VIDAZA-DLI Pre-emptive Azacitidine and Donor Lymphocyte Infusions Following Allogeneic Hematopoietic Stem Cell Transplantation for High Risk Acute Myeloid Leukemia and Myelodysplastic Syndrome - Clinical Trial for Acute Myeloid Leukemia | NCT01541280

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Primary Purpose

Status

Completed

Phase

Phase 2

Locations

France

Study Type

Interventional

Intervention

Azacitidine

DLI

About this trial

This is an interventional treatment trial for Acute Myeloid Leukemia focused on measuring Allogreffe, LAM , MDS, Azacitidine (VidazaÒ), Injection de lymphocytes de donneur (DLI)

Eligibility Criteria

18 Years - 70 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Patients with high risk acute myeloid leukemia undergoing allogeneic transplantation with either a familial or an unrelated donor.

High risk AML is defined as :

AML in CR1 with unfavorable cytogenetics defined by complex caryotype, autosomal monosomy combined or not with other cytogenetics abnormalities inv(3)/t(3,3), t(6;9), t(6;11), t(11;19), del(5q), del(7q).
AML in CR2 or greater remission prior allogeneic transplantation
AML in PR or relapse prior allogeneic transplantation
Or Patients with high risk myelodysplastic syndrome undergoing allogeneic transplantation with either a familial or an unrelated donor.

High risk MDS is defined as :

MDS with intermediate-2 group and higher risk group according to IPSS criteria
Age 18 - 70 years.
Availability of an HLA identical family donor or unrelated donor with matching in 10/10 alleles (HLA-A, B, C, DRB1, DQB1) or maximum of 1 allele or antigen mismatch OR family donor with maximum 1 allele mismatch.
Conditioning regimen to allogeneic transplantation may be either myeloablative or reduced.
Be able to understand and sign informed consent.
Affiliation number to National Health Care System
Men and women of childbearing potential must use effective contraception during and up to 3 months after treatment.

Exclusion Criteria:

The presence of any one exclusion criteria renders the patient ineligible:
Patient in full relapse post-transplant (>20% blasts in the bone marrow) following allogeneic transplant
Documented leukemic infiltration of CNS/cerebrospinal fluid.
Karnofsky performance score below 60%.
Acute and chronic heart failure (NYHA Class III or IV) or symptomatic ischemic heart disease.

following allogeneic transplant

Severe liver failure (bilirubin >30 μmoles/L, SGPT > 4 X upper limit of normal).
Hepatic malignancy in advanced stage.
Severe neurological or psychiatric disorders
Acute GVHD grade II-III. Patient with grade I GVHD may be included (see annex 1 for GHVD grade definition).
Active uncontrolled infection.
Denied informed consent.
Treatment with other investigational drugs following allogeneic transplantation.
No effective contraception
Lactating females
Pregnant woman

Sites / Locations

University Hospital of Nantes

Outcomes

Primary Outcome Measures

Evaluation of the cumulative incidence of relapse rate

An A'Hern procedure will be used (cf. 11.1): If the number of patients not relapsed at two year will be 18 or more out of 24 patients, the null hypothesis will be rejected and the relapse rate will be considered acceptable.

Secondary Outcome Measures

Evaluation of disease-free survival (DFS) at 2 years from transplantation

Kaplan-Meier method

Measure the overall survival rate at 2 years

Kaplan-Meier method

Cumulative incidence death from leukemia, and non relapse mortality (NRM)

cumulative incidence function for disease free survival at 2 years from transplantation, GVHD, death from leukaemia and non-relapse mortality will be estimated (patients are at risk not only for relapse but can also be "removed" from possible relapse because of competing events such as death in remission (due to infection or GVHD)).

Feasibility and safety of administrating maintenance azacitidine following allogenic transplantaton

To evaluate toxicity induced by the azacitidine and DLI, different parameters will be studied:Cell Blood Count with differential, liver function tests, serum creatinine, BUN and total protein will be performed weekly from the time of initiation of azacitidine administration until completion of the last DLI. Performance Status,Acute GVHD,Bone marrow aspiration with evaluation of morphological response as well as chimerism from peripheral blood will be performed prior starting azacitidine, following 3 cycles of azacitidine and after the seventh cycle and twelfth cycle of azacitidine.

