Title A phase I/b, open-label, multi-center, dose-escalation study of oral Panobinostat (LBH589) administered with 5-Azacitidine (Vidaza) in adult patients with myelodysplastic syndromes (MDS), chronic myelomonocytic leukemia (CMML) or acute myeloid leukemia (AML)


CC CC850

Hospital Main Campus

Stage N/A

Phase Phase 1

Disease Leukemia, Acute Myeloid (AML), Myelodysplastic Syndrome (MDS)

Drug LBH589, Vidaza (Azacitidine)



Primary objectives

  • To determine the MTD of oral panobinostat in combination with a fixed dose of 5-Aza in adult patients with IPSS INT-2 or high risk MDS, CMML, or AML.
  • End-points for primary objectives:
    • Incidence of DLT

Secondary objectives

  • To characterize the safety and tolerability of panobinostat in combination with 5-Aza in the target patients population.
  • End-points for secondary objectives:
    • Type, duration, frequency and relatedness of Adverse Events (AE). AE severity will also be assessed according to NCI Common Terminology Criteria for Adverse Events (CTCAE), version 3.0
    • Laboratory (such as biochemistry, hematology)
    • ECG monitoring (central review by eRT)

Exploratory objectives

  • To evaluate preliminary anti-leukemic activity of panobinostat in combination with 5-Aza in terms of response, according to IWG response criteria in AML and MDS as implemented in the Post-text supplement 1 (Cheson 2003, Cheson 2006)
  • To assess the effect of combined study treatment on gene expression and methylation status of specific genes known or suspected to be relevant to MDS/CMML/AML.
  • Endpoints for exploratory objectives:
    • Clinical response for AML: CR, CRi, PR; for MDS/CMML: CR, bone marrow CR, PR, HI
    • Changes in DNA methylation and changes in gene expression in peripheral blood cells before and during therapy.
Inclusion Criteria

Inclusion Criteria

  1. Adult patients (age ≥ 18 years) who are candidates for treatment with 5-Aza and present with one of the following:
    • intermediate-2 or high-risk MDS according to the International Prognostic Scoring System (IPSS) OR
    • AML with multilineage dysplasia and maximum of 30% bone marrow blasts (former RAEB-T according to FAB, currently AML according to WHO definition) OR
    • Chronic Myelomonocytic Leukemia (CMML)
  2. ECOG performance status ≤ 2
  3. Patients must have the following laboratory values unless elevations are considered due to underlying disease:
    • AST/SGOT and/or ALT/SGPT ≤ 2.5 x ULN
    • Serum creatinine ≤ 1.5 x ULN
    • Serum bilirubin (total and direct) ≤ 2 x ULN
    • Electrolyte panel within normal ranges for the institution.
  4. Negative pregnancy test
  5. Clinically euthyroid (hypothyroidism corrected with supplementation is permitted).
  6. Written informed consent obtained prior to any screening procedures
Exclusion Criteria

Exclusion Criteria

  1. Planned hematopoietic stem-cell transplantation (HSCT)
  2. Patients with therapy- related MDS
  3. Patients with therapy-related AML and/or relapsed/refractory AML
  4. Clinical symptoms suggesting CNS leukemia
  5. Concurrent therapy with any other investigational agent
  6. Prior treatment with deacetylase inhibitor(s)
  7. Prior treatment with 5-Aza or 5-aza-2’-deoxycytidine (decitabine)
  8. Time windows for prior therapies: Last dose of therapy, including cytokines and/or retinoids, immunotherapy, low-dose ara-C, investigational agent no less than 28 days with the exception of hydroxyurea (24 hours) prior to receipt of study medication and AEs that have recovered at least to NCI CTCAE Grade 1.
  9. Patients with impaired cardiac function including any of the following:
    • Complete left bundle branch block or use of a permanent cardiac pacemaker, congenital long QT syndrome, history or presence of ventricular tachyarrhythmia, clinically significant resting bradycardia (<50 beats per minute), QTcF > 460 ms on screening ECG, or right bundle branch block + left anterior hemiblock (bifascicular block)
    • Presence of unstable atrial fibrillation (ventricular response rate >100 bpm). Patients with stable atrial fibrillation are eligible provided they do not meet the other cardiac exclusion criteria
    • Previous history of angina pectoris or acute MI within 6 months
    • Baseline LVEF <45% by echocardiography
    • Other clinically significant heart disease (e.g. uncontrolled hypertension or history of poor compliance with an antihypertensive regimen).
  10. Drugs which may cause QT prolongation and the treatment cannot be discontinued or switched to a different medication prior to starting study drug
  11. Any of concurrent severe and/or uncontrolled medical conditions which could compromise participation in the study. For example:
    • Uncontrolled diabetes
    • Active or uncontrolled infection
    • Uncontrolled hypothyroidism
    • Acute or chronic liver or renal disease
  12. Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of oral panobinostat (e.g., ulcerative diseases, diarrhea, malabsorption syndrome, or small bowel resection).
  13. HIV, Hepatitis B/C infection according to the medical history (testing will not be performed).
  14. Female patients who are pregnant or breast feeding or patients of childbearing potential (WOCBP) not willing to use a double barrier method of contraception during the study and for 3 months following the last dose of study drug.
  15. Male patients whose sexual partner(s) are WOCBP who are not willing to use a double barrier method of contraception, one of which includes a condom, during the study and for 3 months after the end of treatment.
  16. Suspected hypersensitivity to 5-Aza or Mannitol
  17. Inability to swallow capsules
  18. Unwilling or unable to comply with the protocol
  19. Patient has evidence of clinically significant mucosal or internal bleeding