Acute Myeloid Leukaemia (AML)Phase 3NCT04326764
Panobinostat Maintenance After HSCT fo High-risk AML and MDS
A Phase 3 study testing Panobinostat in people with Acute Myeloid Leukaemia (AML) and Myelodysplastic Syndromes (MDS), run by Goethe University at 19 sites in 2 countries.
Trial 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… Read more about this study
- Who is it for?
- Ages 18 to 70 years
- Conditions the study is for
- Acute Myeloid Leukaemia (AML), Myelodysplastic Syndromes (MDS)
- What is being tested?
- Panobinostat
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 52 participants
- Where
- 19 sitesin 2 countries
- Study dates
- 24 Jul 2018to 13 Feb 2023
- Phase
- Phase 3
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 70 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
Show all 26Show fewer
- 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:
- Matched sibling or matched unrelated donor (i.e. 10/10 or 9/10 HLA-matched) or haploidentical family donor
- Conditioning regimens:
- Reduced-intensity conditioning:
- Fludarabine/Melphalan b. Fludarabine/Busulfan2 (FB2) (2) Myeloablative conditioning:
- Fludarabine/Busulfan4 (FB4)
- Busulfan/Cyclophosphamide (BU/CY)
- Fludarabine/TBI 8 Gy
- 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
- Strategies for GvHD prophylaxis:
- HLA-matched donors:
- CSA + MMF +/- ATG b. CSA + MTX +/- ATG c. PT-CY + CSA
- Haploidentical donors:
- 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
Who cannot join
- 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
Trial locations and contacts
19 sites in 2 countries.
19 sites in 2 countries
Germany14 sites
Klinikum Augsburg
Augsburg
University Hospital Bonn
Bonn
Universtity Hospital Dresden
Dresden, 01307
University Hospital Frankfurt
Frankfurt
University Hospital Hamburg-Eppendorf
Hamburg
University Hospital Jena
Jena, Thuringia, 07747
Universitätsklinikum Leipzig
Leipzig, Thuringia, 04103
Otto-von-Guericke University
Magdeburg, 39120
Universitätsmedizin Mainz
Mainz
Klinikum Mannheim
Mannheim
Philipps-Universität Marburg
Marburg
University Hospital Münster
Münster
Klinikum Nürnberg Nord
Nuremberg, 90419
Robert Bosch Krankenhaus
Stuttgart, Baden-Wurttemberg, 70376
Netherlands5 sites
Amsterdam University Medical Center - VUMC
Amsterdam, 1081 HV
University Medical Center Groningen
Groningen, 9713 GZ
Maastricht University Medical Center
Maastricht
Radboud UMC
Nijmegen, 6500 HB
Erasmus University Medical Center
Rotterdam, 3015
About this study
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)
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.
Read the 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.
- Being tested
- Panobinostat
- Medical subject headings
- Leukemia, Myeloid, Acute, Myelodysplastic Syndromes
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
PanobinostatDrug
Also called Farydak
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.
| Study group | Role | What they receive |
|---|---|---|
| Panobinostat | Experimental | Panobinostat 20 mg oral three times weekly every second week Receives: Drug: Panobinostat |
| Standard of Care | No intervention | Treatment according to local standards |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 5 years
Secondary outcomes (10)
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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 5 years
Cumulative incidence of new onset or aggravation of acute GvHD grade III-IV
Cumulative incidence of new onset or aggravation acute GvHD grade III-IV is calculated as number of patients who newly experienced acute GvHD grade III-IV after randomization or whose preexisting lower grade acute GvHD aggravated to grade 3 or 4 divided by all patients in the analysis set. Cumulative incidence is calculated separately for each arm.
Measured: 5 years
Cumulative incidence and maximal grade of severity of chronic GvHD requiring systemic treatment within one year after HSCT
Acute and chronic GvHD will be graded according to NIH consensus criteria. In case of chronic GvHD, evaluation forms provided by the NIH Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host-Disease should be used.
Time to chronic GvHD requiring systemic treatment is defined time from randomization until date of first diagnosis of chronic GvHD requiring systemic treatment. Relapse and death in CR without chronic GvHD requiring systemic treatment are considered as competing events. Patients for whom no chronic GvHD, nor relapse, nor death in CR was observed will be censored at date of last follow up.
Measured: 1 year
Percentage of patients who are free of systemic immunosuppressive therapy at one and two years after HSCT
Percentage of patients who are free of systemic immunosuppressive therapy is calculated as number of patients who are free of systemic immunosuppressive therapy at the respective time point divided by the total number of patients in the analysis set multiplied by 100. The percentage is calculated separately for each arm.
Measured: 2 years
Percentage of patients completing the one year study treatment and duration of panobinostat administration in patients who discontinue study treatment prematurely
Percentage of patients completing the one year study treatment is calculated as number of patients completing the one year study treatment divided by the total number of patients in the analysis set multiplied by 100. The percentage is calculated for the panobinostat arm only.
