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

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

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.

Study Overview

• Status: Completed
• Conditions: Myelodysplastic Syndromes; Leukemia, Myeloid, Acute; Leukemia, Myelomonocytic, Chronic
• Intervention / Treatment: Drug: Lenalidomide; Drug: Azacitidine; Biological: Donor Lymphocyte Infusions

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.

• Study Type: Interventional
• Enrollment (Actual): 50
• Phase: Phase 2

Contacts and Locations

Study Locations

• Germany
  • NRW
    • Duesseldorf, NRW, Germany, 40225
      • University Hospital Duesseldorf, Dept. of Hematology, Oncology and Clinical Immunology

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 99 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Lenalidomide + Aza + DLI; 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.

Drug: Lenalidomide; 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.; Other Names: Revlimid; Drug: Azacitidine; 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.; Other Names: Vidaza; Biological: Donor Lymphocyte Infusions; 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).; Other Names: DLI

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants with Adverse Events as a Measure of Safety	incidence and severity of adverse events	56 months (final analysis, two interim analysis after 10 and 20 patients)
Type of Adverse Events as a Measure of Safety	Type of adverse events	56 months (final analysis, two interim analysis after 10 and 20 patients)
Severity of Adverse Events as a Measure of Safety	Severity of Adverse Events	56 months (final analysis, two interim analysis after 10 and 20 patients)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	8 months
Days from the beginning of treatment to best response in individual patients as a measure of efficacy	Time to response	56 months
Number of participants achieving complete donor chimerism as a measure of efficacy	Rate of complete donor chimerism	56 months
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	56 months
Days from beginning of remission to relapse as a measure of efficacy	Duration of remission	56 months
Days from start of treatment until death or last follow up as a measure of efficacy	Overall survival	56 months
Number of participants with a positive correlation between response and cytogenetics as a measure of efficacy	Correlation of response and cytogenetics/molecular alterations	56 months
Number of participants with acute GvHD according to Glucksberg Criteria as a measure of safety.	Incidence of aGvHD	56 months
Type of manifestations of acute GvHD according to Glucksberg Criteria as a measure of safety.	Type of aGvHD	56 months
Severity of acute GvHD manifestations according to Glucksberg Criteria as a measure of safety.	Severity of aGvHD	56 months
Number of hospitalizations per patients as a measure of safety	Number of hospitalizations	56 months
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)	56 months
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)	56 months
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)	56 months
Days from the beginning of treatment to complete donor chimerism as a measure of efficacy	Time to complete donor chimerisms	56 months
Number of participants with relapse as a measure of efficacy	Incidence of relapse	56 months
Number of participants with chronic GvHD according to NIH Consensus Criteria as a measure of safety.	Incidence of cGvHD	56 months
Type of manifestations of chronic GvHD according to NIH Consensus Criteria as a measure of safety.	Type of cGvHD	56 months
Severity of manifestations of chronic GvHD according to NIH Consensus Criteria as a measure of safety.	Severity of cGvHD	56 months

Collaborators and Investigators

• Sponsor: Heinrich-Heine University, Duesseldorf
• Collaborators: Celgene Corporation
• Investigators: Principal Investigator: Guido Kobbe, Prof. Dr., University Hospital Duesseldorf, Dept. for Hematology, Oncology and Clinical Immunology

Publications and helpful links

General Publications

• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): May 1, 2015
• Primary Completion (Actual): April 23, 2020
• Study Completion (Actual): April 23, 2020

Study Registration Dates

• First Submitted: May 20, 2015
• First Submitted That Met QC Criteria: June 15, 2015
• First Posted (Estimate): June 16, 2015

Study Record Updates

• Last Update Posted (Actual): May 28, 2020
• Last Update Submitted That Met QC Criteria: May 26, 2020
• Last Verified: May 1, 2020

More Information

Terms related to this study

• Keywords: AML; Lenalidomide; MDS; Azacitidine; DLI; relapse after allogeneic transplantation; CMML; C04.557.337.539.275; C15.378.190.625; C04.557.337.539.522
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Bone Marrow Diseases; Hematologic Diseases; Myelodysplastic-Myeloproliferative Diseases; Myelodysplastic Syndromes; Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Leukemia, Myelomonocytic, Chronic; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunologic Factors; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Lenalidomide; Azacitidine
• Other Study ID Numbers: AZALENA-2013/RV-MDS-PI-0777

Drug and device information, study documents

• 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