A Randomized, Multicenter Phase III Study to Assess the Efficacy of Panobinostat Maintenance Therapy vs. Standard of Care Following Allogeneic Stem Cell Transplantation in Patients With High-risk AML or MDS (ETAL-4 / HOVON-145)

Panobinostat Maintenance After HSCT fo High-risk AML and MDS

Sponsors

Lead sponsor: Goethe University

Collaborator: Jan J. Cornelissen (HOVON-SAKK)
Sebastian Giebel (PALG)

Source Goethe University
Brief Summary

Aim of this prospective randomized trial is to compare maintenance treatment with panobinostat interspersed with donor lymphocyte infusions (DLI) versus the standard approach of pre-emptive DLI alone in patients with poor-risk AML/MDS having favorably received an allogeneic HSCT followed by engraftment, donor chimerism and hematopoietic reconstitution.

Detailed Description

Allogeneic hematopoietic stem cell transplantation (HSCT) has been shown to improve the outcome of poor-risk AML and MDS in both younger and older patients. Reduced-intensity conditioning (RIC) regimen have partially abrogated the problem of regimen-related toxicity. However, graft-versus-host disease (GvHD) remains a major cause of non-relapse morbidity and mortality. Despite a strong graft versus leukemia (GvL) effect after allogeneic HSCT, the relapse rate after transplantation in poor-risk leukemia patients is still too high, necessitating new approaches to exploit GvL in a more optimized way. In addition, minimizing the GvHD reaction remains an important goal. One attractive strategy may be the administration of epigenetic therapy early after HSCT in order to optimize the GvL effect, to provide a direct anti-leukemic effect, and to control GvHD. Two preceding phase I/II studies have suggested that post-transplant administration of the histone deacetylase (HDAC) inhibitor panobinostat may be associated with a reduced relapse rate, while allowing for control of GvHD. Based on these two studies, the hypothesis of the present trial is that panobinostat can be an effective drug in preventing relapse by optimizing GvL in MDS and AML patients with high-risk features after HSCT, while at the same time reducing GvHD. It has been designed to test this hypothesis in a prospective randomized trial comparing maintenance with panobinostat interspersed with donor lymphocyte infusions (DLI) versus the standard approach of pre-emptive DLI alone in patients with poor-risk AML/MDS having favorably received an allogeneic HSCT followed by engraftment, donor chimerism and hematopoietic reconstitution.

Overall Status Recruiting
Start Date July 24, 2018
Completion Date October 2023
Primary Completion Date July 2023
Phase Phase 3
Study Type Interventional
Primary Outcome
Measure Time Frame
Overall survival (OS) 5 years
Secondary Outcome
Measure Time Frame
Event-free survival (EFS) 5 years
Disease-free survival (DFS) 5 years
Cumulative incidence of hematologic relapse 5 years
Cumulative incidence, time and cause of non-relapse mortality (NRM) 5 years
Cumulative incidence of new onset or aggravation of acute GvHD grade III-IV 5 years
Cumulative incidence and maximal grade of severity of chronic GvHD requiring systemic treatment within one year after HSCT 1 year
Percentage of patients who are free of systemic immunosuppressive therapy at one and two years after HSCT 2 years
Percentage of patients completing the one year study treatment and duration of panobinostat administration in patients who discontinue study treatment prematurely 1 year
Percentage of patients with minimal residual disease (MRD) conversion from baseline to 6 months after HSCT 6 months
Patient-reported HRQoL during panobinostat maintenance therapy 4 years
Enrollment 350
Condition
Intervention

Intervention type: Drug

Intervention name: Panobinostat

Description: Panobinostat should be taken orally once on each scheduled day at about the same time, either with or without food. Each dose of panobinostat should be taken with a cup of water. The capsules should be swallowed as whole. If vomiting occurs during the course of treatment, no re-dosing is allowed before the next scheduled dose. If one dose is forgotten during the morning on a scheduled treatment day then the missed dose should be taken on that same day within 12 hours. After more than 12 hours, that day's dose should be withheld, and the patient should wait to take panobinostat until the next schedule treatment day. The patient should then continue treatment with the original dosing schedule. Panobinostat will be administered at a dose of 20 mg three times weekly (TIW) every second week and will be dosed on a flat scale of mg/day and not by weight or body surface area. Panobinostat will be dispensed as a 20 mg capsule or as two 10 mg capsules.

