Panobinostat Maintenance After HSCT fo High-risk AML and MDS

NCT ID: NCT04326764

Last Updated: 2023-02-16

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE3
• Total Enrollment: 52 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2018-07-24
• Study Completion Date: 2023-02-13

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.

Conditions

Acute Myeloid Leukaemia (AML); Myelodysplastic Syndromes (MDS)

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Panobinostat

Panobinostat 20 mg oral three times weekly every second week

Group Type: EXPERIMENTAL

Panobinostat

Intervention Type: DRUG

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.

Standard of Care

Treatment according to local standards

Group Type: NO_INTERVENTION

No interventions assigned to this group

Interventions

Panobinostat

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.

Intervention Type: DRUG

Other Intervention Names

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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 70 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Stichting Hemato-Oncologie voor Volwassenen Nederland

OTHER

Sponsor Role: collaborator

Polish Adult Leukemia Group

OTHER

Sponsor Role: collaborator

Schweizerische Arbeitsgemeinschaft für klinische Krebsforschung

UNKNOWN

Sponsor Role: collaborator

Goethe University

OTHER

Sponsor Role: lead

Responsible Party

Gesine Bug

Director of Transplant Program, Principal Investigator

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Gesine Bug, PD Dr.

Role: PRINCIPAL_INVESTIGATOR

Goethe University Frankfurt

Locations

Robert Bosch Krankenhaus

Stuttgart, Baden-Wurttemberg, Germany

University Hospital Jena

Jena, Thuringia, Germany

Universitätsklinikum Leipzig

Leipzig, Thuringia, Germany

Klinikum Augsburg

Augsburg, , Germany

University Hospital Bonn

Bonn, , Germany

Universtity Hospital Dresden

Dresden, , Germany

University Hospital Frankfurt

Frankfurt, , Germany

University Hospital Hamburg-Eppendorf

Hamburg, , Germany

Otto-von-Guericke University

Magdeburg, , Germany

Universitätsmedizin Mainz

Mainz, , Germany

Klinikum Mannheim

Mannheim, , Germany

Philipps-Universität Marburg

Marburg, , Germany

University Hospital Münster

Münster, , Germany

Klinikum Nürnberg Nord

Nuremberg, , Germany

Amsterdam University Medical Center - VUMC

Amsterdam, , Netherlands

University Medical Center Groningen

Groningen, , Netherlands

Maastricht University Medical Center

Maastricht, , Netherlands

Radboud UMC

Nijmegen, , Netherlands

Erasmus University Medical Center

Rotterdam, , Netherlands

Countries

Germany; Netherlands

Other Identifiers

ETAL-4 / HOVON-145

Identifier Type: -

Identifier Source: org_study_id