E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Patients with myelodysplastic syndrome (MDS), chronic myelomonocytic leukemia (CMML) or acute myelogenous leukemia (AML) after allogeneic stem cell transplantation (allo-SCT) and with an IDH2 mutation (IDH2 R172 or R140 mutation) |
Patienten mit myelodysplastischem Syndrom (MDS), chronischer myelomonozytärer Leukämie (CMML) oder akuter myeloischer Leukämie (AML) nach allogener Stammzelltransplantation (allo-SCT) und einer IDH2-Mutation (IDH2 R172 oder R140-Mutation) |
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E.1.1.1 | Medical condition in easily understood language |
Patients with certain forms of leukemia after stem cell transplantation |
Patienten mit bestimmten Formen von Leukämie nach Stammzelltransplantation |
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E.1.1.2 | Therapeutic area | Diseases [C] - Blood and lymphatic diseases [C15] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10024329 |
E.1.2 | Term | Leukemia |
E.1.2 | System Organ Class | 100000004864 |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
Consolidation arm:
• To evaluate the safety and feasibility of Enasidenib (investigational drug) as 12 months consolidation therapy after allo-SCT in patients with myeloid malignancies (AML, MDS and CMML) carrying an IDH2 R172 or R140 Mutation
Salvage arm:
• To evaluate the safety and feasibility of Enasidenib (investigational drug) – optionally in combination with DLI (according to local practice/as per standard of care) - as first salvage therapy for relapsed myeloid neoplasms (AML, MDS and CMML) carrying an IDH2 R172 or R140 mutation after allo-SCT
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E.2.2 | Secondary objectives of the trial |
Consolidation arm:
• To descriptively assess the efficacy of Enasidenib (investigational drug) as 12 months consolidation therapy after allo-SCT in patients with myeloid malignancies (AML, MDS and CMML) carrying an IDH2 R172 or R140 Mutation
Salvage arm:
• To descriptively assess the efficacy of Enasidenib (investigational drug) - optionally in combination with DLI (according to local practice/as per standard of care) - as first salvage therapy for relapsed myeloid neoplasms (AML, MDS and CMML) carrying an IDH2 R172 or R140 mutation after allo-SCT |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Consolidation arm:
• Patients with myeloid malignancy (AML, MDS and CMML) and known IDH2 mutation (IDH2 R172 or R140 mutation) at diagnosis prior to first allo-SCT
• molecular CR after allo-SCT determined during screening period between day+25 and day +35 (detected by the local laboratory of the respective center; the report has to be sent to the principle investigator for review at screening to include the patient; a sample will be stored for central retesting, which will be performed in batch during the course of the study)
• Hematopoietic recovery after transplantation indicated by an absolute neutrophil count of at least 1.000/microliter and platelet count of at least 50.000/microliter
Salvage arm:
• First hematological or molecular relapse (reoccurrence or persistence of IDH2 mutation) of de novo or therapy related AML, MDS or CMML according to WHO 2016 classification after first allo-SCT (HLA-identical related or matched unrelated donor [≥9/10], haploidentical donor)
• IDH2 R172 or R140 mutation at the time of relapse after allo-SCT (detected by the local laboratory of the respective center, the report has to be sent to the principle investigator for review at screening to include the patient; a sample will be stored for central retesting, which will be performed in batch during the course of the study)
• Possibility of DLI (no cord blood)
• no previous therapy for relapse after allo-SCT except for hydroxyurea for a maximum of 14 days during screening phase prior start of study medication
Both arms:
• no previous therapy with Enasidenib or any other IDH2 inhibitor
• ECOG performance status ≤ 2 at study entry (s. Appendix)
• no active, steroid refractory GvHD treated with additional systemic immunosuppression within 4 weeks before inclusion
• no uncontrolled infection at inclusion
• Understand and voluntarily sign an informed consent form.
• Age ≥18 years at the time of signing the informed consent form.
• Able to adhere to the study visit schedule and other protocol requirements.
