Clinical trial NCT04326764: Panobinostat Maintenance After HSCT fo High-risk AML and MDS
Official title: 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)
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
Conditions: Acute Myeloid Leukaemia (AML)
Myelodysplastic Syndromes (MDS)
Lead sponsor: Goethe University
Sponsor class: OTHER
Collaborators: name: Stichting Hemato-Oncologie voor Volwassenen Nederland
name: Polish Adult Leukemia Group
name: Schweizerische Arbeitsgemeinschaft für klinische Krebsforschung
First posted: 2020-03-30
Enrollment: 52
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Overall survival (OS)
timeFrame: 5 years
Secondary outcomes:
measure: Event-free survival (EFS)
timeFrame: 5 years
measure: Disease-free survival (DFS)
timeFrame: 5 years
measure: Cumulative incidence of hematologic relapse
timeFrame: 5 years
measure: Cumulative incidence, time and cause of non-relapse mortality (NRM)
timeFrame: 5 years
measure: Cumulative incidence of new onset or aggravation of acute GvHD grade III-IV
timeFrame: 5 years
measure: Cumulative incidence and maximal grade of severity of chronic GvHD requiring systemic treatment within one year after HSCT
timeFrame: 1 year
measure: Percentage of patients who are free of systemic immunosuppressive therapy at one and two years after HSCT
timeFrame: 2 years
measure: Percentage of patients completing the one year study treatment and duration of panobinostat administration in patients who discontinue study treatment prematurely
timeFrame: 1 year
measure: Percentage of patients with minimal residual disease (MRD) conversion from baseline to 6 months after HSCT
timeFrame: 6 months
measure: Patient-reported HRQoL during panobinostat maintenance therapy
timeFrame: 4 years
Other outcomes:
Locations:
city: Stuttgart
country: Germany
facility: Robert Bosch Krankenhaus
state: Baden-Württemberg
city: Jena
country: Germany
facility: University Hospital Jena
state: Thüringen
city: Leipzig
country: Germany
facility: Universitätsklinikum Leipzig
state: Thüringen
city: Augsburg
country: Germany
facility: Klinikum Augsburg
city: Bonn
country: Germany
facility: University Hospital Bonn
city: Dresden
country: Germany
facility: Universtity Hospital Dresden
city: Frankfurt
country: Germany
facility: University Hospital Frankfurt
city: Hamburg
country: Germany
facility: University Hospital Hamburg-Eppendorf
city: Magdeburg
country: Germany
facility: Otto-von-Guericke University
city: Mainz
country: Germany
facility: Universitätsmedizin Mainz
city: Mannheim
country: Germany
facility: Klinikum Mannheim
city: Marburg
country: Germany
facility: Philipps-Universität Marburg
city: Münster
country: Germany
facility: University Hospital Münster
city: Nürnberg
country: Germany
facility: Klinikum Nürnberg Nord
city: Amsterdam
country: Netherlands
facility: Amsterdam University Medical Center - VUMC
city: Groningen
country: Netherlands
facility: University Medical Center Groningen
city: Maastricht
country: Netherlands
facility: Maastricht University Medical Center
city: Nijmegen
country: Netherlands
facility: Radboud UMC
city: Rotterdam
country: Netherlands
facility: Erasmus University Medical Center
Study officials:
affiliation: Goethe University Frankfurt
name: Gesine Bug, PD Dr.
role: PRINCIPAL_INVESTIGATOR
References: