A Phase Ib Study of Panobinostat (LBH589) in Combination With 5-Azacitidine for Myelodysplastic Syndromes (MDS), Chronic Myelomonocytic Leukemia (CMML) or Acute Myeloid Leukemia (AML) Patients

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to confirm the safety and tolerability of oral panobinostat (PAN) in combination with a fixed dose of 5-Azacitidine (5-Aza) in adult Japanese patients with Myelodysplastic Syndromes (MDS), Chronic Myelomonocytic Leukemia (CMML) or Acute Myeloid Leukemia (AML).

Official Title
-----------------
A Phase Ib, Open-label, Multi-center, Dose-escalation Study of Oral Panobinostat (LBH589) Administered With 5-Azacitidine (Vidaza®) in Adult Japanese Patients With Myelodysplastic Syndromes (MDS), Chronic Myelomonocytic Leukemia (CMML) or Acute Myeloid Leukemia (AML)

Conditions
-----------------
Myelodysplastic Syndromes (MDS), Chronic Myelomonocytic Leukemia (CMML), Acute Myeloid Leukemia (AML)

Intervention / Treatment
-----------------
* Drug: Panobinostat


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Japanese patients 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% blasts (former RAEB-T according to FAB) OR CMML Patient has an ECOG performance status of ≤ 2 Patients must have the following laboratory values unless elevations are considered due to MDS or leukemia: 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 without clinically relevant abnormalities Exclusion Criteria: Patient who is planned for or has history of hematopoietic stem-cell transplantation (HSCT) Patients with relapsed/refractory AML Patient is receiving concurrent anti-cancer therapy Patient has received prior treatment with deacetylase inhibitors (DACi) Patient has received prior treatment with 5-Aza or 6-aza-2'-deoxycytidine (decitabine) 7. Patient has shown suspected hypersensitivity to 5-Aza or Mannitol 8. Patients with impaired cardiac function 9. Patient taking medications with relative risk of prolonging the QT interval or inducing Torsade de pontes if such treatment cannot be discontinued or switched to a different medication prior to starting study treatment 10. Patients with clinical evidence of relevant mucosal or internal bleeding 11. Patient has any other concurrent severe and/or uncontrolled medical conditions Other protocol-defined inclusion/exclusion criteria may apply

Ages Eligible for Study
-----------------
Minimum Age: 20 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Panobinostat and Azacitidine<br>combination regimen | Drug: Panobinostat<br> <br> * Other names: LBH589;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Dose Limiting Toxicitiy(DLT) | DLT will be assessed during PK run-in period (up to 7 days) and 1st cycle (28 days) | first 5 weeks of treatment period | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PK parameter - Cmax |  | Day 1 to 3 of PK run-in period; pre-dose (0 hour), 0.5, 1, 2, 3, 4, 6, 8, 24 and 48 hours | 
| PK parameter - Tmax |  | Day 1 to 3 of PK run-in period; pre-dose (0 hour), 0.5, 1, 2, 3, 4, 6, 8, 24 and 48 hours | 
| PK parameter - AUC (AUC0-48, AUC0-tlast) |  | Day 1 to 3 of PK run-in period; pre-dose (0 hour), 0.5, 1, 2, 3, 4, 6, 8, 24 and 48 hours | 
| PK parameter - T1/2 (apparent oral clearance, volume distribution) |  | Day 1 to 3 of PK run-in period; pre-dose (0 hour), 0.5, 1, 2, 3, 4, 6, 8, 24 and 48 hours | 
| PK parameter - AUC0-inf |  | Day 1 to 3 of PK run-in period; pre-dose (0 hour), 0.5, 1, 2, 3, 4, 6, 8, 24 and 48 hours | 
| Trough level of PAN in combination with 5-Aza |  | Day 4, 5, 8 of the 1st cycle; pre-dose (0 hour) | 
| Frequency and severity of Adverse Events (AEs) | Safety will be measured in terms of type, frequency and severity of adverse events according to CTCAE v4.03. | Participants will be followed for the duration of treatment, an expected average of 6 months | 
| Laboratory abnormalities |  | duration of treatment, an expected average of 6 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Myelodysplastic Syndromes, MDS, Chronic Myelomonocytic Leukemia, CMML, Acute Myeloid Leukemia, AML, Panobinostat, LBH589, 5-Aza, Azacitidine