Study of Panobinostat (LBH589) in Patients With Sickle Cell Disease

This is a one-arm, open-label, Phase I, dose-escalation study of Panobinostat administered
via different dosing schedules. In each schedule, this study is designed to determine the MTD
(maximum tolerated dose) and DLT (dose limiting toxicities) of panobinostat as a single
agent, and to characterize the safety and tolerability of panobinostat in adult patients with
sickle cell disease who have failed to respond to hydroxyurea therapy (clinically or
hematologically) or are intolerant of or refuse hydroxyurea therapy. The study consists of a
Screening Phase, Treatment Phase, and Post-Treatment Follow-up.

Screening Phase:

Subjects will be screened for eligibility within 28 days of baseline visit (Day 1). Screening
assessments will include informed consent, physical exam, vital signs (height, weight, blood
pressure, heart rate, height, weight, and respirations), review of medical history, review of
concomitant medications, 12-lead electrocardiogram (ECG), echocardiogram, and laboratory
assessments. Screening laboratory assessments will include the following: CBC with
differential, reticulocytes, complete chemistry panel, LDH, serum ferritin, thyroid function
testing, Hb F percentage, F-cells, HIV, urine albumin/creatinine ratio, and serum pregnancy
in all females of childbearing potential. Approximately 15 ml (1 tablespoon) of blood will be
collected at the screening visit.

Treatment Phase:

The treatment phase is twelve weeks in duration. Each subject will be assigned to a specified
dose level and dosing schedule and will remain with the assigned regimen, if tolerated,
throughout the twelve week period. Regardless of specific dosing assignment, all subjects
will take study drug thrice weekly (Monday, Wednesday, and Friday). The first three patients
to enroll in the study (Cohort 1) will be assigned to a dose level of 15 mg panobinostat,
with a dosing schedule of two weeks of thrice weekly treatment followed by two weeks off
treatment for the entire 12-week treatment period. The next three subjects (Cohort 2) will be
assigned to a dose level of 15 mg panobinostat, with continuous thrice weekly dosing for the
entire 12-week period. The following three subjects (Cohort 3) will be assigned to a dose
level of 20 mg panobinostat, with a dosing schedule of two weeks of thrice weekly treatment
followed by two weeks off treatment for the entire 12-week treatment period. The final group
of 3 patients (Cohort 4) will be assigned to a dose level of 20 mg panobinostat, with
continuous thrice weekly dosing for the entire 12-week period. Patient assignment will
continue in this manner until all Cohorts are filled or until the maximum tolerated dose
(MTD) is found. All three subjects at a given dose level must complete at least 4 weeks of
treatment before enrollment can begin in the next dose level. MTD is defined as one dose
level lower than the dose on which 2/3 patients developed a dose limiting toxicity (DLT). If
the MTD is reached prior to patients starting a given dose level, the remaining number of
patients required to complete the study will be enrolled at the identified MTD, level and
schedule. During the Treatment Phase, safety and efficacy assessments will be performed at
specified times, and will include: physical examination, vital signs (weight, blood pressure,
heart rate, height, weight, and respirations), adverse events assessment, ECG, quality of
life questionnaire (ASCQMe), and laboratory assessments. Treatment phase lab assessments are
to be performed at specified visits and include CBC with differential, reticulocytes,
complete chemistry panel, LDH, serum ferritin, Hb F percentage, F-cells, thyroid function
testing, urine albumin/creatinine ratio, and urine pregnancy test for women of childbearing
potential. Approximately 15 ml (3 teaspoons) of blood will be collected at each treatment
visit. Every four weeks, an additional 5 ml of blood will be collected for inflammatory
markers and protein biomarkers, for a total of 20 ml. On Day 1 (pre-treatment) and Day 85
(post-treatment), when additional samples are collected for genetic/ mechanistic studies,
total volume collected is 25 ml.

Study drug will initially be dispensed at the baseline visit and every four weeks thereafter.
Study drug accountability should be assessed at every visit. All baseline assessments will be
completed prior to the first dose of study drug.

Follow-Up Phase:

A follow-up visit will be performed 4 weeks after end of treatment. Follow-up assessments
will include: physical examination, vital signs, adverse events assessment, ECG, and
laboratory assessments (CBC with differential, reticulocytes, complete chemistry panel, LDH,
Hb F percentage, F-cells, and inflammatory markers). Approximately 15 ml (3 teaspoons) of
blood will be collected at the follow-up visit.

Inclusion Criteria:

1.Male or female patients ages ≥ 18 years

2.Confirmed diagnosis of homozygous hemoglobin S or S- Beta0 Thalassemia

3.Intolerance to hydroxyurea therapy, refusal of hydroxyurea therapy, or failure to respond
(refractoriness) to hydroxyurea therapy, either clinically or hematologically

4.Clinically significant sickle cell disease as defined by:

1. At least two hospitalizations over the past twelve months for any complication of
sickle cell disease; or

2. At least three pain crises over the past twelve months that last four or more hours
and require a visit to a medical facility for treatment with oral or parenteral
narcotics; or

3. History of recurrent leg ulcers; or

4. History of Acute Chest Syndrome within the past five years; or

5. History of priapism requiring medical intervention within the past two years; or

6. History of stroke (but not currently on a chronic blood transfusion regimen).

Exclusion Criteria:

1. Use of agents that can induce Hb F within 60 days of Day 1 (i.e. hydroxyurea,
butyrates, decitabine, 5-azacytidine, IMiDs, or erythropoietin)

2. Prior HDAC, DAC, HSP90 inhibitors or valproic acid for the treatment of cancer

3. Patients who have had a vaso-occlusive crisis or another acute complication of
SCD (acute chest syndrome, hepatic sequestration, or CVA) within the past 2 weeks

5.Patients on a chronic transfusion regimen or any patient who has a HbA% > 20% from
prior transfusion

6. Certain laboratory abnormalities derived from the screening visit.

7.Known impaired cardiac function or clinically significant cardiac diseases.

8.Other concurrent severe and/or uncontrolled medical conditions (e.g., uncontrolled
diabetes, active or uncontrolled infection, chronic obstructive or chronic restrictive
pulmonary disease) that could cause unacceptable safety risks or compromise compliance
with the protocol

9.Patients who are currently receiving treatment with any study drug or have been on
any study medications within the past 60 days.

10.Patients who have undergone major surgery 2 weeks prior to starting study drug or
who have not recovered from side effects of such therapy.

11.Women of child-bearing potential (WCBP) who are pregnant or breast feeding or who
do not agree to use two methods of birth control, including a barrier method. WCBP,
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 at screening and negative urine pregnancy test within 72 hours prior to
starting study treatment. In addition, all sexually active WCBP must agree to use
double method of contraception (oral, injectable, or implantable hormonal
contraceptive; tubal ligation; intra-uterine device; barrier contraceptive with
spermicide; or vasectomized partner) during the study and 3 months after the end of
treatment. One of these methods of contraception must be a barrier method.

12.Male patients whose sexual partners are WCBP not using a double method of
contraception during and 3 months after the end of treatment. Males must agree to use
a condom during any sexual contact with WCBP during study drug treatment, during dose
interruptions, and for 3 months after the end of treatment.

13.Known diagnosis of HIV infection, Hepatitis B; or acute/chronic, active Hepatitis C

14.Patients with a prior malignancy with in the last 5 years.

15.Patients with any significant history of non-compliance to medical regimens or
unwilling or unable to comply with the instructions given to him/her by the study
staff.

16.Patients who are currently receiving treatment with certain medications and cannot
either discontinue this treatment or switch to a different medication prior to study
enrollment.