| Conditions: |
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Sickle Cell Disease |
| Purpose: |
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The goal of this clinical research study is to find out about the safety and effects of a
drug called panobinostat when given to adults with sickle cell disease. Panobinostat is a
pan histone deacetylase (HDAC) inhibitor. HDAC inhibitors have been shown to significantly
increase hemoglobin F induction, which is well documented to improve outcomes in sickle cell
disease. HDAC inhibitors are also known to potently inhibit cell-specific inflammation,
which is a primary contributor to the debilitating effects of sickle cell disease. Given the
relevance of these mechanisms of action in SCD, panobinostat may prove to contribute
significantly to the management of SCD patients, a population in critical need of further
effective treatment options.
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| Study Summary: |
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This is a one-arm, open-label, multi-center, 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 hydroxyurea
therapy.
The study consists of a Screening Phase, Treatment Phase, and Post-Treatment
Follow-up.Screening 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, urinalysis (with
microscopic evaluation if indicated), and serum pregnancy in all females of childbearing
potential. Approximately 15 ml (1 tablespoon) of blood will be collected at the screening
visit.
Treatment 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 will be assigned to dose level 1 (10 mg), with a
dosing schedule of one week of treatment (Monday, Wednesday, and Friday) followed by three
weeks off treatment for the entire 12 week treatment period. The next three subjects will
be assigned to dose level 1 (10 mg), with two weeks of treatment (Monday, Wednesday, and
Friday) followed by two weeks off treatment for the entire 12 week treatment period. The
following three subjects will be assigned to dose level 1 (10 mg), with continuous thrice
weekly dosing during the entire 12 week treatment period. Patient assignment will continue
in this same manner until all three dose levels and schedules are filled or until the
maximum tolerated dose (MTD) is found. All three subjects in a given cohort must complete
one cycle of treatment before enrollment can begin in the next cohort. If the MTD is
identified before all cohorts are completed, all subsequent subjects will be enrolled at
that dosage and will be assigned one of the three dosing schedules to be followed for the
entire 12 week treatment period. 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. 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, 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, inflammatory markers, exploratory studies, urinalysis (with
microscopic evaluation if indicated), and urine pregnancy test for women of childbearing
potential. Approximately 10 ml (2 teaspoons) of blood will be collected at each of the
treatment visits.
For all patients, a minimum of 3 sequential 12-lead ECGs, separated by at least 5 minutes,
must be performed on Day 1 (baseline) and Day 5 pre-dose and 3 hours post-dose. Other ECG's
(Day 29 and Day 57) are single pre-dose recordings
Study personnel should place a telephone call to each patient on Days 50 and 71 to assess
interim study drug compliance and to obtain information regarding any adverse events that
may have occurred between study visits.
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 A follow-up visit will be performed 4 weeks after the Day 85 visit. 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 10 ml (2
teaspoons) of blood will be collected at the follow-up visit.
Optional genetic sub-study Exploratory genetic labs will be done on subjects who agree to
participate. Histone acetylation and methylation assays of gamma genes will be performed as
an assessment of the mechanism of action of panobinostat. Approximately 15ml of extra blood
will be collected at four separate visits.
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| Criteria: |
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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 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).
5. Ability to provide written informed consent obtained prior to participation in the
study and any related procedures being performed
6. Clinically euthyroid. Note: Patients are permitted to receive thyroid hormone
supplements to treat underlying hypothyroidism.
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 4 weeks
4. Impairment of GI function or GI disease that may significantly alter the absorption
of panobinostat (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea,
malabsorption syndrome, or small bowel resection)
5. Patients on a chronic transfusion regimen or any patient who has had a transfusion
within last 90 days or has HbA% > 20% from prior transfusion
6. Any of the following laboratory abnormalities derived from the screening visit:
- ANC < 1.5 x 109/L
- Hemoglobin < 6 g/dl
- Platelets < 100x 109/L
- Serum creatinine >1.5 x ULN
- AST and ALT > 2.5 x ULN
- Serum total bilirubin > 10 mg/dL
- Serum direct bilirubin >1 mg/dL
- Albumin <3.0 g/dl
- Serum potassium <LLN
- Total serum calcium [corrected for serum albumin] or ionized calcium <LLN,
- Serum magnesium < LLN
- Serum phosphorus < LLN
7. Known impaired cardiac function or clinically significant cardiac diseases, including
any one of the following:
- LVEF < lower limit of the institutional normal as determined by screening
echocardiogram
- Complete left bundle branch block
- Obligate use of a cardiac pacemaker
- Congenital long QT syndrome
- History or presence of ventricular tachyarrhythmia
- Presence of unstable atrial fibrillation (ventricular response > 100 bpm).
Patients with stable atrial fibrillation are eligible, provided they do not meet
any of the other cardiac exclusion criteria.
- Clinically significant resting bradycardia (< 50 bpm)
- QTc > 450 msec on screening ECG
- Right bundle branch block + left anterior hemiblock (bifasicular block)
- Angina pectoris 3 months prior to starting study drug
- Acute MI 3 months prior to starting study drug
- Other clinically significant heart disease (e.g., CHF, uncontrolled
hypertension, history of labile hypertension, or history of poor compliance with
an antihypertensive regimen)
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 (except for basal or
squamous cell carcinoma, or in situ cancer of the cervix)
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 any of the following medications
and cannot either discontinue this treatment or switch to a different medication
prior to study enrollment:
ALL Class IA antiarrhythmics
• quinidine (Quinaglute, Quinalan, Quinate, Quinidex, Quinora)
• procainamide (Procanbid, Pronestyl)
- disopyramide (Norpace, Rythmodan-LA)
- any other class IA antiarrhythmic drug
ALL Class III antiarrhythmics
- amiodarone (Cordarone, Pacerone)
- sotalol (Betapace, Rylosol, Sotacar)
- bretylium (Bretylol, Bretylate)
- disopryamide (Norpace)
- dofetilide (Tikosyn)
- ibutilide (Corvert)
- any other class III antiarrhythmic drug
Antibiotics Macrolide antibiotics*
• erythromycin (Eryc, E-mycin, EES, Erythrocin)
- clarithromycin (Biaxin)
- telithromycin (Ketek)
Quinolone antibiotics*
• sparfloxacin (Zagam)
Antiemetics
• dolasetron mesylate (Anzemet)
Antipsychotics
- thioridazine (Mellaril)
- mesoridazine (Serentil)
- chlorpromazine (Thorazine, Largactif)
- pimozide (Orap)
Antimalarials
• halofantrine (Halfan)
• chloroquine (Aralen)
Miscellaneous drugs or products:
• arsenic trioxide (Trisenox)
• astemizole (Hismanal)
• bepridil (Vascor)
• domperidone (Motilium, Motillium, Motinorm, Costi)
- levomethadyl (Orlaam)
- methadone (Dolophine, Methadose)
- pentamidine (Pentam, NeboPent, Pentacarina)
- droperidol (Inapsine)
- Note: azithromycin, ciprofloxacin, levofloxacin, pefloxacin, ofloxacin,
tosufloxacin, difloxacin, temafloxacin, fleroxacin, acrosoxacin, nalidixic
acid and enoxacin are allowed.
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| NCT ID: |
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NCT01245179 |
| Primary Contact: |
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Principal Investigator
Abdullah Kutlar, MD
Georgia Health Sciences University
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| Backup Contact: |
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N/A |
| Location Contact: |
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Augusta, Georgia 30912
United States
Leigh Wells, MSN, FNP
Phone: 706-721-2171
Email: lwells@georgiahealth.edu
Site Status: Recruiting |