Testing panobinostat for treating sickle cell disease

Phase I Study to Determine the Safety and Tolerability of Escalating Doses of Panobinostat (LBH589) in Patients With Sickle Cell Disease

This study is testing if a new drug called panobinostat can help adults with sickle cell disease who haven't found relief with standard treatment.

Quick facts

• Phase: Phase 1
• Study type: Interventional
• Enrollment: 18 (estimated)
• Ages: 18 Years and up
• Sex: All
• Sponsor: Augusta University (Academic / other)
• Locations: 1 site (Augusta, Georgia)
• Trial ID: NCT01245179 on ClinicalTrials.gov

What this trial studies

This clinical research focuses on evaluating the safety and effects of panobinostat, a pan histone deacetylase (HDAC) inhibitor, in adults with sickle cell disease who have not responded to hydroxyurea therapy. The study is designed as a one-arm, open-label, Phase I trial that will assess the maximum tolerated dose and dose-limiting toxicities of panobinostat over a twelve-week treatment phase. Participants will undergo a screening phase to determine eligibility based on specific criteria related to their sickle cell disease history and treatment response. The goal is to explore the potential of panobinostat to improve outcomes for patients suffering from this debilitating condition.

Who should consider this trial

Good fit: Ideal candidates are adults aged 18 and older with a confirmed diagnosis of homozygous SS or S-β0Thalassemia who are intolerant to or have failed hydroxyurea therapy.

Not a fit: Patients currently on chronic blood transfusion regimens or those without significant complications from sickle cell disease may not benefit from this study.

Why it matters

Potential benefit: If successful, this treatment could provide a new effective option for managing sickle cell disease in patients who have not benefited from existing therapies.

How similar studies have performed: While the use of HDAC inhibitors in sickle cell disease is a novel approach, similar studies have shown promise in increasing hemoglobin F levels and reducing inflammation.

Eligibility 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.

Where this trial is running

Augusta, Georgia

• Augusta University — Augusta, Georgia, United States (Recruiting)

Study contacts

• Principal investigator: Abdullah Kutlar, MD — Augusta University

Conditions Sickle Cell Disease; sickle cell anemia; sickle cell thalassemia; HDAC inhibitor; hemoglobin F; sickle beta thalassemia; Fetal Hemoglobin