Phase IB Trial of LDE225 and Paclitaxel in Recurrent Ovarian Cancer

Ovarian cancer remains the deadliest gynecologic cancer with a fairly low long-term cure
rate. LDE225 is a new type of drug that inhibits or blocks a pathway responsible for cancer
cell growth. LDE225 is an investigational drug that has been used either solely or in
combination with chemotherapy in other types of cancer but not in ovarian cancer. Research
evidence suggests that by combining LDE225 and paclitaxel together, ovarian cancer cells may
become more responsive to treatment.

Inclusion Criteria:

- Recurrent epithelial ovarian, fallopian tube or primary peritoneal carcinoma
Histologic confirmation of the original primary tumor is required

- Papillary serous, endometrioid, clear cell, undifferentiated and mixed histologies

- Platinum resistant or refractory disease as per standard clinical and Gynecologic
Oncology Group definition. Patients have had a treatment-free interval of less than 6
months from last platinum-based treatment to recurrence or progression during platinum
based therapy

- Patients must have received at least one-prior platinum based chemotherapy regimen, to
include cisplatin, carboplatin or other organoplatinum compound, for treatment of
primary or recurrent ovarian, fallopian tube or primary peritoneal cancer

- Patients must have received a taxane as part of their prior treatment

- Measurable disease is required. By definition, measurable disease is at least one
lesion that can be accurately measured in at least one dimension with the longest
dimension to be recorded. Each lesion must be ≥ 20 mm when measured by conventional
techniques, including palpation, plain x-ray, CT, MRI or ≥ 10 mm when measured by
spiral CT imaging

- Patients must have one target lesion to be utilized in order to assess response per
RECIST criteria

- ECOG Performance statuses of 0, 1, or 2

- Adequate organ function as evidenced by:

1. Hematology: WBC ≥3.0 x 10^9/L; ANC ≥1.5 x 10^9/L; Platelets ≥100 x 10^9/L

2. Renal function: Creatinine less than or equal to 1.5 x institutional upper limit
of normal (ULN) or 24-hour clearance greater than or equal to 50 mL/min

3. Hepatic function: Bilirubin ≤ 1.5 x ULN and ALT, SGOT and alkaline phosphatase ≤
2.5 x ULN

4. Plasma creatine phosphatase (CK) less than 1.5 x ULN

5. Serum creatinine less than or equal to 1.5 x ULN or 24-hour clearance greater
than or equal to 50 mL/min

- Signed informed consent.

- Female patients of any ethnic group. Female patients must be surgically sterile,
postmenopausal (no menses for at least one year), or using medically approved method
of contraception (excluding rhythm, withdraw or abstinence)

- Age greater than or equal to 19

- Recovery from effects of any recent surgery, chemotherapy and/or radiation

1. No evidence of active infection requiring antibiotic therapy

2. Hormonal therapy being utilized, as an anti-neoplastic treatment must be
discontinued at least one week prior to study entry. Hormonal replacement therapy
for symptom management is allowed

3. Any prior therapy directed at the malignancy including biologic or immunologic
agents, must have be discontinued at least three weeks prior to study entry

Exclusion Criteria:

- Patients with pathology demonstrating mucinous, carcinosarcoma or low malignant
potential tumor histology are excluded. In addition, non-ovarian malignancies,
malignant germ cell or stromal tumors are also excluded

- Previous or concurrent malignancies at other sites within the last 5 years, with the
exception of in situ carcinoma of the cervix and adequately treated basal cell
carcinoma or squamous cell carcinoma of the skin. In addition, patients with prior or
concomitant, based on hysterectomy, Stage IA endometrial adenocarcinoma with less than
3 mm depth on invasion, absence of lymphovascular space invasion and absence of grade
3, papillary serous or clear cell histology are allowed

- Patients with prior radiation to the abdominal cavity or pelvis are excluded

- Patients unable to take oral drugs or with lack of physical integrity of the upper
gastrointestinal tract or known malabsorption syndromes

- Patients who have previously been treated with systemic sonidegib (LDE225) or with
other Hh pathway inhibitors

