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Azacitidine, Lenalidomide and DLI as Salvage Therapy for MDS, CMML and sAML Relapsing After Allo-HSCT (AZALENA)

Primary Purpose

Leukemia, Myeloid, Acute, Myelodysplastic Syndromes, Leukemia, Myelomonocytic, Chronic

Status
Completed
Phase
Phase 2
Locations
Germany
Study Type
Interventional
Intervention
Lenalidomide
Azacitidine
Donor Lymphocyte Infusions
Sponsored by
Heinrich-Heine University, Duesseldorf
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Leukemia, Myeloid, Acute focused on measuring relapse after allogeneic transplantation, MDS, AML, CMML, DLI, Azacitidine, Lenalidomide, C04.557.337.539.275, C15.378.190.625, C04.557.337.539.522

Eligibility Criteria

18 Years - 99 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • First relapse of de novo or therapy-related MDS, CMML or AML according to WHO classification (revised version 2016) without FLT3 mutation and without known IDH mutation after first allo-SCT (related or unrelated donor with < 2 HLA mismatches)
  • Possibility of DLI (no cord blood, no haploidentical donor)
  • no previous therapy for relapse after allo-SCT
  • ECOG performance status ≤ 2 at study entry
  • no active GvHD treated with 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.
  • All females must acknowledge to have understood the hazards and necessary precautions associated with the use of lenalidomide

Exclusion Criteria:

  • Relapse after second allogeneic Transplantation
  • AML with FLT3 mutation (ITD or TKD)
  • AML with known IDH mutation (IDH1 or IDH2)
  • Any previous therapy (chemotherapy, radiation or investigational drugs) administered as therapy for relapse after allo-SCT

  • previous transplantation with cord blood, an haploidentical donor or a related/unrelated donor with

    ≥2 HLA mismatches

  • Active GvHD 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 < 20 ml/min)
  • Impaired hepatic function
  • Known hypersensitivity to thalidomide, lenalidomide or any components of the treatment
  • The development of erythema nodosum if characterized by a desquamating rash while taking thalidomide or similar drugs.
  • Concurrent use of other anti-cancer agents or treatments.
  • Known positive for HIV or infectious hepatitis, type A, B or C.
  • Neuropathy ≥ grade 2
  • Prior history of malignancy other than MDS or AML (except basal cell or squamous cell carcinoma or carcinoma in situ of the cervix or breast) unless the subject has been free of disease for ≥ 3 years
  • Participation in another study with ongoing use of unlicensed investigational product from 28 days before study enrollment until the end of the study

Sites / Locations

  • University Hospital Duesseldorf, Dept. of Hematology, Oncology and Clinical Immunology

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Lenalidomide + Aza + DLI

Arm Description

Patients will be included at the time of relapse after first allo-SCT. As standard of care all patients will receive Azacitidine 75 mg/m2/d for 7 days every 28 days for up to 8 cycles and DLIs given after cycle 4, 6 and 8 at a dose of 0.5-1x106CD3/kg (1st DLI), 1-5x106CD3/kg (2nd DLI) and 5-15x106CD3/kg (3rd DLI). As intervention (investigational drug), Lenalidomide will be also started on day 1 for 21 days every 28 days for a maximum of 8 cycles. Starting dose of Lenalidomide 2.5 mg per day for the first 10 patients. If no dose limiting toxicity is identified in a first interim analysis, the next 10 patients will be treated with 5 mg per day. In case of no DLT after a second interim analysis, the remaining 30 patients are envisaged to be treated with 5 mg per day.

