Phase I/II Study With Oral Panobinostat Maintenance Therapy Following Allogeneic Stem Cell Transplantation in Patients With High Risk Myelodysplastic Syndrome (MDS) or Acute Myeloid Leukemia (AML)

Study Overview
=================
Brief Summary
-----------------
The study's primary objective is to determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of Panobinostat when administered within 150 days after hematopoietic stem cell transplantation (HSCT) and given in conjunction with standard immunosuppressive therapy after HSCT for patients with high-risk Myelodysplastic Syndrome (MDS) or Acute Myeloid Leukemia (AML). Secondary objectives are To determine safety and tolerability of panobinostat To determine overall and disease-free survival at 12 months after HSCT To evaluate immunoregulatory properties of panobinostat To evaluate patient-reported health-related quality of life (HRQL) The hypothesis of this study is that panobinostat can be an effective drug in preventing relapse of MDS and AML patients with high-risk features after hematopoietic stem cell transplantation with reduced-intensity conditioning (RIC-HSCT) while at the same time reducing graft-versus-host disease (GvHD) with preservation of graft-versus-leukemia (GvL) effect.

Official Title
-----------------
Phase I/II Study With Oral Panobinostat Maintenance Therapy Following Allogeneic Stem Cell Transplantation in Patients With High Risk MDS or AML (PANOBEST)

Conditions
-----------------
Myelodysplastic Syndrome, Acute Myeloid Leukemia

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


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: AML (except acute promyelocytic leukemia, AML M3) with high-risk features defined as one or more of the following criteria: refractory to or relapsed after at least one cycle of standard chemotherapy > 10% bone marrow blasts at day 15 of the first induction cycle adverse risk cytogenetics including complex karyotype (≥ 3 abnormalities or abnormalities of chromosomes 3, 5 or 7) regardless of stage secondary to MDS or radio-/chemotherapy or MDS RAEB according to the WHO classification or intermediate-2 or high-risk according to IPSS or Chronic myelomonocytic leukemia (CMML) with ≥ 5% bone marrow blasts and Allogeneic HSCT with reduced intensity conditioning (see Section 15.1 for definition) performed within 60 - 150 days prior to study entry Complete hematologic remission documented by bone marrow aspiration within 28 days prior to study entry Exclusion Criteria: Active acute GvHD overall grade 2 - 4 Prior treatment with a deacetylase (DAC) inhibitor Patients with impaired cardiac function or other concurrent severe and/or uncontrolled medical conditions Clinical symptoms suggesting central nervous system (CNS) leukemia Patient has an impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of oral panobinostat

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

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

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

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

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Panobinostat Arm A<br> | Drug: Panobinostat<br>* 10mg upto 40mg Panobinostat dose escalation in consequent cohorts; frequency: three times a week, every week; duration: one year<br>* Other names: LBH589;|
| Experimental: Panobinostat Arm B<br> | Drug: Panobinostat<br>* Start of Arm B after completion of Arm A; initial dose-level: one level below MTD of Arm A; 10mg upto 60mg Panobinostat dose escalation in consequent cohorts; frequency: three times a week, every other week; duration: one year<br>* Other names: LBH589;|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum tolerated dose (MTD) of panobinostat |  | after 28 days of administration | 
| Dose-limiting toxicity (MTD) of Panobinostat |  | after 28 days of administration | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cumulative incidence of hematologic relapse and death |  | one year after HSCT | 
| Reconstitution of the immune system as measured by changes in numbers, ratio, phenotype and activation state of peripheral blood cell populations during panobinostat therapy |  | patients will be followed for up to 2 years depending on the duration of study participation | 
| Time to complete donor chimerism |  | patients will be followed for up to 2 years depending on the duration of study participation | 
| Cumulative incidence of extensive chronic GvHD |  | one year after HSCT | 
| Duration of complete donor chimerism |  | patients will be followed for up to 2 years depending on the duration of study participation | 
| Cumulative incidence of severe acute GvHD |  | one year after HSCT | 
| patient-reported health-related quality of life |  | after 3 months of administration and one month after last intake of study drug | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
MDS, 60 to 150 Days After Allogeneic Stem Cell Transplantation, High Risk MDS, AML