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

NCT02472691 | Completed Phase 2 DMC

• 1 other identifier: AZALENA-2013/RV-MDS-PI-0777
• Study Type: interventional
• Target: 50
• Locations: 1 country
• Sites: 1

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.

Conditions

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

Outcome Measures

Primary Outcomes (3)

• 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 Outcomes (19)

• Number of participants with responses according to International Working Group (IWG) criteria as a measure of efficacy

  8 months

• Days from the beginning of treatment to best response in individual patients as a measure of efficacy

  56 months

• Number of participants achieving complete donor chimerism as a measure of efficacy

  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

  56 months

• Days from beginning of remission to relapse as a measure of efficacy

  56 months

Study Arms (1)

Lenalidomide + Aza + DLI

EXPERIMENTAL

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; Drug: Azacitidine; Biological: Donor Lymphocyte Infusions

Interventions

Lenalidomide DRUG

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.

Also known as: Revlimid

Lenalidomide + Aza + DLI

Azacitidine DRUG

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.

Also known as: Vidaza

Lenalidomide + Aza + DLI

Donor Lymphocyte Infusions BIOLOGICAL

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).

Also known as: DLI

Lenalidomide + Aza + DLI

Eligibility Criteria

• Age: 18 Years - 99 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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
• 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

You may not qualify if:

• 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.

Sponsors & Collaborators

• Heinrich-Heine University, Duesseldorf: lead
• Celgene Corporation: collaborator

Study Sites (1)

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

Düsseldorf, North Rhine-Westphalia, 40225, Germany

Location

Related Publications (3)

• 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.

  PMID: 23314834 BACKGROUND

• 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.

  PMID: 25540937 RESULT

• Schroeder T, Stelljes M, Christopeit M, Esseling E, Scheid C, Mikesch JH, Rautenberg C, Jager P, Cadeddu RP, Drusenheimer N, Holtick U, Klein S, Trenschel R, Haas R, Germing U, Kroger N, Kobbe G. Azacitidine, lenalidomide and donor lymphocyte infusions for relapse of myelodysplastic syndrome, acute myeloid leukemia and chronic myelomonocytic leukemia after allogeneic transplant: the Azalena-Trial. Haematologica. 2023 Nov 1;108(11):3001-3010. doi: 10.3324/haematol.2022.282570.

  PMID: 37259567 DERIVED

MeSH Terms

Conditions

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

Interventions

Lenalidomide; Azacitidine

Condition Hierarchy (Ancestors)

Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Bone Marrow Diseases; Myelodysplastic-Myeloproliferative Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Phthalimides; Phthalic Acids; Acids, Carbocyclic; Carboxylic Acids; Organic Chemicals; Piperidones; Piperidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Isoindoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Aza Compounds; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Ribonucleosides

Study Officials

• Guido Kobbe, Prof. Dr.

  University Hospital Duesseldorf, Dept. for Hematology, Oncology and Clinical Immunology

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 20, 2015
• First Posted: June 16, 2015
• Study Start: May 1, 2015
• Primary Completion: April 23, 2020
• Study Completion: April 23, 2020
• Last Updated: May 28, 2020

Record last verified: 2020-05

Locations

DE (1)