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

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ClinicalTrials.gov Identifier: NCT01245179
Recruitment Status : Active, not recruiting
First Posted : November 22, 2010
Last Update Posted : June 4, 2019
Sponsor:
Collaborator:
Novartis Pharmaceuticals
Information provided by (Responsible Party):
Abdullah Kutlar, Augusta University

Brief Summary:
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 or disease Intervention/treatment Phase
Sickle Cell Disease Drug: panobinostat Phase 1

  Show Detailed Description

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 18 participants
Intervention Model: Single Group Assignment
Masking: None (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
Actual Study Start Date : November 2010
Estimated Primary Completion Date : July 2023
Estimated Study Completion Date : July 2024


Arm Intervention/treatment
Experimental: Panobinostat
All patients will receive Panobinostat at specified dose levels and dosing schedules.
Drug: panobinostat

Panobinostat oral capsules taken THRICE WEEKLY (Monday, Wednesday, and Friday) for 12 weeks, exploring the following dosing regimens:

  1. 15 mg MWF 3 weeks on, 1 week off (if needed)
  2. 15 mg MWF every week (starting dose)
  3. 20 mg MWF 3 weeks on, 1 week off
  4. 20 mg MWF every week
Other Names:
  • LBH589
  • LBH589 lactate
  • FARYDAK®




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


Secondary Outcome Measures :
  1. Secondary Outcome Measure [ Time Frame: Days 1, 8, 15, 22, 29, 43, 53, 85, 113 ]

    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. Effect on serum inflammation markers and cytokines (every 4 weeks)

    IV. Effect on quality of life as measured by ASCQMe questionnaire (pre- and post-treatment)


  2. Define mechanisms of effect of panobinostat (Hb F induction and anti-inflammatory effects) and discover biomarkers of treatment response [ Time Frame: Day 1 and Day 85 ]

    I. Define epigenetic changes in the HBB locus mediated by panobinostat to reverse Hb F silencing in vivo

    II. Define the mechanism(s) of anti-inflammatory effects

    III. Determine the effect of panobinostat on RBC sickling

    IV. Perform an integrated bioinformatics analysis of histone acetylation and gene expression transcriptome of SCD patients treated with panobinostat




Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria

  1. Male or female patients ages ≥ 18 years
  2. Confirmed diagnosis of homozygous SS or S-β0Thalassemia
  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).
  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). Prior use of HDACi, including panobinostat, is not an exclusion criterion if discontinued > 60 days.
  2. Patients who have had a vaso-occlusive crisis within the past 2 weeks that required treatment with parenteral medication.
  3. 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)
  4. Patients on a chronic transfusion regimen, or any patient who has Hb A% > 20% from a recent transfusion
  5. Any of the following laboratory abnormalities derived from the screening visit:

    • Absolute neutrophil count (ANC) < 1.5 x 109/L
    • Hemoglobin < 6 g/dl
    • Platelets < 100x 109/L
    • Serum creatinine >1.5 x Upper limits of normal (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 < Lower limits of normal (LLN)
    • Total serum calcium [corrected for serum albumin] or ionized calcium <LLN
    • Serum magnesium < LLN
    • Serum phosphorus < LLN
  6. Known impaired cardiac function or clinically significant cardiac diseases, including any one of the following:

    • Left ventricular ejection fraction (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 > 470 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)
  7. 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
  8. Patients who are currently receiving treatment with any study drug or have been on any study medications within the past 60 days.
  9. Patients who have undergone major surgery 2 weeks prior to starting study drug or who have not recovered from side effects of such therapy.
  10. 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, if they are sexually active. 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.
  11. 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.
  12. Known diagnosis of HIV infection, Hepatitis B; or acute/chronic, active Hepatitis C
  13. 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)
  14. 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.
  15. Patients who are currently receiving treatment with certain prohibited medications and cannot either discontinue this treatment or switch to a different medication prior to study enrollment.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01245179


Locations
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United States, Georgia
Augusta University
Augusta, Georgia, United States, 30912
Sponsors and Collaborators
Abdullah Kutlar
Novartis Pharmaceuticals
Investigators
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Principal Investigator: Abdullah Kutlar, MD Augusta University

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Responsible Party: Abdullah Kutlar, Professor of Medicine, Director of Augusta University Sickle Cell Center, Augusta University
ClinicalTrials.gov Identifier: NCT01245179     History of Changes
Other Study ID Numbers: CLBH589BUS43T
First Posted: November 22, 2010    Key Record Dates
Last Update Posted: June 4, 2019
Last Verified: June 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Abdullah Kutlar, Augusta University:
sickle cell anemia
sickle cell thalassemia
HDAC inhibitor
hemoglobin F
sickle beta thalassemia
Fetal Hemoglobin
Additional relevant MeSH terms:
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Anemia, Sickle Cell
Anemia, Hemolytic, Congenital
Anemia, Hemolytic
Anemia
Hematologic Diseases
Hemoglobinopathies
Genetic Diseases, Inborn
Panobinostat
Antineoplastic Agents
Histone Deacetylase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action