Outcomes

Primary Outcome Measures

Number of Participants with Adverse Events as a Measure of Safety
incidence and severity of adverse events
Type of Adverse Events as a Measure of Safety
Type of adverse events
Severity of Adverse Events as a Measure of Safety
Severity of Adverse Events

Secondary Outcome Measures

Number of participants with responses according to International Working Group (IWG) criteria as a measure of efficacy
Best response within the first 8 months of treatment according to the International Working Group (IWG) criteria
Days from the beginning of treatment to best response in individual patients as a measure of efficacy
Time to response
Number of participants achieving complete donor chimerism as a measure of efficacy
Rate of complete donor chimerism
Number of participants with molecular response determined by disease-specific marker (e.g. FISH, mutations like TET2, ASXL1 etc.) or WT1 mRNA expression as a measure of efficacy
Molecular response measured by disease-specific marker (e.g. FISH, mutations like TET2, ASXL1 etc.) or WT1 mRNA expression
Days from beginning of remission to relapse as a measure of efficacy
Duration of remission
Days from start of treatment until death or last follow up as a measure of efficacy
Overall survival
Number of participants with a positive correlation between response and cytogenetics as a measure of efficacy
Correlation of response and cytogenetics/molecular alterations
Number of participants with acute GvHD according to Glucksberg Criteria as a measure of safety.
Incidence of aGvHD
Type of manifestations of acute GvHD according to Glucksberg Criteria as a measure of safety.
Type of aGvHD
Severity of acute GvHD manifestations according to Glucksberg Criteria as a measure of safety.
Severity of aGvHD
Number of hospitalizations per patients as a measure of safety
Number of hospitalizations
Number of participants with Adverse events specifying seriousness and expectedness (AE, SAE, SUSAR) according to ICH-GCP as a measure of safety.
Number of Adverse Events specifying seriousness and expectedness (AE, SAE, SUSAR)
Type of Adverse events specifying seriousness and expectedness (AE, SAE, SUSAR) according to ICH-GCP as a measure of safety.
Type of Adverse Events specifying seriousness and expectedness (AE, SAE, SUSAR)
Severity of Adverse events specifying seriousness and expectedness (AE, SAE, SUSAR) according to ICH-GCP as a measure of safety.
Severity of Adverse Events specifying seriousness and expectedness (AE, SAE, SUSAR)
Days from the beginning of treatment to complete donor chimerism as a measure of efficacy
Time to complete donor chimerisms
Number of participants with relapse as a measure of efficacy
Incidence of relapse
Number of participants with chronic GvHD according to NIH Consensus Criteria as a measure of safety.
Incidence of cGvHD
Type of manifestations of chronic GvHD according to NIH Consensus Criteria as a measure of safety.
Type of cGvHD
Severity of manifestations of chronic GvHD according to NIH Consensus Criteria as a measure of safety.
Severity of cGvHD

Full Information

First Posted
May 20, 2015
Last Updated
May 26, 2020
Sponsor
Heinrich-Heine University, Duesseldorf
Collaborators
Celgene Corporation
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1. Study Identification

Unique Protocol Identification Number
NCT02472691
Brief Title
Azacitidine, Lenalidomide and DLI as Salvage Therapy for MDS, CMML and sAML Relapsing After Allo-HSCT
Acronym
AZALENA
Official Title
Phase-II Trial to Assess the Efficacy and Safety of Lenalidomide in Addition to 5-Azacitidine and Donor Lymphocyte Infusions (DLI) for the Treatment of Patients With MDS, CMML or AML Who Relapse After Allogeneic Stem Cell Transplantation
Study Type
Interventional

2. Study Status

Record Verification Date
May 2020
Overall Recruitment Status
Completed
Study Start Date
May 2015 (Actual)
Primary Completion Date
April 23, 2020 (Actual)
Study Completion Date
April 23, 2020 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Heinrich-Heine University, Duesseldorf
Collaborators
Celgene Corporation

