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IDH2-Post-Allo-Trial for Patients With IDH2-mut Myeloid Neoplasms After Allo-SCT

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ClinicalTrials.gov Identifier: NCT04522895
Recruitment Status : Recruiting
First Posted : August 21, 2020
Last Update Posted : September 2, 2020
Sponsor:
Collaborators:
Celgene Corporation
Koordinierungszentrum für Klinische Studien Düsseldorf
Information provided by (Responsible Party):
Heinrich-Heine University, Duesseldorf

Brief Summary:
This is a prospective, open label, multi-centre phase II trial with a two-arm non comparative design aiming to evaluate the safety and efficacy of Enasidenib (investigational product) as prophylactic consolidation in patients with IDH2-mutated MDS, CMML and AML in remission after allo-SCT and as salvage therapy in patients with IDH2-mutated MDS, CMML and AML who have relapsed after allo-SCT.

Condition or disease Intervention/treatment Phase
Leukemia, Myeloid, Acute Myelodysplastic Syndromes Chronic Myelomonocytic Leukemia IDH2 Gene Mutation IDH2 R172 IDH2 R140 Drug: Enasidenib Phase 2

Detailed Description:

This is a prospective, open label, multi-centre phase II trial with a two-arm non comparative design aiming to evaluate the safety and efficacy of Enasidenib (investigational product) as prophylactic consolidation in patients with IDH2-mutated MDS, CMML and AML in remission after allo-SCT (Arm A) and as salvage therapy in patients with IDH2-mutated MDS, CMML and AML who have relapsed after allo-SCT (Arm B).

Study Design:

  • interventional
  • prospective, open-label, non-randomized with 2 single non-comparative arms, multicenter phase-II trial
  • total patients sample size: 30 patients (Arm A) + 30 patients (Arm B) = 60 patients
  • number of trial sites: 10 all located in Germany and members of the EBMT

Arm A (Consolidation):

Patients with AML, MDS and CMML, in whom an IDH2 mutation has been detected at diagnosis prior allo-SCT, are eligible for consolidation therapy, if they are in complete molecular remission (no IDH2 mutation detected) after first allo-SCT. Remission will be evaluated within a screening period between day +25 and day +35. Evaluation of remission will be performed locally with IDH2 mutation analysis performed at an experienced local laboratory of the respective center. Reports about IDH2 mutation testing at diagnosis and at screening have to be sent to the principle investigator for review at screening to include the patient; a BM sample will be stored for central retesting, which will be performed in batch during the course of the study. Having a documented molecular CR, patients will enter the treatment phase within 30 days after this BM evaluation (latest time point day +65) and start treatment with Enasidenib. They are envisaged to receive Enasidenib (100 mg per day, day 1-28) for up to 12 cycles (=12 months). Patients will go off protocol prematurely in case of relapse, intolerability of study treatment and in case of withdrawal of consent. In those patients who relapse during study treatment subsequent therapy for relapse will be performed according to the choice of the individual treating physician. Patients who finish study as planned or prematurely will be regularly followed for one year, lost to follow up, death or withdrawal of consent.

Arm B (Salvage):

Patients, either with known IDH2 mutation prior transplant or with unknown IDH2 mutation status, who have already relapsed after first allo-SCT either on a molecular or hematological level at any time point and have an IDH2 mutation at relapse, are not eligible for part A of this study. They are eligible for screening for Arm B of this study. Screening will be performed locally with IDH2 mutation analysis performed at an experienced local laboratory of the respective center. Reports about IDH2 mutation testing at diagnosis and at screening have to be sent to the principle investigator for review at screening to include the patient; a BM sample will be stored for central retesting, which will be performed in batch during the course of the study. In case of ineligibility according to exclusion and inclusion criteria, patients will not enter the treatment phase and go off protocol. They should be treated according to the choice of the individual treating physician and the chosen treatment will be recorded. If an IDH2 mutation is present and patients also fulfill all other inclusion criteria, they will be included and enter treatment phase of the study. They will be treated according to the treatment schedule outlined below:

  • Enasidenib 100 mg/day for 28 days per cycle up to 12 cycles (investigational product)
  • Optionally: DLI after cycle 4, 6 and 8 at a dose of 1-5 x10^6 CD3/kg (1st DLI), 5 x10^6 -5x10^7 CD3/kg (2ndDLI) and 5 x10^7-5x10^8 CD3/kg (3rd DLI) (in case of HLA-identical donors or at lower dosages in case of unrelated, mismatched or haploidentical donors, as per standard of care)

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 60 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: 2 single non-comparative arms
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: IDH2-Post-Allo-Trial: Enasidenib as Consolidation or Salvage Therapy for Patients With IDH2 Mutated AML or MDS Following Allogeneic Blood Stem Cell Transplantation
Actual Study Start Date : August 27, 2020
Estimated Primary Completion Date : June 30, 2024
Estimated Study Completion Date : June 30, 2024


Arm Intervention/treatment
Experimental: Consolidation Arm
Enasidenib (investigational product) will be started on day 1 for 28 days every 28 days for a maximum of 12 cycles. The starting dose of Enasidenib will be 100 mg once daily in every patient and may be reduced individually according to a dose modification scheme.
Drug: Enasidenib
Participants in both arms receive up to 12 cycles of Enasidenib.

Experimental: Salvage Arm

Enasidenib (investigational product) will be started on day 1 for 28 days every 28 days for a maximum of 12 cycles. The starting dose of Enasidenib will be 100 mg once daily in every patient and may be reduced individually according to a dose modification scheme.

DLI as standard of care can be given to patients optionally after cycle 4, 6 and 8 in case of HLA-identical donors at a dose of 1-5 x10^6 CD3/kg (1st DLI), 5 x10^6 - 5x107 CD3/kg (2nd DLI) and 5x10^7 - 5x10^8 CD3/kg (3rd DLI) or at lower dosages in case of unrelated, mismatched or haploidentical donors. Additional DLI may be given due to the treating physician's decision in case of urgent medical need, but only beyond the fourth cycle of Enasidenib.

Drug: Enasidenib
Participants in both arms receive up to 12 cycles of Enasidenib.




Primary Outcome Measures :
  1. Type, incidence and severity of adverse events specifying seriousness and expectedness (AE, SAE, SUSAR) [ Time Frame: through study completion, an average of 2 years ]
    Number of participants with Adverse Events as assessed by CTCAE v5.0


Secondary Outcome Measures :
  1. Number of participants who maintain remission (molecular/hematological) after allo-SCT (Consolidation Arm) [ Time Frame: through study completion, an average of 2 years ]
    Number of participants who maintain Remission (molecular/hematological) as a measure of efficacy (Consolidation Arm)

  2. Overall Survival [ Time Frame: through study completion, an average of 2 years ]
    Days from start of Treatment until death or last follow up as a measure of efficacy

  3. Relapse-free Survival (Consolidation Arm) [ Time Frame: through study completion, an average of 2 years ]
    Days from evaluation of remission at screening until relapse or death or last follow up as a measure of efficacy (Consolidation Arm)

  4. Numbers of Participants Meeting Criteria of Treatment Failure (Consolidation Arm) [ Time Frame: through study completion, an average of 2 years ]
    Number of participants who require any cellular or pharmacological intervention due to pending or frank relapse (defined as treatment-failure) as a measure of efficacy (Consolidation Arm)

  5. Correlation of cytogenetics/molecular alterations and relapse-free survival (Consolidation Arm) [ Time Frame: through study completion, an average of 2 years ]
    Correlation of relapse-free survival and cytogenetics/molecular alterations as a measure of efficacy (Consolidation Arm)

  6. Correlation of cytogenetics/molecular alterations and response (Salvage Arm) [ Time Frame: through study completion, an average of 2 years ]
    Correlation of response and cytogenetics/molecular alterations as a measure of efficacy (Salvage Arm)

  7. Best response within the first 12 months of treatment (Salvage Arm) [ Time Frame: through treatment completion, an average of 1 year ]
    Best response within the first 12 months of treatment according to the International Working Group (IWG) and European Leukemia Net (ELN) criteria as a measure of efficacy (Salvage Arm)

  8. Time to response (Salvage Arm) [ Time Frame: through study completion, an average of 2 years ]
    Days from beginning of Treatment to best Response in individual participants as a measure of efficacy (Salvage Arm)