- Serious concomitant illness including but not limited to: uncontrolled diabetes
mellitus, dementia, active infection (including HIV infection) requiring IV or oral
antibiotics and psychiatric illness and/or other uncontrolled medical conditions which
may preclude compliance with study protocol

- Patients who have neuromuscular disorder (e.g. inflammatory myopathies, muscular
dystrophy, amyotrophic lateral sclerosis and spinal muscular atrophy) or are on
concomitant treatment with drugs that are recognized to cause rhabdomyolysis, such as
HMG CoA inhibitors (statins), clofibrate and gemfibrozil, and the cannot be
discontinued at least 2 weeks prior to starting sonidegib treatment. If it is
essential that the patient remain on a statin to control hyperlididemia, only
pravastatin may be used with extra caution

- Patients who are planning on embarking on a new strenuous exercise regimen after
initiation of study treatment. Muscular activities, such as strenuous exercise, that
can result in significant increases in plasma CK levels should be avoided whilst on
sonidegib treatment

- Patients who have taken part in an experimental drug study within 4 weeks or 5
half-lives, whichever is longer, of initiating treatment with sonidegib

- Patients who are receiving other anti-neoplastic therapy (e.g. chemotherapy, targeted
therapy or radiotherapy) concurrently or within 2 weeks of starting treatment with
sonidegib

- Peripheral Neuropathy of NCI-CTC (National Cancer Institute-Common Toxicity Criteria)
grade greater than or equal to 2

- Impaired cardiac function or clinically significant heart disease, including any one
of the following:

1. Angina pectoris within 3 months

2. Acute myocardial infarction within 3 months

3. QTcF > 470 msec on the screening ECG

4. A past medical history of clinically significant ECG abnormalities or a family
history of prolonged QT-interval syndromes

5. Other clinically significant heart disease (e.g. congestive heart failure,
uncontrolled hypertension, history of labile hypertension, or history of poor
compliance with an antihypertensive regimen)

- Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a
female after conception and until the termination of gestation, confirmed by a
positive hCG laboratory test (>5 mIU/mL)

- Patients who are not willing to apply highly effective contraception during the study
and through the duration as defined below after the final dose of study treatment

a. Women of childbearing 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. Highly effective
contraception is defined as either:

1. Total abstinence: When this is in line with the preferred and usual lifestyle of
the patient. Periodic abstinence (e.g. calendar, ovulation, symptothermal,
post-ovulation methods) and withdrawal are not acceptable methods of
contraception

2. Sterilization: Patient has had surgical bilateral oophorectomy (with or without
hysterectomy) or tubal ligation at least six weeks before taking study treatment.
In case of oophorectomy alone, only when the reproductive status of the woman had
been confirmed by follow- up hormone level assessment

3. Male partner sterilization (with the appropriate post-vasectomy documentation of
the absence of sperm in the ejaculate). For female study patients, the
vasectomized male partner should be the sole partner for that patient

4. Use a combination of the following (both a + b):

1. Placement of a non-hormonal intrauterine device (IUD) or non- hormonal
intrauterine system (IUS)

2. Barrier method of contraception: Condom or occlusive cap (diaphragm or
cervical vault caps) with spermicidal foam/gel/film/cream/vaginal
suppository.

Note: Hormonal contraception methods (e.g. oral, injected, implanted) are
not allowed as it cannot be ruled out that the study drug decreases the
effectiveness of hormonal contraception.

Note: Women are considered post-menopausal and not 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 FSH levels >40
mIU/mL and estradiol <20 pg/mL or have had surgical bilateral oophorectomy
(with or without hysterectomy) at least six week 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.

- History of hypersensitivity to paclitaxel

- Mental condition rendering the subject unable to understand the nature, scope, and
possible consequences of the study

- Patients who are receiving treatment with medications known to be moderate and strong
inhibitors or inducers of CYP3A4/5 or drugs metabolized by CYP2B6 or CYP2C9 that have
narrow therapeutic index, and that cannot be discontinued before starting treatment
with sonidegib. Medications that are strong CYP3A4/5 inhibitors should be discontinued
at least 7 days and strong CYP3A/5 inducers for at least 2 weeks prior to starting
treatment with sonidegib