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
This is a prospective, open-label, single-arm multi-center phase II study aiming to evaluate the safety and feasibility of the addition of Lenalidomide (investigational drug) to the standard therapy of Azacitidine and DLI (standard of care) as first salvage therapy for relapse of MDS, CMML and AML with MDS-related changes (sAML, with 20%-30% bone marrow blasts, formerly RAEB-T) after allo-SCT. The starting dose of Lenalidomid is 2.5 mg per day for 21 days with a 7 day rest. The study incorporates 2 interim safety analyses after 10 and 20 patients in order to find the optimal and safe dose of Lenalidomide.
Detailed Description
This is a prospective, open-label, single-arm multi-center phase II study aiming to evaluate the safety and feasibility of the addition of Lenalidomide (investigational drug) to the standard therapy of Azacitidine and DLI (standard of care) as first salvage therapy for relapse of MDS, CMML and AML with MDS-related changes (sAML, with 20%-30% bone marrow blasts, formerly RAEB-T) after allo-SCT. Study Design: prospective, open-label, single arm, multicenter phase-II trial total patients sample size: 50 patients number of trial sites: 6 all located in Germany and members of the EBMT Patients will be included at the time of relapse after first allo-SCT. Starting on day 1 all patients will receive Azacitidine 75 mg/m2/d for 7 days every 28 days for up to 8 cycles. DLIs will be given after cycle 4, 6 and 8. Lenalidomide will be also started on day 1 for 21 days every 28 days for a maximum of 8 cycles. The concomitant administration of Aza and Lenalidomide will be used since safety and efficacy of this schedule has been demonstrated. Azacitidine and DLI represent a standard of care in this setting and are therefore not considered as investigational. As 5-Azacytidine is given in-label, treatment may be continued beyond 8 cycles. Additional DLIs may be given according to the investigators choice. However, to avoid severe GvHD it is recommended to give at least one more cycle 5-Azacytidine after additional DLIs. The study incorporates a dose escalating schedule for Lenalidomide and two safety interim analyses. A first interim analysis will be performed as soon as 10 patients have been treated with Lenalidomide at a dose of 2.5mg/day If no dose limiting toxicity is observed in this cohort the next cohort of 10 patients will be treated with 5 mg per day for 21 days starting on day 1. If dose limiting toxicity occurs the study will be closed. A second interim analysis will be performed as soon as 10 patients have been treated with Lenalidomide at a dose of 5mg/day and the 10th patient of this cohort has either completed 4 cycles or has discontinued treatment whichever occurs first. If no dose limiting toxicity is observed in this cohort, the dose of 5 mg per day for 21 days starting on day 1 will be chosen and the remaining patients will be treated with this dose of Lenalidomide. If dose limiting toxicity occurs in patients treated with 5mg per day the remaining patients will be treated with Lenalidomide at a dose of 2.5mg/day. A total number of 50 patients will be treated. Independent of the dose level, Lenalidomide will be stopped individually in the case of GvHD ≥ grade II.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Leukemia, Myeloid, Acute, Myelodysplastic Syndromes, Leukemia, Myelomonocytic, Chronic
Keywords
relapse after allogeneic transplantation, MDS, AML, CMML, DLI, Azacitidine, Lenalidomide, C04.557.337.539.275, C15.378.190.625, C04.557.337.539.522

