Trial record 1 of 1 for:    "Hemoglobin sickle-beta thalassemia"
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Study of Panobinostat (LBH589) in Patients With Sickle Cell Disease

This study is currently recruiting participants. (see Contacts and Locations)
Verified May 2012 by Georgia Regents University
Sponsor:
Collaborator:
Novartis Pharmaceuticals
Information provided by (Responsible Party):
Abdullah Kutlar, Georgia Health Sciences University
ClinicalTrials.gov Identifier:
NCT01245179
First received: November 19, 2010
Last updated: May 7, 2012
Last verified: May 2012
  Purpose

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.


Condition Intervention Phase
Sickle Cell Disease
Drug: panobinostat
Phase 1

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Phase I Study to Determine the Safety and Tolerability of Escalating Doses of Panobinostat (LBH589) in Patients With Sickle Cell Disease

Resource links provided by NLM:


Further study details as provided by Georgia Regents University:

Primary Outcome Measures:
  • Primary Outcome Measure [ Time Frame: Days 1, 5, 8, 15, 22, 29, 43, 57, 85, 113 ] [ Designated as safety issue: Yes ]
    To determine the safety and dose limiting toxicities of escalating doses of oral panobinostat in sickle cell disease


Secondary Outcome Measures:
  • Secondary Outcome Measure [ Time Frame: Days 1, 5, 8, 15, 22, 29, 43, 53, 85, 113 ] [ Designated as safety issue: No ]

    To determine the effect of escalating doses of oral panobinostat on the following parameters:

    I.Overall HbF percentage and F cells

    II. Change in total hemoglobin

    III. Rate of change of total hemoglobin

    IV. Effect on serum inflammation markers and cytokines


  • Exploratory Outcome Measure [ Time Frame: Day 1 and Day 85 ] [ Designated as safety issue: No ]

    I. Histon acetylation of gamma genes

    II. Methylation of gamma genes



Estimated Enrollment: 27
Study Start Date: November 2010
Estimated Study Completion Date: December 2014
Estimated Primary Completion Date: December 2013 (Final data collection date for primary outcome measure)
Intervention Details:
    Drug: panobinostat

    Oral capsules taken Monday, Wednesday,Friday for 12 weeks:

    I. 10mg 1 week on/3 weeks off, 10 mg/ 2 weeks on 2 weeks off, 10mg/continuous

    II. 15mg 1 week on/3 weeks off, 15mg/ 2 weeks on 2 weeks off, 15mg/continuous

    III. 20mg 1 week on/3 weeks off, 20mg/ 2 weeks on 2 weeks off, 20mg/continuous

    Other Names:
    • LBH589
    • LBH589 lactate
  Show Detailed Description

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01245179

Locations
United States, Georgia
Georgia Health Sciences University Recruiting
Augusta, Georgia, United States, 30912
Contact: Leigh Wells, MSN, FNP    706-721-2171    lwells@georgiahealth.edu   
Contact: Latanya Bowman, RN, BSN    706-721-2171    lbowman@georgiahealth.edu   
Sponsors and Collaborators
Abdullah Kutlar
Novartis Pharmaceuticals
Investigators
Principal Investigator: Abdullah Kutlar, MD Georgia Regents University
  More Information

No publications provided

Responsible Party: Abdullah Kutlar, Professor of Medicine, Director of GHSU Sickle Cell Center, Georgia Health Sciences University
ClinicalTrials.gov Identifier: NCT01245179     History of Changes
Other Study ID Numbers: CLBH589BUS43T
Study First Received: November 19, 2010
Last Updated: May 7, 2012
Health Authority: United States: Food and Drug Administration

Keywords provided by Georgia Regents University:
sickle cell anemia
sickle cell thalassemia
HDAC inhibitor
hemoglobin F
sickle beta thalassemia

Additional relevant MeSH terms:
Anemia, Sickle Cell
Anemia, Hemolytic, Congenital
Anemia, Hemolytic
Anemia
Hematologic Diseases
Hemoglobinopathies
Genetic Diseases, Inborn
Panobinostat
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions
Histone Deacetylase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on August 18, 2014