Myelodysplastic Syndromes (MDS) Clinical Trial
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)
Verified date | February 2023 |
Source | Goethe University |
Contact | n/a |
Is FDA regulated | No |
Health authority | |
Study type | Interventional |
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.
Status | Terminated |
Enrollment | 52 |
Est. completion date | February 13, 2023 |
Est. primary completion date | February 13, 2023 |
Accepts healthy volunteers | No |
Gender | All |
Age group | 18 Years to 70 Years |
Eligibility | 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 |
Country | Name | City | State |
---|---|---|---|
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 | University Hospital Jena | Jena | Thüringen |
Germany | Universitätsklinikum Leipzig | Leipzig | Thüringen |
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 | Nürnberg | |
Germany | Robert Bosch Krankenhaus | Stuttgart | Baden-Württemberg |
Netherlands | 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 |
Lead Sponsor | Collaborator |
---|---|
Goethe University | Polish Adult Leukemia Group, Schweizerische Arbeitsgemeinschaft für klinische Krebsforschung, Stichting Hemato-Oncologie voor Volwassenen Nederland |
Germany, Netherlands,
Type | Measure | Description | Time frame | Safety issue |
---|---|---|---|---|
Primary | 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. | 5 years | |
Secondary | 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. | 5 years | |
Secondary | 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. | 5 years | |
Secondary | 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. | 5 years | |
Secondary | 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. | 5 years | |
Secondary | 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. | 5 years | |
Secondary | 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. |
1 year | |
Secondary | 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. | 2 years | |
Secondary | 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. |
1 year | |
Secondary | 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. |
6 months | |
Secondary | 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. | 4 years |
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