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
50 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Lenalidomide + Aza + DLI
Arm Type
Experimental
Arm Description
Patients will be included at the time of relapse after first allo-SCT. As standard of care all patients will receive Azacitidine 75 mg/m2/d for 7 days every 28 days for up to 8 cycles and DLIs given after cycle 4, 6 and 8 at a dose of 0.5-1x106CD3/kg (1st DLI), 1-5x106CD3/kg (2nd DLI) and 5-15x106CD3/kg (3rd DLI). As intervention (investigational drug), Lenalidomide will be also started on day 1 for 21 days every 28 days for a maximum of 8 cycles. Starting dose of Lenalidomide 2.5 mg per day for the first 10 patients. If no dose limiting toxicity is identified in a first interim analysis, the next 10 patients will be treated with 5 mg per day. In case of no DLT after a second interim analysis, the remaining 30 patients are envisaged to be treated with 5 mg per day.
Intervention Type
Drug
Intervention Name(s)
Lenalidomide
Other Intervention Name(s)
Revlimid
Intervention Description
Lenalidomide (investigational drug) will be added to standard of care (Aza and DLI) starting from day 1 for 21 days every 28 days for a maximum of 8 cycles. Starting dose of Lenalidomide 2.5 mg per day for the first 10 patients. If no dose limiting toxicity is identified in a first interim analysis, the next 10 patients will be treated with 5 mg per day. In case of no DLT after a second interim analysis, the remaining 30 patients are envisaged to be treated with 5 mg per day.
Intervention Type
Drug
Intervention Name(s)
Azacitidine
Other Intervention Name(s)
Vidaza
Intervention Description
Starting on day 1 all patients will receive Azacitidine (standard of care) 75 mg/m2/d for 7 days every 28 days for up to 8 cycles.
Intervention Type
Biological
Intervention Name(s)
Donor Lymphocyte Infusions
Other Intervention Name(s)
DLI
Intervention Description
DLIs will be given after cycle 4, 6 and 8 at a dose of 0.5-1x10^6 CD3/kg (1st DLI), 1-5x10^6 CD3/kg (2nd DLI) and 5-15x10^6 CD3/kg (3rd DLI).
Primary Outcome Measure Information:
Title
Number of Participants with Adverse Events as a Measure of Safety
Description
incidence and severity of adverse events
Time Frame
56 months (final analysis, two interim analysis after 10 and 20 patients)
Title
Type of Adverse Events as a Measure of Safety
Description
Type of adverse events
Time Frame
56 months (final analysis, two interim analysis after 10 and 20 patients)
Title
Severity of Adverse Events as a Measure of Safety
Description
Severity of Adverse Events
Time Frame
56 months (final analysis, two interim analysis after 10 and 20 patients)
Secondary Outcome Measure Information:
Title
Number of participants with responses according to International Working Group (IWG) criteria as a measure of efficacy
Description
Best response within the first 8 months of treatment according to the International Working Group (IWG) criteria
Time Frame
8 months
Title
Days from the beginning of treatment to best response in individual patients as a measure of efficacy
Description
Time to response
Time Frame
56 months
Title
Number of participants achieving complete donor chimerism as a measure of efficacy
Description
Rate of complete donor chimerism
Time Frame
56 months
Title
Number of participants with molecular response determined by disease-specific marker (e.g. FISH, mutations like TET2, ASXL1 etc.) or WT1 mRNA expression as a measure of efficacy
Description
Molecular response measured by disease-specific marker (e.g. FISH, mutations like TET2, ASXL1 etc.) or WT1 mRNA expression
Time Frame
56 months
Title
Days from beginning of remission to relapse as a measure of efficacy
Description
Duration of remission
Time Frame
56 months
Title
Days from start of treatment until death or last follow up as a measure of efficacy
Description
Overall survival
Time Frame
56 months
Title
Number of participants with a positive correlation between response and cytogenetics as a measure of efficacy
Description
Correlation of response and cytogenetics/molecular alterations
Time Frame
56 months
Title
Number of participants with acute GvHD according to Glucksberg Criteria as a measure of safety.
Description
Incidence of aGvHD
Time Frame
56 months
Title
Type of manifestations of acute GvHD according to Glucksberg Criteria as a measure of safety.
Description
Type of aGvHD
Time Frame
56 months
Title
Severity of acute GvHD manifestations according to Glucksberg Criteria as a measure of safety.
Description
Severity of aGvHD
Time Frame
56 months
Title
Number of hospitalizations per patients as a measure of safety
Description
Number of hospitalizations
Time Frame
56 months
Title
Number of participants with Adverse events specifying seriousness and expectedness (AE, SAE, SUSAR) according to ICH-GCP as a measure of safety.
Description
Number of Adverse Events specifying seriousness and expectedness (AE, SAE, SUSAR)
Time Frame
56 months
Title
Type of Adverse events specifying seriousness and expectedness (AE, SAE, SUSAR) according to ICH-GCP as a measure of safety.
Description
Type of Adverse Events specifying seriousness and expectedness (AE, SAE, SUSAR)
Time Frame
56 months
Title
Severity of Adverse events specifying seriousness and expectedness (AE, SAE, SUSAR) according to ICH-GCP as a measure of safety.
Description
Severity of Adverse Events specifying seriousness and expectedness (AE, SAE, SUSAR)
Time Frame
56 months
Title
Days from the beginning of treatment to complete donor chimerism as a measure of efficacy
Description
Time to complete donor chimerisms
Time Frame
56 months
Title
Number of participants with relapse as a measure of efficacy
Description
Incidence of relapse
Time Frame
56 months
Title
Number of participants with chronic GvHD according to NIH Consensus Criteria as a measure of safety.
Description
Incidence of cGvHD
Time Frame
56 months
Title
Type of manifestations of chronic GvHD according to NIH Consensus Criteria as a measure of safety.
Description
Type of cGvHD
Time Frame
56 months
Title
Severity of manifestations of chronic GvHD according to NIH Consensus Criteria as a measure of safety.
Description
Severity of cGvHD
Time Frame
56 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
99 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: First relapse of de novo or therapy-related MDS, CMML or AML according to WHO classification (revised version 2016) without FLT3 mutation and without known IDH mutation after first allo-SCT (related or unrelated donor with < 2 HLA mismatches) Possibility of DLI (no cord blood, no haploidentical donor) no previous therapy for relapse after allo-SCT ECOG performance status ≤ 2 at study entry no active GvHD treated with 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. All females must acknowledge to have understood the hazards and necessary precautions associated with the use of lenalidomide Exclusion Criteria: Relapse after second allogeneic Transplantation AML with FLT3 mutation (ITD or TKD) AML with known IDH mutation (IDH1 or IDH2) Any previous therapy (chemotherapy, radiation or investigational drugs) administered as therapy for relapse after allo-SCT previous transplantation with cord blood, an haploidentical donor or a related/unrelated donor with ≥2 HLA mismatches Active GvHD 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 < 20 ml/min) Impaired hepatic function Known hypersensitivity to thalidomide, lenalidomide or any components of the treatment The development of erythema nodosum if characterized by a desquamating rash while taking thalidomide or similar drugs. Concurrent use of other anti-cancer agents or treatments. Known positive for HIV or infectious hepatitis, type A, B or C. Neuropathy ≥ grade 2 Prior history of malignancy other than MDS or AML (except basal cell or squamous cell carcinoma or carcinoma in situ of the cervix or breast) unless the subject has been free of disease for ≥ 3 years Participation in another study with ongoing use of unlicensed investigational product from 28 days before study enrollment until the end of the study
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Guido Kobbe, Prof. Dr.
Organizational Affiliation
University Hospital Duesseldorf, Dept. for Hematology, Oncology and Clinical Immunology
Official's Role
Principal Investigator
Facility Information:
Facility Name
University Hospital Duesseldorf, Dept. of Hematology, Oncology and Clinical Immunology
City
Duesseldorf
State/Province
NRW
ZIP/Postal Code
40225
Country
Germany