Feasibility and safety of performing prophylactic donor lymphocytes infusion

The relatedness of observed toxicity to DLI will be evaluated and documented: Maximum toxicity with respect to mucositis, liver, kidney, lung, heart, neurological system according to CTC criteria (cf. appendices). Infections (bacteremia, fungemia, invasive fungal infection, CMV reactivation and disease, other viral reactivation or infection). Grade of acute and chronic GVHD (cf. appendices); GVHD is classified according to clinical symptoms, irrespective to the time interval to DLI. Bone marrow aspiration, as well as chimerism in PB.

Incidence and severity of acute and chronic graft-versus-host disease

Symptoms related to GVHD should be reported within the GVHD section of the case reporting files. AE and SAE are documented in the patient's chart on a daily basis, as long as the patient is on ward, and on a weekly to two-monthly basis during outpatient follow up, depending on the frequency of outpatient visits on the respective patient.

Full Information

NCT ID

NCT01541280

First Posted

December 13, 2011

Last Updated

March 17, 2016

Sponsor

Nantes University Hospital

1. Study Identification

Unique Protocol Identification Number

NCT01541280

Brief Title

VIDAZA-DLI Pre-emptive Azacitidine and Donor Lymphocyte Infusions Following Allogeneic Hematopoietic Stem Cell Transplantation for High Risk Acute Myeloid Leukemia and Myelodysplastic Syndrome

Acronym

VIDAZA-DLI

Official Title

Pre-emptive Azacitidine and Donor Lymphocyte Infusions Following Allogeneic Hematopoietic Stem Cell Transplantation for High Risk Acute Myeloid Leukemia and Myelodysplastic Syndrome

Study Type

Interventional

2. Study Status

Record Verification Date

February 2016

Overall Recruitment Status

Completed

Study Start Date

November 2011 (undefined)

Primary Completion Date

July 2015 (Actual)

Study Completion Date

July 2015 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Nantes University Hospital

4. Oversight

5. Study Description

Brief Summary

Patients included in the study with high risk acute myeloid leukemia or myelodysplastic syndrome as defined will receive an allogeneic transplantation conditioned by either myeloablative or reduced regimen. Following allogeneic transplantation, patients will receive a maintenance regimen combining chemotherapy with azacitidine (aza) and immunotherapy with donor lymphocyte infusion.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Acute Myeloid Leukemia, Myelodysplastic Syndrome

Keywords

Allogreffe, LAM , MDS, Azacitidine (VidazaÒ), Injection de lymphocytes de donneur (DLI)

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

30 (Actual)

8. Arms, Groups, and Interventions

Intervention Type

Drug

Intervention Name(s)

Azacitidine

Intervention Description

Azacitidine (AZA) is to be administered every 28 days beginning day +56 to 100 posttransplant for one year provided the patients has a platelet count of >15 x 109/L without transfusion for at least 2 successive days, and an absolute neutrophil count of >1 x 109/L without growth factor for at least 2 successive days, and no acute GVHD greater than grade I and no clinical evidence of life-threatening infection. AZA is given 32 mg /m²/day subcutaneously for 5 days every 28 days (

Intervention Type

Other

Intervention Name(s)

DLI

Intervention Description

Donor lymphocyte infusion (DLI) is to be given from day +126 (week 18) in patients without immunosuppressive therapy for at least one month and following 3 cycles of AZA, and without clinical signs of GVHD, and without uncontrolled infection and without a recent history of >grade 2 acute GVHD. DLI are schedules every 8 weeks. There are 3 DLI scheduled. If first cycle of AZA is postponed beyond day 56 (maximum to Day 100), all subsequent cycles and DLI will be post poned too.

Primary Outcome Measure Information:

Title

Evaluation of the cumulative incidence of relapse rate

Description

An A'Hern procedure will be used (cf. 11.1): If the number of patients not relapsed at two year will be 18 or more out of 24 patients, the null hypothesis will be rejected and the relapse rate will be considered acceptable.

