Primary objective:To asses the safety and feasibility of post-transplant panobinostat combined with midostaurin in patients with adverse risk AML/RAEB with FLT3-ITD with high allelic ratio in terms of dose limiting toxicity.Secondary objectives:To…
ID
Source
Brief title
Condition
- Leukaemias
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Feasibility of protocol treatment as defined by the number of dose limiting
toxicities (DLTs) during the first cycle of PNB/MST.
Secondary outcome
• Number of PNB/MST cycles given.
• Complete hematological remission (with full peripheral blood recovery)
rate at 3, 6 and 12 months post alloHSCT
• MRD after PNB/MST cycle 3, or at 6 months post alloHSCT if patient goes off
protocol treatment early.
• Relapse/progression rate as assessed after cycle 1, 3, 5 and 7 and at 12
months post alloHSCT, or at approx. 3, 6 and 12 months post alloHSCT in case of
early termination of protocol treatment.at 3, 6, and 12 months post alloHSCT
• OS defined as the time from alloHSCT to death from any cause
• PFS from alloHSCT with relapse (for patients in CR) and progression (for
patients in PR) and death from any cause as events
• Engraftment and chimerism at 3, 6, and 12 months post alloHSCT
• (Serious) adverse events
• The incidence and severity of acute and chronic GvHD up to 12 months post
alloHSCT
• NRM up to 12 months post alloHSCT
• Number and percentage of registered patients starting protocol treatment)
• Number and percentage of patients receiving post-transplant epigenetic
therapy after alloHSCT and the duration of epigenetic treatment in patients who
discontinue study treatment prematurely
Background summary
The hypothesis of this study is that a combination of panobinostat with
midostaurin may be effective for preventing relapse of patients with a high
allelic ratio FLT3-ITD positive AML after hematopoietic stem cell
transplantation (HSCT). We have previously demonstrated that panobinostat as
post-HSCT maintenance therapy for high-risk AML and MDS is feasible and
associated with a favourable outcome, presumably through modulation of the
allogeneic anti-leukemic immune response. Midostaurin has been shown by the
RATIFY trial to be effective in FLT3-ITD-positive AML. Patients with a high
allelic ratio of FLT3-ITD are at high risk of relapse after an allogeneic HSCT.
Therefore, we reason that FLT3 inhibition in addition to panobinostat-mediated
immunomodulation may be more effective to prevent relapse than either therapy
alone. Furthermore, the combination seems rational, since panobinostat is known
to induce proteasomal degradation of FLT3-ITD and might therefore add
antileukemic activity to midostaurin. Also, FLT3-ITD inhibition alone runs the
risk of secondary resistance due to resistance mutations or due to the
activation of redundant signalling pathways.
Here, we therefore plan to select patients with high allelic ratio of FLT3-ITD
(>0.5) prior to allogeneic HSCT to be treated after HSCT with the combination
of panobinostat and midostaurin with the aim to:
- Administer antileukemic activity and at the same time to
- Modulate the immune system to enhance the graft-versus-leukemia (GvL) effect.
Study objective
Primary objective:
To asses the safety and feasibility of post-transplant panobinostat combined
with midostaurin in patients with adverse risk AML/RAEB with FLT3-ITD with high
allelic ratio in terms of dose limiting toxicity.
Secondary objectives:
To assess feasibility in terms of completion of the protocol treatment
To assess efficacy in terms of complete hematological remission rate with full
peripheral blood recovery, residual disease response rate, overall and
progression free survival, chimerism, immune recovery, and toxicities.
Study design
Multicenter, prospective phase Ib trial
Intervention
This is a dose-escalation study of midostaurin (MST) in combination with a
fixed dose panobinostat in high allelic ratio FLT3-ITD positive AML. Patients
will receive panobinostat (PNB) at a starting dose of 20 mg once a day three
times a week every other week for each cycle of 4 weeks. Midostaurin treatment
will start at a daily dose of 50 mg and escalated in successive cohorts of
5-10 patients to 75 mg (50-25 mg) and 100 mg (50 mg bid) which is the maximum
target dose. No intrapatient dose escalation is allowed. Treatment will be
continued for a maximum of one year as from transplantation in the absence of
relapse or unacceptable toxicity.
Study burden and risks
Although alloHSCT is standard care in adverse risk AML/RAEB with FLT3-ITD, the
incidence of relapse after alloHSCT is high, especially if the allelic ratio >
0.5.
We recently showed that PNB post-transplant may prevent relapse, although
very-poor risk patients and/or patients with MRD are at greater risk for
relapse. It is hypothesized that the addition of midostaurin to PNB may further
reduce the risk of relapse and thereby improve outcome. The risks associated
with this procedure are opportunistic infections associated with neutropenia
and lymphopenia, that may occur after PNB/MST, as compared to standard
alloHSCT.
VUMC, HOVON Centraal Bureau, De Boelelaan 1117
Amsterdam 1081 HV
NL
VUMC, HOVON Centraal Bureau, De Boelelaan 1117
Amsterdam 1081 HV
NL
Listed location countries
Age
Inclusion criteria
• Adult patients (18-70 years of age);
• AML (except acute promyelocytic leukemia, AML M3 and bcr/abl positive AML) according to WHO 2016 classification or RAEB with IPSS-R > 4.5 with high mutant to wild-type allelic ratio of FLT3-ITD;
• Newly diagnosed or in first relapse having obtained remission after induction chemotherapy;
• First allogeneic HSCT scheduled within the next 2 months upon having achieved hematological remission (<5% blasts at the bone marrow level);
• Matched sibling or matched unrelated donor (i.e. 10/10 or 9/10 HLA-matched) or haploidentical donor;
• Using one of the following conditioning regimens:
-Fludarabine/Cyclophosphamide/TBI 2 Gy in combination with post-Tx cyclophosphamide (PT-CY) only;
-Fludarabine/Busulfan or Melphalan/Fludarabine/TBI or fludarabin/TBI 8 Gy with post-transplant cyclophosphamide;
or one of the alternative regimen in the protocol;
• No history of significant cardiac disease and absence of active symptoms, otherwise documented left ventricular EF> 40%;
• Negative serum pregnancy test for female patients of childbearing potential, at registration;
• Female patients of childbearing potential and all men must be willing and able to use an effective contraceptive method during the study and for a minimum of 6 months after study treatment;
• Written informed consent.
Exclusion criteria
• Known HIV or HCV positivity;
• History of active malignancy during the past 2 years with the exception of basal carcinoma of the skin or carcinoma *in situ* of the cervix or breast;
• Pregnant or breast-feeding female patients;
• Psychiatric disorder that interferes with ability to understand the study and give informed consent, and/or impacts study participation or follow-up;
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2017-002335-42-NL |
| CCMO | NL62303.078.17 |