note: topical applications (eg, rash), inhaled sprays (eg, obstructive airways
      diseases), eye drops or local injections (eg, intr-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), dehydroepiandrosterone (DHEA), gingko biloba, 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 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

   - Use of statin drugs or other medications known to associate with rhabdomyolysis; these
   drugs must be discontinued at enrollment

   - 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; low molecular weight heparin is allowed

   - 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 (ie, 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 (eg, age appropriate, history of vasomotor symptoms) or 6 months
      of spontaneous amenorrhea with serum follicle stimulating hormone (FSH) levels >
      40 mIU/mL (for US only: and estradiol < 20 pg/mL) or have had surgical bilateral
      oophorectomy (with or without hysterectomy) at least 6 weeks prior; 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 the study and
      through 20 months after the final dose of study treatment; for males with
      partners with childbearing potential, highly effective contraception is required
      for 6 months; 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 (eg, 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, must use highly effective (double barrier) methods of
      contraception (eg, spermicidal gel plus condom) for the entire duration of the
      study, and continuing using contraception and refrain from fathering a child for
      6 months following the study drug; a condom is required to be used also by
      vasectomized men as well as during intercourse with a male partner in order to
      prevent delivery of the study treatment via seminal fluid; 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

      - Note: hormonal contraception methods (eg, oral, injected, implanted) are not
      allowed

      - Note: woman are considered post-menopausal and not child bearing potential if
      they have had 12 months of natural (spontaneous) amenorrhea with an appropriate
      clinical profile (eg, age appropriate, history of vasomotor symptoms) or six
      months of spontaneous amenorrhea with serum FSH levels > 40 mIU/mL 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

   - Known diagnosis of human immunodeficiency virus (HIV) infection, hepatitis B or
   hepatitis C

   - 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