The duration of panobinostat administration is calculated from date of first administered dose of study medication until date of last administered dose of study medication.
Measured: 1 year
Percentage of patients with minimal residual disease (MRD) conversion from baseline to 6 months after HSCT
Percentage of patients with MRD conversion from baseline to 6 months after HSCT is calculated as number of patients who were MRD positive at baseline and are MRD negative at 6 months after HSCT divided by the number of patients who were MRD positive at baseline.
Patients who were MRD negative at baseline will not be considered in this endpoint.
Measured: 6 months
Patient-reported HRQoL during panobinostat maintenance therapy
Patient reported health-related quality of life will be assessed using the cancer generic 'European Organization for Research and Treatment of Cancer' quality of life questionnaire.
Measured: 4 years
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted30 Mar 2020
- Study start24 Jul 2018
- Primary completion13 Feb 2023
- Study completion13 Feb 2023
Why it stopped: Change of marketing authorisation holder
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Acute Myeloid Leukaemia (AML)Studies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 52 participants (actual)
Sponsor and investigators
- Lead sponsor
- Goethe University
- Sponsor type
- University, hospital or other
- Collaborators
- Stichting Hemato-Oncologie voor Volwassenen Nederland, Polish Adult Leukemia Group, Schweizerische Arbeitsgemeinschaft für klinische Krebsforschung
- Responsible party
- Principal investigator, Gesine Bug, Goethe University
- Investigators
- Gesine Bug, PD Dr., Principal investigator, Goethe University Frankfurt
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04326764
- Sponsor's protocol ID
- ETAL-4 / HOVON-145
- Status last verified
- Feb 2023
- First submitted
- 21 Mar 2019
- Last updated
- 16 Feb 2023
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
Study at a glance
From the registry record, last updated by the sponsor on 16 Feb 2023. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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)
- ClinicalTrials.gov ID
- NCT04326764
- Acronym / sponsor ID
- ETAL-4 / HOVON-145
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: Change of marketing authorisation holder
- Enrolment
- 52 participants (actual)
- Lead sponsor
- Goethe UniversityUniversity, hospital or other
- Collaborators
- Stichting Hemato-Oncologie voor Volwassenen Nederland, Polish Adult Leukemia Group, Schweizerische Arbeitsgemeinschaft für klinische Krebsforschung
- Study start
- 24 Jul 2018 (actual)
- Primary completion
- 13 Feb 2023 (actual)
- Study completion
- 13 Feb 2023 (actual)
- First posted
- 30 Mar 2020 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Panobinostat | Experimental | Drug: PanobinostatPanobinostat 20 mg oral three times weekly every second week |
| Standard of Care | No intervention | –Treatment according to local standards |
Who may qualify
- Ages
- 18 to 70 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (26 listed)
- 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:
- 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
Key exclusion criteria (6 listed)
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| PanobinostatAlso: FarydakPanobinostat 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. | Drug | Panobinostat |
Primary outcome
Overall survival (OS)
Time frame: 5 years
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.
10 secondary outcomes
Event-free survival (EFS)
Time frame: 5 years
Disease-free survival (DFS)
Time frame: 5 years
Cumulative incidence of hematologic relapse
Time frame: 5 years
Cumulative incidence, time and cause of non-relapse mortality (NRM)
Time frame: 5 years
Cumulative incidence of new onset or aggravation of acute GvHD grade III-IV
Time frame: 5 years
Cumulative incidence and maximal grade of severity of chronic GvHD requiring systemic treatment within one year after HSCT
Time frame: 1 year
Percentage of patients who are free of systemic immunosuppressive therapy at one and two years after HSCT
Time frame: 2 years
Percentage of patients completing the one year study treatment and duration of panobinostat administration in patients who discontinue study treatment prematurely
Time frame: 1 year
Percentage of patients with minimal residual disease (MRD) conversion from baseline to 6 months after HSCT
Time frame: 6 months
Patient-reported HRQoL during panobinostat maintenance therapy
Time frame: 4 years
Results and safety
The study was stopped early (reason given: Change of marketing authorisation holder). Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 16 Feb 2023.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Gesine Bug, PD Dr. principal investigator
Goethe University Frankfurt
19 sites in 2 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing Panobinostat in people with Acute Myeloid Leukaemia (AML) and Myelodysplastic Syndromes (MDS), run by Goethe University at 19 sites in 2 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 26 inclusion and 6 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: stopped early, as of the sponsor's last update on 16 Feb 2023. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 19 sites in Germany, Netherlands. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study was stopped early (reason given: Change of marketing authorisation holder). Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Overall survival (OS) (time frame: 5 years). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 16 Feb 2023.