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) (PANOBEST)

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

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.

Study Overview

• Status: Unknown
• Conditions: Acute Myeloid Leukemia; Myelodysplastic Syndrome
• Intervention / Treatment: Drug: Panobinostat; Drug: Panobinostat

• Study Type: Interventional
• Enrollment (Anticipated): 62
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Germany
  • Düsseldorf, Germany, 40225
    • University Hospital Düsseldorf
  • Essen, Germany, 45147
    • University Hospital Essen
  • Frankfurt am Main, Germany, 60590
    • University Hospital Frankfurt
  • Hamburg, Germany, 20246
    • University Hospital Hamburg-Eppendorf
  • Mainz, Germany, 55131
    • University Hospital Mainz
  • Marburg, Germany, 35043
    • University Hospital Marburg

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Panobinostat Arm A	Drug: Panobinostat; 10mg upto 40mg Panobinostat dose escalation in consequent cohorts; frequency: three times a week, every week; duration: one year; Other Names: LBH589; Drug: Panobinostat; 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; Other Names: LBH589
Experimental: Panobinostat Arm B	Drug: Panobinostat; 10mg upto 40mg Panobinostat dose escalation in consequent cohorts; frequency: three times a week, every week; duration: one year; Other Names: LBH589; Drug: Panobinostat; 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; Other Names: LBH589

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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	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

Collaborators and Investigators

• Sponsor: Johann Wolfgang Goethe University Hospital
• Investigators: Principal Investigator: Gesine Bug, MD, Johann Wolfgang Goethe University Hospital

Study record dates

Study Major Dates

• Study Start (Actual): January 1, 2011
• Primary Completion (Anticipated): April 1, 2018
• Study Completion (Anticipated): April 1, 2018

Study Registration Dates

• First Submitted: September 30, 2011
• First Submitted That Met QC Criteria: October 11, 2011
• First Posted (Estimate): October 13, 2011

Study Record Updates

• Last Update Posted (Actual): March 20, 2018
• Last Update Submitted That Met QC Criteria: March 19, 2018
• Last Verified: March 1, 2018

More Information

Terms related to this study

• Keywords: AML; MDS; High Risk MDS; 60 to 150 Days After Allogeneic Stem Cell Transplantation
• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms by Histologic Type; Neoplasms; Disease; Bone Marrow Diseases; Hematologic Diseases; Precancerous Conditions; Syndrome; Myelodysplastic Syndromes; Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Preleukemia; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Histone Deacetylase Inhibitors; Panobinostat
• Other Study ID Numbers: CLBH589 BDE05T