Time Frame

2 years

Secondary Outcome Measure Information:

Title

Evaluation of disease-free survival (DFS) at 2 years from transplantation

Description

Kaplan-Meier method

Time Frame

2 years

Title

Measure the overall survival rate at 2 years

Description

Kaplan-Meier method

Time Frame

2 years

Title

Cumulative incidence death from leukemia, and non relapse mortality (NRM)

Description

cumulative incidence function for disease free survival at 2 years from transplantation, GVHD, death from leukaemia and non-relapse mortality will be estimated (patients are at risk not only for relapse but can also be "removed" from possible relapse because of competing events such as death in remission (due to infection or GVHD)).

Time Frame

2 years

Title

Feasibility and safety of administrating maintenance azacitidine following allogenic transplantaton

Description

To evaluate toxicity induced by the azacitidine and DLI, different parameters will be studied:Cell Blood Count with differential, liver function tests, serum creatinine, BUN and total protein will be performed weekly from the time of initiation of azacitidine administration until completion of the last DLI. Performance Status,Acute GVHD,Bone marrow aspiration with evaluation of morphological response as well as chimerism from peripheral blood will be performed prior starting azacitidine, following 3 cycles of azacitidine and after the seventh cycle and twelfth cycle of azacitidine.

Time Frame

2 years

Title

Feasibility and safety of performing prophylactic donor lymphocytes infusion

Description

The relatedness of observed toxicity to DLI will be evaluated and documented: Maximum toxicity with respect to mucositis, liver, kidney, lung, heart, neurological system according to CTC criteria (cf. appendices). Infections (bacteremia, fungemia, invasive fungal infection, CMV reactivation and disease, other viral reactivation or infection). Grade of acute and chronic GVHD (cf. appendices); GVHD is classified according to clinical symptoms, irrespective to the time interval to DLI. Bone marrow aspiration, as well as chimerism in PB.

Time Frame

2 years

Title

Incidence and severity of acute and chronic graft-versus-host disease

Description

Symptoms related to GVHD should be reported within the GVHD section of the case reporting files. AE and SAE are documented in the patient's chart on a daily basis, as long as the patient is on ward, and on a weekly to two-monthly basis during outpatient follow up, depending on the frequency of outpatient visits on the respective patient.

Time Frame

2 years

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

70 Years

Accepts Healthy Volunteers

No

Eligibility Criteria

Inclusion Criteria: Patients with high risk acute myeloid leukemia undergoing allogeneic transplantation with either a familial or an unrelated donor. High risk AML is defined as : AML in CR1 with unfavorable cytogenetics defined by complex caryotype, autosomal monosomy combined or not with other cytogenetics abnormalities inv(3)/t(3,3), t(6;9), t(6;11), t(11;19), del(5q), del(7q). AML in CR2 or greater remission prior allogeneic transplantation AML in PR or relapse prior allogeneic transplantation Or Patients with high risk myelodysplastic syndrome undergoing allogeneic transplantation with either a familial or an unrelated donor. High risk MDS is defined as : MDS with intermediate-2 group and higher risk group according to IPSS criteria Age 18 - 70 years. Availability of an HLA identical family donor or unrelated donor with matching in 10/10 alleles (HLA-A, B, C, DRB1, DQB1) or maximum of 1 allele or antigen mismatch OR family donor with maximum 1 allele mismatch. Conditioning regimen to allogeneic transplantation may be either myeloablative or reduced. Be able to understand and sign informed consent. Affiliation number to National Health Care System Men and women of childbearing potential must use effective contraception during and up to 3 months after treatment. Exclusion Criteria: The presence of any one exclusion criteria renders the patient ineligible: Patient in full relapse post-transplant (>20% blasts in the bone marrow) following allogeneic transplant Documented leukemic infiltration of CNS/cerebrospinal fluid. Karnofsky performance score below 60%. Acute and chronic heart failure (NYHA Class III or IV) or symptomatic ischemic heart disease. following allogeneic transplant Severe liver failure (bilirubin >30 μmoles/L, SGPT > 4 X upper limit of normal). Hepatic malignancy in advanced stage. Severe neurological or psychiatric disorders Acute GVHD grade II-III. Patient with grade I GVHD may be included (see annex 1 for GHVD grade definition). Active uncontrolled infection. Denied informed consent. Treatment with other investigational drugs following allogeneic transplantation. No effective contraception Lactating females Pregnant woman

Overall Study Officials: