European investigation on the efficacy of panobinostat treatment after donor stem cell transplantatio
- Conditions
- High risk acute myeloid leukemia or myelodysplastic syndromeTherapeutic area: Diseases [C] - Cancer [C04]
- Registration Number
- EUCTR2017-000764-15-NL
- Lead Sponsor
- niversitätsklinikum Frankfurt
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- ot Recruiting
- Sex
- All
- Target Recruitment
- 52
Eligibility criteria for registration prior to HSCT:
• 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:
o refractory to or relapsed after at least one cycle of standard chemotherapy
o > 10% bone marrow blasts at day 14-21 of the first induction cycle
o adverse risk according to ELN 2017 risk stratification by genetics regardless of stage
o secondary to MDS or radio-/chemotherapy
o 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:
o Matched sibling or matched unrelated donor (i.e. 10/10 or 9/10 HLA-matched) or haploidentical family donor
o conditioning regimens:
(1) Reduced-intensity conditioning:
o Fludarabine/Melphalan
o Fludarabine/Busulfan2 (FB2)
(2) Myeloablative conditioning:
a. Fludarabine/Busulfan4 (FB4)
b. Busulfan/Cyclophosphamide (BU/CY)
c. Fludarabine/TBI 8 Gy
d. Cyclophosphamide/TBI 12 Gy
(3) Fludarabine/Cyclophosphamide/TBI 2 Gy in combination with post-Tx cyclophosphamide (PT-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
o strategies for GvHD prophylaxis:
• HLA-matched donors:
o CSA + MMF +/- ATG
o CSA + MTX +/- ATG
o PT-CY + CSA
• Haploidentical donors:
o 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
Eligibility criteria for enrollment after HSCT:
• Adult patients with high-risk AML or MDS as defined above
and
• First allogeneic HSCT performed within 30 - 65 days prior to enrollment
• Eastern Cooperative Group (ECOG) performance status = 2
• Complete hematologic remission or complete hematologic remission with incomplete recovery documented by bone marrow aspiration within 14 days prior to enrollment
• Laboratory test results maximum 14 days prior to enrollment within the following ranges:
o Absolute neutrophil count = 1.0 x 109/L
o Platelet count = 75 x 109/L
o Potassium, magnesium and phosphate within normal limits
o Serum creatinine clearance = 30 mL/min
o Total bilirubin = 1.5 x ULN
o AST (SGOT) and ALT (SGOT) = 2.5 x ULN
• Negative serum pregnancy test (within 14 days prior to enrollment) in women of child-bearing potential (WOCBP)
• Willingness of WOCBP to use a highly effective method of contraception during study treatment and for three months following the last dose of study drug. Highly effective methods of contraception include:
o oral, intravaginal or transdermal combined (estrogen and progestogen containing) hormonal contraceptive associated with inhibition of ovulation
plus barrier contraceptive
o oral, injectable or implantable progestogen-only hormone contraception associated with inhibition of ovulation plus barrier contraceptive
o intrauterine hormone-releasing system (IUS) plus barrier contraceptive
o intrauterine device (IUD)
o bilateral tube occlusion
o vasectomised partner
o sexual abstinence
Women using hormonal contraceptives should addi
Eligibility criteria for registration prior to HSCT:
• Prior treatment with a DAC inhibitor
• Hypersensitivity to the active substance or to any of the excipients of panobinostat
• HIV or HCV antibody positivity
• 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
Eligibility criteria for enrollment after HSCT:
• Active acute GvHD grade III-IV according to modified Glucksberg criteria
• Active acute GvHD grade II or chronic GvHD moderate/severe according to NIH criteria requiring systemic corticosteroids > 0.5 mg/kg body weight of methylprednisolone equivalent or combination immunosuppressive treatment
• Uncontrolled or significant heart disease, including recent myocardiac infarction, cardiac failure (NYHA II-IV), unstable angina pectoris, or clinically significant bradycardia
• Long QT syndrome
• QTcF = 480 msec on screening ECG to be performed within 14 days prior to enrollment
• Concurrent use of medications that have a relative risk of prolonging QT interval or of inducing Torsade de Pointes, if such treatment cannot be discontinued or switched to a different medication prior to the first dose of study drug
• Other concurrent severe and/or uncontrolled medical conditions (e.g., uncontrolled diabetes mellitus, chronic obstructive or chronic restrictive pulmonary disease including dyspnoea at rest from any cause) or history of serious organ dysfunction or disease involving the heart, kidney, or liver and/or seropositive HIV or HCV (screening HIV or HCV testing is not required).
• Serious active infection
• CMV reactivation, which is not responsive to first-line valganciclovir or ganciclovir
• Impaired gastrointestinal (GI) function or GI disease that may significantly alter the absorption of oral panobinostat (e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, obstruction, or stomach and/or small bowel resection).
Study & Design
- Study Type
- Interventional clinical trial of medicinal product
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method Main Objective: To determine the efficacy of panobinostat maintenance therapy versus standard of care administered to patients with high-risk MDS or AML in complete hematologic remission after an allogeneic hematologic stem cell transplantation (HSCT);Secondary Objective: - To assess the safety and tolerability of panobinostat maintenance therapy after HSCT compared with standard of care.<br>- To evaluate HRQoL of patients under panobinostat maintenance therapy after HSCT.<br>- To study the treatment effect in subgroups of patients defined by treatment approach (i.e. HOVON-approach vs. RIC vs MAC conditioning), donor type (HLA-compatible versus haploidentical) and molecular distinct subgroups of AML/MDS.<br>;Primary end point(s): Overall survival (OS);Timepoint(s) of evaluation of this end point: Minimum of 24 months after HSCT or until death
- Secondary Outcome Measures
Name Time Method Secondary end point(s): • Event-free survival (EFS)<br>• Disease-free survival (DFS)<br>• Cumulative incidence of hematologic relapse<br>• Cumulative incidence, time and cause of non-relapse mortality <br>• Cumulative incidence of new onset or aggravation of acute GvHD grade III-IV<br>• Cumulative incidence and maximal grade of severity of chronic GvHD requiring systemic treatment within one year after HSCT<br>• Percentage of patients who are free of systemic immunosuppressive therapy at one and two years after HSCT<br>• Percentage of patients completing the one year study treatment and duration of panobinostat administration in patients who discontinue study treatment prematurely<br>• Patient-reported HRQoL during panobinostat maintenance therapy ;Timepoint(s) of evaluation of this end point: Minimum of 24 months after HSCT or until death