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

Sponsor

Heinrich-Heine University, Duesseldorf (Other)

Overall Status

Active, not recruiting

CT.gov ID

NCT04522895

Collaborator

Celgene Corporation (Industry), Koordinierungszentrum für Klinische Studien Düsseldorf (Other)

Enrollment

Locations

Arm

48.1

Anticipated Duration (Months)

4.5

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This is a prospective, open label, single arm, multi-centre phase II trial 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.

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

Study Design:

interventional
prospective, open-label, single arm, multicenter phase-II trial
total patients sample size: 50 patients
number of trial sites: 11 all located in Germany and members of the EBMT

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 hematological remission after first allo-SCT. IDH2 mutation might be absent at this time (CRMRDnegative), or might be detectable at submicroscopical levels (CRMRDpositive) given the high sensitivity of detection methods nowadays available. 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. The report about IDH2 mutation testing at diagnosis has 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 hematological 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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

50 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Intervention Model Description:

single armsingle arm

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 :

Aug 27, 2020

Anticipated Primary Completion Date :

Aug 30, 2024

Anticipated Study Completion Date :

Aug 30, 2024

Arms and Interventions

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 receive up to 12 cycles of Enasidenib.

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 receive up to 12 cycles of Enasidenib.

Outcome Measures

Primary Outcome Measures

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

Secondary Outcome Measures

Number of participants who maintain remission (molecular/hematological) after allo-SCT [through study completion, an average of 2 years]
Number of participants who maintain Remission (molecular/hematological) as a measure of efficacy
Overall Survival [through study completion, an average of 2 years]
Days from start of Treatment and from date of allo-SCT until death or last follow up as a measure of efficacy
Relapse-free Survival [through study completion, an average of 2 years]
Days from evaluation of remission at screening and from date of allo-SCT until relapse, death, or last follow up as a measure of efficacy
Non-relapse mortality [through study completion, an average of 2 years]
Days from evaluation of remission at screening and from date of allo-SCT until death without relapse or last follow up as a measure of efficacy
Relapse incidence [through study completion, an average of 2 years]
number of participants that relapse during the study as a measure of efficacy
Numbers of Participants Meeting Criteria of Treatment Failure [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
Correlation of cytogenetics/molecular alterations and relapse-free survival [through study completion, an average of 2 years]
Comparison of relapse-free survival between different cytogenetics/molecular subtypes as a measure of efficacy using time to event curves and log-rank test
Incidence, course and severity of aGvHD and cGvHD [through study completion, an average of 2 years]
Incidence, course and severity of aGvHD and cGvHD as a measure of safety
Number of hospitalizations [through treatment completion, an average of 1 year]
Number of hospitalizations per participant as a measure of safety
Number of participants who require dose reductions for toxicity reasons [through treatment completion, an average of 1 year]
Number of participants who require dose reductions for toxicity reasons as a measure of safety
Number of participants who have to stop consolidation therapy due to toxicity (Consolidation Arm) [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)
Number of participants who can receive all 12 cycles of consolidation therapy(Consolidation Arm) [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)
Number of screened participants that can start consolidation therapy within the envisaged time frame (Consolidation Arm) [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)

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Patients with myeloid malignancy (AML, MDS and CMML) and known IDH2 mutation (IDH2 R172 or R140 mutation) at diagnosis prior to first allo-SCT
hematological CR after allo-SCT determined during screening period between day +25 and day +35 (the hematological remission will be confirmed locally by cytomorphological/histological evaluation)
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
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:

Any evidence of hematological relapse 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
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 or 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)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University Hospital Duesseldorf Dept. of Hematology, Oncology and Clinical Immunology	Duesseldorf	NRW	Germany	40225
2	Uniklinik RWTH Aachen Klinik für Hämatologie, Onkologie, Hämostaseologie und Stammzelltransplantation (Med. Klinik IV)	Aachen		Germany	52074
3	Universitätsklinikum Carl Gustav Carus Medizinische Klinik und Poliklinik I	Dresden		Germany	01307
4	Universitätsklinikum Essen Klinik für Hämatologie und Stammzelltransplantation	Essen		Germany	45147
5	Universitätsklinikum Frankfurt Med. Klinik II	Frankfurt		Germany	60590
6	Universitätsklinikum Hamburg-Eppendorf Interdisziplinäre Klinik für Stammzelltransplantation	Hamburg		Germany	20246
7	Universitätsklinikum Heidelberg Innere Medizin V: Hämatologie, Onkologie und Rheumatologie	Heidelberg		Germany	69120
8	Universitätsklinikum Köln Klinik I für Innere Medizin	Köln		Germany	50937
9	Universitätsklinikum Leipzig Medizinische Klinik und Poliklinik I, Hämatologie und Zelltherapie	Leipzig		Germany	04103
10	Klinikum rechts der Isar der TU München Klinik und Poliklinik für Innere Medizin III, Hämatologie und Onkologie	München		Germany	81675
11	Universitätsklinikum Münster Medizinische Klinik A / KMT Zentrum	Münster		Germany	48149