12. IPD Sharing Statement

Citations:
PubMed Identifier
23314834
Citation
Schroeder T, Czibere A, Platzbecker U, Bug G, Uharek L, Luft T, Giagounidis A, Zohren F, Bruns I, Wolschke C, Rieger K, Fenk R, Germing U, Haas R, Kroger N, Kobbe G. Azacitidine and donor lymphocyte infusions as first salvage therapy for relapse of AML or MDS after allogeneic stem cell transplantation. Leukemia. 2013 Jun;27(6):1229-35. doi: 10.1038/leu.2013.7. Epub 2013 Jan 14.
Results Reference
background
PubMed Identifier
25540937
Citation
Schroeder T, Rachlis E, Bug G, Stelljes M, Klein S, Steckel NK, Wolf D, Ringhoffer M, Czibere A, Nachtkamp K, Dienst A, Kondakci M, Stadler M, Platzbecker U, Uharek L, Luft T, Fenk R, Germing U, Bornhauser M, Kroger N, Beelen DW, Haas R, Kobbe G. Treatment of acute myeloid leukemia or myelodysplastic syndrome relapse after allogeneic stem cell transplantation with azacitidine and donor lymphocyte infusions--a retrospective multicenter analysis from the German Cooperative Transplant Study Group. Biol Blood Marrow Transplant. 2015 Apr;21(4):653-60. doi: 10.1016/j.bbmt.2014.12.016. Epub 2014 Dec 23.
Results Reference
result

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Azacitidine, Lenalidomide and DLI as Salvage Therapy for MDS, CMML and sAML Relapsing After Allo-HSCT

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