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van CCT (UK)


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van CCT (UK)


A phase I/II feasibility study of the combination of panobinostat and midostaurin in recipients of allogeneic stem cell transplantation with Flt3-ITD AML


- candidate number27370
- NTR NumberNTR6511
- ISRCTNISRCTN no longer applicable
- Date ISRCTN created
- date ISRCTN requested
- Date Registered NTR12-jun-2017
- Secondary IDsHO148 AML 2017-002335-42
- Public TitleA phase I/II feasibility study of the combination of panobinostat and midostaurin in recipients of allogeneic stem cell transplantation with Flt3-ITD AML
- Scientific TitleA phase I/II feasibility study of the combination of panobinostat and midostaurin in recipients of allogeneic stem cell transplantation with Flt3-ITD AML
- ACRONYMHOVON 148 AML
- hypothesisThe 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).
- Healt Condition(s) or Problem(s) studiedAcute Myeloid Leukemia (AML)
- Inclusion criteriaEligibility for registration
---------------------------
• Adult patients (18-70 years of age)
• AML (except acute promyelocytic leukemia, AML M3 and bcr/abl positive AML) according to WHO 2016 classification (Appendix x) with high mutant to wild-type allelic ratio of Flt3-ITD
• 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 (TP-CY) only
- Fludarabine/Busulfan or Melphalan/Fludarabine/TBI or fludarabin/TBI 8 Gy with post-transplant cyclophosphamide.
• Strategies for GvHD prophylaxis:
- HLA-matched donors:
- 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%
• Negative serum pregnancy test for female patients of childbearing potential, at registration
• Female patients of childbearing potential must use an effective contraceptive method during the study and for a minimum of 6 months after study treatment
• Written informed consent



Eligibility criteria for start of protocol treatment after alloHSCT
-----------------------------------------------------------------------
• Adult patients with FLT3-ITD with high allelic ratio AML
• Eastern Cooperative Group (ECOG) performance status ≤ 2
• Complete hematologic remission or complete hematologic remission with incomplete recovery (see x) documented by bone marrow aspiration
• Laboratory test results maximum 14 days prior to start protocol treatment within the following ranges:
- Absolute neutrophil count ≥ 1.0 x 109/L
- Platelet count ≥ 50 x 109/L
- Serum creatinine clearance > 35 mL/min
- Total bilirubin ≤ 1.5 x ULN
- AST (SGOT) and ALT (SGOT) ≤ 3 x ULN
• Negative serum pregnancy test (within 14 days prior to enrollment) in women of child-bearing potential (WOCBP)
• Willingness of WOCBP to use double-barrier contraception or oral contraceptive plus barrier contraceptive during the study and for three months following the last dose of study drug, or must have undergone clinically documented total hysterectomy and/or bilateral oophorectomy, bilateral tubal ligation or be postmenopausal defined by amenorrhea for at least 12 months.
• Willingness of male subjects whose sexual partners are WOCBP to use a double barrier method of contraception or oral contraceptive (WOCBP) plus barrier contraceptive during the study and for 6 months following the last dose of study drug or the partner must have undergone clinically documented total hysterectomy and/or bilateral oophorectomy, bilateral tubal ligation or be postmenopausal defined by amenorrhea for at least 12 months.

- Exclusion criteriaEligibility for registration
---------------------------
• 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
• Known HIV-positivity
• Pregnant or breast-feeding female patients



Eligibility criteria for start of protocol treatment after alloHSCT
-----------------------------------------------------------------------
• Active acute GvHD grade III-IV according to modified Glucksberg criteria (Appendix x)
• Active acute GvHD grade II 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
• 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 (see Table 9).
• 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 of 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).
• 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
• Any psychological, familial, sociological and geographical condition potentially hampering compliance with the study protocol and follow-up schedule


- mec approval receivedno
- multicenter trialyes
- randomisedno
- group[default]
- TypeSingle arm
- Studytypeintervention
- planned startdate 1-dec-2017
- planned closingdate1-mei-2023
- Target number of participants40
- InterventionsThis is a dose-escalation study of midostaurin 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 in week 5 (second PNB cycle) at a daily dose of 75 mg and escalated in successive cohorts of 5-10 patients to 100 mg (50 mg BID) and 150 mg (75 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.
- Primary outcome• To assess the safety and feasibility of post-transplant panobinostat combined with midostaurin in patient with (very) poor-risk AML/RAEB with FLT3-ITD with high allelic ratio.
- Secondary outcomeTo assess efficacy in terms of:
• Complete hematological remission rate at 3, 6, and 12 months post alloHSCT
• Immunological remission (residual disease assessed by multicolor flowcytometry) at 6 months post alloHSCT
• Relapse/progression rate at 3, 6, and 12 months post alloHSCT
• Overall survival (OS) from alloHSCT
• Progression free survival (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 post alloHSCT

To assess toxicity in terms of:
• The incidence and nature of (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
- TimepointsThe first cycle of combination therapy will start in between day 30 and day 65 after alloHSCT upon meeting the eligibility criteria.
Every next cycle of combination therapy is given at day 29 after start of cycle 1, or as soon as possible thereafter upon hematological recovery, requiring neutrophils ≥ 1.0 x109/L and platelets ≥ 50x 109/L.
- Trial web sitewww.HOVON.nl
- statusplanned
- CONTACT FOR PUBLIC QUERIESProf. Dr. J.J. Cornelissen
- CONTACT for SCIENTIFIC QUERIESProf. Dr. J.J. Cornelissen
- Sponsor/Initiator HOVON Data Center
- Funding
(Source(s) of Monetary or Material Support)
HOVON, Novartis
- PublicationsN/A
- Brief summaryData have demonstrated that panobinostat as post-HSCT maintenance therapy for high-risk AML and MDS is feasible and associated with a favorable 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.
Study Design:
Multicenter, prospective phase I/II trial
Study population:
Patients aged 18-70 years (inclusive), with (very) poor-risk AML or RAEB with IPSS ≥ 1.5 and FLT3-ITD with high allelic ratio (>0.5), either newly diagnosed or in first relapse having obtained remission prior to intended alloHSCT.
Intervention:
This is a dose-escalation study of midostaurin in combination with a fixed dose panobinostat in high allelic ratio FLT3-ITD positive AML.
- Main changes (audit trail)
- RECORD12-jun-2017 - 11-jul-2017


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