Phase I Trial of LDE225 for Steroid-refractory Chronic GVHD After Allogeneic HSCT

This phase I clinical trial will enroll participants with steroid-refractory chronic GVHD,
and likely take approximately 24 months to complete accrual. Treatment will consist of LDE225
given daily for continuous dosing in 28-day cycles. Participants will have undergone
allogeneic SCT and have developed chronic GVHD which has not responded sufficiently to
systemic corticosteroids (dose of at least 0.25 mg/kg/day of ideal body weight), have
relapsed disease while tapering steroids, or not having an adequate response to steroids plus
other therapies. Participants who are responding will then be eligible to receive additional
courses of therapy. Participants will be followed on trial for 12 months after starting
therapy and the trial will be completed when all participants have reached 12 months of
follow-up or have withdrawn from the trial.

The initial dose escalation phase of 4 cohorts of participants (each cohort 3-6 participants)
will have a primary endpoint of safety and toxicity of administering LDE225 in this setting.

Inclusion Criteria:

Patients eligible for inclusion in this study have to meet all of the following criteria:

- Patients must provide written informed consent prior to any screening procedures.

- Age 18 years or older.

- Recipients of allogeneic hematopoietic cell transplantation (HCT) after either
myeloablative or reduced intensity conditioning regimens. Any donor source of stem
cells is eligible.

- Participants must be at least 100 days after HCT.

- Patients must have steroid refractory classic cutaneous, myofascial, or
sclerodermatous cGVHD (+/- other organ involvement, clinically diagnosed), defined as
having persistent signs and symptoms of chronic GVHD despite the use of prednisone at
≥ 0.25 mg/kg/day (or 0.5 mg/kg every other day) for at least 4 weeks in the preceding
12 months (or equivalent dosing of alternate corticosteroids) without complete
resolution of signs and symptoms or if not improving on any line of therapy beyond
steroids or if treating physician feels that increasing or adding steroids is not in
the patient's best interests. Note that the dose of systemic steroids can certainly be
lower than 0.25 mg/kg/day at enrollment.

- Stable dose of corticosteroids for 4 weeks prior to enrollment

- No addition or subtraction of other immunosuppressive medications (e.g., calcineurin
inhibitors, sirolimus, mycophenolate mofetil) for 4 weeks prior to enrollment. The
dose of immunosuppressive medicines may be adjusted based on the therapeutic range of
that drug

- ECOG performance status ≤ 3

- Serum Cr ≤ 2 gm / dL

- Adequate hepatic function (total bilirubin < 2.0 mg/dl, AST < 5x ULN), unless hepatic
dysfunction is a manifestation of cGVHD. For patients in whom a diagnosis of hemolysis
or Gilbert's is made, the total bilirubin is allowed to be elevated. For patients with
abnormal LFTs above the thresholds, documented cGVHD on liver biopsy will be required
prior to enrollment.

- Patients must have adequate bone marrow function as defined by ANC ≥ 1000 / µl and
platelets ≥ 20,000 / µl without growth factor or transfusional support

- Plasma creatine phosphokinase (CK) < 1.5 x ULN

- Patient is able to swallow and retain oral medication

Exclusion Criteria:

- Patients who have had major surgery within 4 weeks of initiation of study medication.

- Patients with concurrent uncontrolled medical conditions that may interfere with their
participation in the study or potentially affect the interpretation of the study data.

- 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 LDE225 or with other Hh
pathway inhibitors.

- Patients who have neuromuscular disorders (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 that cannot
be discontinued at least 2 weeks prior to starting LDE225 treatment. If it is
essential that the patient stays on a statin to control hyperlipidemia, 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. NB: Muscular activities, such as strenuous
exercise, that can result in significant increases in plasma CK levels should be
avoided whilst on LDE225 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 LDE225.

- Patients who are receiving other anti-neoplastic therapy (e.g. chemotherapy, targeted
therapy or radiotherapy) concurrently or within 2 weeks of starting treatment with
LDE225.

- Patients who are receiving treatment with medications known to be strong inhibitors or
inducers of CYP3A4/5 or drugs metabolized by CYP2B6 or CYP2C9 that have a narrow
therapeutic index, and that cannot be discontinued before starting treatment with
LDE225. 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 LDE225. Note that patients who require antifungal prophylaxis are
preferred to be on fluconazole, and, patients taking voriconazole or posaconazole who
must continue are excluded from the dose escalation phase of the study. Once the MTD
is established, patients taking voriconazole or posaconazole will be allowed to enroll
but at a dose adjustment to be determined before the expansion phase opens.

- Ongoing prednisone requirement > 1 mg/kg/day (or equivalent)

- Exposure to any new immunosuppressive medication in the 4 weeks prior to enrollment.

- ECP therapy within 4 weeks prior to enrollment

- Active disease relapse

- Active, uncontrolled infection

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

- Angina pectoris within 3 months

- Acute myocardial infarction within 3 months

- QTc > 450 msec for males and > 470 msec for females on the screening ECG

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

- Other clinically significant heart disease (e.g. congestive heart failure,
uncontrolled hypertension, history of labile hypertension, or history of poor
adherence 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.

- Women of child-bearing potential, defined as all women physiologically capable of
becoming pregnant, must use highly effective contraception during the study and
through 6 months after the final dose of study treatment. Highly effective
contraception is defined as either:

- 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.

- 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 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 study patients, the
vasectomized male partner should be the sole partner for that patient]

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

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

- 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 to count as contraception as it cannot be ruled out that the
study drug decreases the effectiveness of hormonal contraception. Patients
are able to continue taking oral contraceptives if desired.

- Note: Woman 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 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

- Male patient must use highly effective (double barrier) methods of contraception
(e.g., spermicidal gel plus condom) for the entire duration of the study, and
continue 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

- Sexually active males who are unwilling to use a condom during intercourse while
taking the study drug and for 6 months after stopping investigational medications
and agree not to father a child in this period.

- Patients unwilling or unable to comply with the protocol.