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

PRIMARY OBJECTIVES:

Estimate the overall response rate (ORR) of sonidegib (erismodegib) in combination with
buparlisib (hereby referred to as "LB therapy") for patients with locally advanced or
metastatic basal cell carcinoma (BCC) in Smoothened inhibitor-naive patients (Cohort 1) and
those whose disease is refractory or relapsed on Smoothened inhibitor monotherapy (Cohort 2).

NOTE: This study does not compare the treatment effect between these 2 dissimilar participant
groups.

SECONDARY OBJECTIVES:

- Estimate the median duration of response, on or after LB therapy.

- Assess the safety and tolerability of LB therapy.

- Assess the histopathologic effect of LB therapy in tumor biopsies obtained at baseline
and following 12 weeks of treatment.

- Assess the effect of LB therapy on gene expression including Hedgehog pathway and
phosphatidylinositol 3-kinase (PI3K) pathways.

- Assess correlation between gene mutations in Smoothened, suppressor of fused homolog
(Sufu), patched (PTCH), glioma-associated oncogene homolog (Gli)1, 2 and gene expression
profiles and response to LB therapy.

OUTLINE:

Patients receive sonidegib orally (PO) once daily (QD) and buparlisib PO QD on days 1 to 28.
Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days and then every 3
months.

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