  9. Rate and time to complete donor chimerism (Salvage Arm) [ Time Frame: through study completion, an average of 2 years ]
    Number of participants achieving complete donor chimerism as a measure of efficacy (Salvage Arm)

  10. Molecular response measured by IDH2 mutation burden and other disease-specific marker (Salvage Arm) [ Time Frame: through study completion, an average of 2 years ]
    Number of participants with molecular Response determined by IDH2 mutation and other disease-specific markers (e.g. FISH, mutations like TET2, ASXL1 or WT1 mRNA expression) (Salvage Arm)

  11. Incidence of relapse (Salvage Arm) [ Time Frame: through study completion, an average of 2 years ]
    Number of participants with relapse (Salvage Arm)

  12. Duration of remission (Salvage Arm) [ Time Frame: through study completion, an average of 2 years ]
    Days from beginning of remission to relapse as a measure of efficacy (Salvage Arm)

  13. Number of hospitalizations [ Time Frame: through treatment completion, an average of 1 year ]
    Number of hospitalizations per participant as a measure of safety

  14. Number of participants who require dose reductions for toxicity reasons [ Time Frame: through treatment completion, an average of 1 year ]
    Number of participants who require dose reductions for toxicity reasons as a measure of safety

  15. Number of participants who have to stop consolidation therapy due to toxicity (Consolidation Arm) [ Time Frame: through treatment completion, an average of 1 year ]
    Number of participants who have to stop consolidation therapy due to toxicity as a measure of safety (Consolidation Arm)

  16. Number of participants who can receive all 12 cycles of consolidation therapy(Consolidation Arm) [ Time Frame: through treatment completion, an average of 1 year ]
    Number of participants who can receive all 12 cycles of consolidation therapy as a measure of Safety (Consolidation Arm)

  17. Number of screened participants that can start consolidation therapy within the envisaged time frame (Consolidation Arm) [ Time Frame: up to 65 days ]
    Number of screened participants that can start consolidation therapy within the envisaged time Frame as a measure of safety (Consolidation Arm)



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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/µl and platelet count of at least 50.000/µl

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 within 72 hours prior study start and at day 1 of every treatment cycle 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 Understand that Enasidenib may impair fertility in males of reproductive potential and this effect may be not reversible

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 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:

Aspartate aminotransferase (19) ≥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 active 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)

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04522895


Contacts
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Contact: Thomas Schroeder, PD Dr. +49 211 81 18 ext 524 Thomas.Schroeder@med.uni-duesseldorf.de
Contact: Guido Kobbe, Prof. Dr. +49 211 81 18 ext 524 Kobbe@med.uni-duesseldorf.de

Locations
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Germany
University Hospital Duesseldorf Dept. of Hematology, Oncology and Clinical Immunology Recruiting
Duesseldorf, NRW, Germany, 40225
Contact: Thomas Schroeder, PD Dr.    +49 211 81 18 ext 524    thomas.schroeder@med.uni-duesseldorf.de   
Sponsors and Collaborators
Heinrich-Heine University, Duesseldorf
Celgene Corporation
Koordinierungszentrum für Klinische Studien Düsseldorf
Investigators
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Principal Investigator: Thomas Schroeder, PD Dr. University Hospital Duesseldorf Dept. of Hematology, Oncology and Clinical Immunology
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Responsible Party: Heinrich-Heine University, Duesseldorf
ClinicalTrials.gov Identifier: NCT04522895    
Other Study ID Numbers: AG-221CL-AML-PI13299
2019-001416-30 ( EudraCT Number )
First Posted: August 21, 2020    Key Record Dates
Last Update Posted: September 2, 2020
Last Verified: September 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Keywords provided by Heinrich-Heine University, Duesseldorf:
IDH2 Gene Mutation
MDS
CMML
AML
allogeneic blood stem cell transplantation
relapse after allogeneic transplantation
maintenance
consolidation
Additional relevant MeSH terms:
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Leukemia
Leukemia, Myelomonocytic, Chronic
Leukemia, Myelomonocytic, Juvenile
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Myelodysplastic Syndromes
Neoplasms by Histologic Type
Neoplasms
Bone Marrow Diseases
Hematologic Diseases
Myelodysplastic-Myeloproliferative Diseases