Arm group label: Panobinostat

Other name: Farydak

Eligibility

Criteria:

Inclusion Criteria:

- Adult patients (18-70 years of age)

- AML (except acute promyelocytic leukemia with PML-RARA and AML with BCR-ABL1) according to WHO 2016 classification 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 14-21 of the first induction cycle

- adverse risk according to ELN 2017 risk stratification by genetics (Appendix 2) regardless of stage

- secondary to MDS or radio-/chemotherapy

- MRD positive before HSCT based on flow cytometry or PCR

or

- MDS with excess blasts (MDS-EB) according to the WHO 2016 classification, or high-risk or very high-risk according to IPSS-R

and

First allogeneic HSCT scheduled within the next 4-6 weeks using one of the following donors, conditioning regimens and strategies for GvHD prophylaxis:

1. Matched sibling or matched unrelated donor (i.e. 10/10 or 9/10 HLA-matched) or haploidentical family donor

2. Conditioning regimens:

1. Reduced-intensity conditioning:

a. Fludarabine/Melphalan b. Fludarabine/Busulfan2 (FB2) (2) Myeloablative conditioning:

1. Fludarabine/Busulfan4 (FB4)

2. Busulfan/Cyclophosphamide (BU/CY)

3. Fludarabine/TBI 8 Gy

4. Cyclophosphamide/TBI 12 Gy (3) Fludarabine/Cyclophosphamide/TBI 2 Gy in combination with post-Tx cyclophosphamide (TP-CY) only (4) Thiotepa/Busulfan/Fludarabine (TBF) in the context of an haploidentical HSCT only (5) In case of active disease at HSCT, salvage chemotherapy prior to conditioning is permitted

c. Strategies for GvHD prophylaxis:

1. HLA-matched donors:

a. CSA + MMF +/- ATG b. CSA + MTX +/- ATG c. PT-CY + CSA

2. Haploidentical donors:

d. PT-CY + CSA + MMF

- No history of significant cardiac disease and absence of active symptoms, otherwise documented left ventricular EF ≥ 40%

- Written informed consent for registration

Exclusion Criteria:

- Prior treatment with a DAC inhibitor

- Hypersensitivity to the active substance or to any of the excipients of panobinostat

- HIV or HCV antibody positive

- Psychiatric disorder that interferes with ability to understand the study and give informed consent, and/or impacts study participation or follow-up.

- Female patients who are pregnant or breast feeding

- History of another primary malignancy that is currently clinically significant or currently requires active intervention

Gender: All

Minimum age: 18 Years

Maximum age: 70 Years

Healthy volunteers: No

Overall Official
Last Name Role Affiliation
Gesine Bug, PD Dr. Principal Investigator Goethe University Frankfurt
Overall Contact

Last name: Gesine Bug, PD Dr.

Phone: +49 (0)69 6301 7369

Email: [email protected]

Location
facility status contact
Robert Bosch Krankenhaus | Stuttgart, Baden-Württemberg, 70376, Germany Recruiting Martin Kaufmann, Dr.
University Hospital Jena | Jena, Thüringen, 07747, Germany Recruiting Inken Hilgendorf, PD Dr.
Universitätsklinikum Leipzig | Leipzig, Thüringen, 04103, Germany Not yet recruiting Uwe Platzbecker, Prof. Dr.
Klinikum Augsburg | Augsburg, Germany Recruiting Christof Schmid, PD Dr.
University Hospital Bonn | Bonn, Germany Recruiting Tobias Holderried, Dr.
Universtity Hospital Dresden | Dresden, 01307, Germany Recruiting Jan Moritz Middeke, Dr.
University Hospital Frankfurt | Frankfurt, Germany Recruiting Gesine Bug, PD Dr.
University Hospital Hamburg-Eppendorf | Hamburg, Germany Not yet recruiting Christina Wolschke, Prof. Dr.
Otto-von-Guericke University | Magdeburg, 39120, Germany Recruiting Heinicke Thomas, Dr.
Universitätsmedizin Mainz | Mainz, Germany Not yet recruiting Eva Maria Wagner, Dr.
Klinikum Mannheim | Mannheim, Germany Recruiting Stefan Klein, PD Dr.
Philipps-Universität Marburg | Marburg, Germany Recruiting Andreas Burchert, Prof. Dr.
University Hospital Münster | Münster, Germany Recruiting Matthias Stelljes, Prof.Dr.
Klinikum Nürnberg Nord | Nürnberg, 90419, Germany Recruiting Kerstin Schäfer-Eckart, Dr.
Amsterdam University Medical Center - VUMC | Amsterdam, 1081 HV, Netherlands Recruiting Ellen Meijer, Prof. Dr.
AMC | Amsterdam, 1105, Netherlands Recruiting B. J Biemond, Prof. Dr.
Radboud UMC | Nijmegen, 6500 HB, Netherlands Recruiting Suzanne van Dorp, Dr.
Erasmus University Medical Center | Rotterdam, 3015, Netherlands Recruiting Jan Cornelissen, Prof. Dr.
Location Countries

Germany

Netherlands

Verification Date

March 2020

Responsible Party

Responsible party type: Principal Investigator

Investigator affiliation: Goethe University

Investigator full name: Gesine Bug

Investigator title: Director of Transplant Program, Principal Investigator

Has Expanded Access No
Condition Browse
Number Of Arms 2
Arm Group

Arm group label: Panobinostat

Arm group type: Experimental

Description: Panobinostat 20 mg oral three times weekly every second week

Arm group label: Standard of Care

Arm group type: No Intervention

Description: Treatment according to local standards

Study Design Info

Allocation: Randomized

Intervention model: Parallel Assignment

Primary purpose: Treatment

Masking: None (Open Label)

Source: ClinicalTrials.gov