Panobinostat Maintenance After HSCT fo High-risk AML and MDS

Phase 3TerminatedNCT04326764

Goethe University52 enrolled

Overview

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.

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.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

Acute Myeloid Leukaemia (AML)Myelodysplastic Syndromes (MDS)

Interventions

PanobinostatDRUG

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.

Eligibility

Sex: ALLMin age: 18 YearsMax age: 70 Years

Medical Language ↔ Plain English

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

Locations (19)

Robert Bosch Krankenhaus

Stuttgart, Baden-Wurttemberg, Germany

University Hospital Jena

Jena, Thuringia, Germany

Outcomes

Primary Outcomes

Overall survival (OS)

OS is measured from date of randomization to the date of death or date of last follow up. Observations of patients alive at last follow up will be censored at date of last follow up.

Time frame: 5 years

Secondary Outcomes

Event-free survival (EFS)

EFS is defined as time interval from randomization until relapse of MDS or AML, any treatment of molecular relapse (except DLI) or death from any cause, whichever occurs first. Observations of patients without any event will be censored at time of last follow up.

Time frame: 5 years

Disease-free survival (DFS)

DFS is defined as time interval from randomization until relapse of MDS or AML, or death from any cause, whichever occurs first. Observations of patients without any event will be censored at time of last follow up.

Time frame: 5 years

Cumulative incidence of hematologic relapse

Remission duration is defined as time from randomization until relapse (including any treatment (except DLI) of molecular relapse). Death in complete remissions (CR) is considered as competing event for relapse. Patients for whom no relapse nor death in CR was observed will be censored at date of last follow up.

Time frame: 5 years

Cumulative incidence, time and cause of non-relapse mortality (NRM)

Time to NRM is defined as time from randomization until death in CR from any cause. Relapse is considered as competing event for NRM. Patients for whom no death in CR nor relapse was observed will be censored at date of last follow up.

Time frame: 5 years

Cumulative incidence of new onset or aggravation of acute GvHD grade III-IV

Data from ClinicalTrials.gov

This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.