• Female of childbearing potential (FCBP) must:
• Understand that Enasidenib can cause embryo-fetal harm when administered to a pregnant woman
• Agree to have a medically supervised pregnancy test prior to starting of Enasidenib
• Use effective contraception during treatment with Enasidenib and for at least 2 months after the last dose
• Coadministration of Enasidenib may increase or decrease the concentrations of combined hormonal contraceptives
• Avoid becoming pregnant while receiving Enasidenib
• Notify her study doctor immediately if there is a risk of pregnancy
• Agree to abstain from breastfeeding during study participation and for at least 30 days after study drug discontinuation
• Understand that Enasidenib may impair fertility in females of reproductive potential and this effect may be not reversible
•Males must:
• Understand that Enasidenib can cause embryo-fetal harm
• Use effective contraception during treatment with Enasidenib and for at least 2 months after the last dose of Enasidenib if engaged in sexual activity with a pregnant female or a female with childbearing potential
• Agree to notify the investigator immediately, if pregnancy or a positive pregnancy test occurs in his partner during study participation
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E.4 | Principal exclusion criteria |
Consolidation arm:
• Any evidence of activity of the underlying IDH2-mutated myeloid malignancy (AML, MDS and CMML) determined during screening period until start of treatment
• Any previous prophylactic therapy given within the interval between allo-SCT and screening period
• Patients with myeloid malignancy (AML, MDS and CMML) and known IDH2 mutation (IDH2 R172 or R140 mutation) after second allo-SCT
Salvage arm:
• No IDH2 R172 or R140 mutation at the time of relapse
• Relapse after second allogeneic transplantation
• Any previous therapy (chemotherapy, radiation or investigational drugs) administered as therapy for relapse after allo-SCT except for hydroxyurea for a maximum of 14 days during screening phase prior start of study medication
• Non-infectious leukocytosis (WBC > 30x10^9/L)
Both arms:
• previous transplantation with cord blood
• Active, steroid refractory GvHD treated with additional requiring systemic immunosuppression within the last 4 weeks
• Uncontrolled infection
• Any serious medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from signing the informed consent form.
• Pregnant or lactating females
• Any condition, including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study or confounds the ability to interpret data from the study
• Impaired renal function (GFR < 30 ml/min)
• Impaired hepatic function, as follows:primar
Aspartate aminotransferase ≥3 x ULN or Alanine aminotransferase (ALT) ≥3 x ULN or
Total bilirubin ≥3 x ULN
Alkaline Phosphatase ≥3 x ULN
• Known hypersensitivity to Enasidenib or any other component of the treatment
• Prior history of malignancy other than AML, MDS or CMML (except basal and squamous cell carcinoma or carcinoma in situ of the cervix or breast) unless the subject has been free of disease for ≥3 years
• Concurrent use of other anti-cancer agents or treatments
• Known positive for HIV or infectious hepatitis, type A, B or C
• Participation in another study with ongoing use of unlicensed investigational product from 28 days before study enrollment until the end of the study (in cases where the investigational product has an unusually long half-life (e.g. antibodies), the interval until study enrollment must be at least five times the plasma half-life of the investigational product)
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E.5 End points |
E.5.1 | Primary end point(s) |
Consolidation arm:
• To evaluate the safety and feasibility of Enasidenib (investigational drug) as 12 months consolidation therapy after allo-SCT in patients with myeloid malignancies (AML, MDS and CMML) carrying an IDH2 R172 or R140 Mutation
Salvage arm:
• To evaluate the safety and feasibility of Enasidenib (investigational drug) – optionally in combination with DLI (according to local practice/as per standard of care) - as first salvage therapy for relapsed myeloid neoplasms (AML, MDS and CMML) carrying an IDH2 R172 or R140 mutation after allo-SCT |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
1. Annual Review of Safety Data by DMC, based on DSUR data
2. Interim Analysis (as 10 patients will have been treated within each arm and the 10th patient in each arm has either completed 4 cycles or has discontinued treatment whichever occurs first. In case one of the two arms is recruiting significantly slower than the other arm, an independent interim analysis of the individual arms may be performed optionally.)
3. End of Study |
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E.5.2 | Secondary end point(s) |
Efficacy variables:
Consolidation arm:
• Number of patients who maintain remission (molecular/hematological) after allo-SCT
• Overall survival
• Relapse-free survival
• Number of patients who require any cellular or pharmacological intervention due to pending or frank relapse (defined as treatment-failure)
• Correlation of relapse-free survival and cytogenetics/molecular alterations
Salvage arm:
• Best response within the first 12 months of treatment according to the International Working Group (IWG) and European Leukemia Net (ELN) criteria
• Time to response
• Rate of and time to complete donor chimerism
• Molecular response measured by IDH2 mutation burden and other disease-specific marker (e.g. FISH, mutations like TET2, ASXL1 or WT1 mRNA expression)
• Duration of remission and incidence of relapse
• Overall survival
• Correlation of response and cytogenetics/molecular alterations
Safety variables:
Both arms (if not otherwise indicated):
• Incidence, course and severity of aGvHD and cGvHD
• Number of hospitalizations
• Number of patients who require dose reductions due to toxicity reasons
• Number of patients who have to stop consolidation therapy due to toxicity (only consolidation arm)
• Number of patients who can receive all 12 cycles of consolidation therapy (only consolidation arm)
• Number of screened patients that can start consolidation therapy within the envisaged time frame (only consolidation arm)
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Annual Review of Safety Data by DMC, based on DSUR data
2. Interim Analysis (as 10 patients will have been treated within each arm and the 10th patient in each arm has either completed 4 cycles or has discontinued treatment whichever occurs first. In case one of the two arms is recruiting significantly slower than the other arm, an independent interim analysis of the individual arms may be performed optionally.)
3. End of Study |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 10 |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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Last visit of the last subject (after end of treatment phase plus 1 year follow-up). |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 5 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |