Ignite Creation Date:
2024-05-05 @ 10:50 PM
Last Modification Date:
2024-10-26 @ 10:24 AM
Study NCT ID:
NCT01191957
Status:
COMPLETED
Last Update Posted:
2023-03-10
First Post:
2010-06-10
Brief Title:
Busulfan BU Plus Fludarabine Vs Intravenous BU Plus Cyclophosphamide as Conditioning Regimens Prior Allogeneic Hematopoetic Stem Cells Transplant HSCT in AML
Sponsor:
Gruppo Italiano Trapianto di Midollo Osseo
Organization:
Gruppo Italiano Trapianto di Midollo Osseo
Study Overview
Official Title:
Randomized Study Comparing iv Busulfan Busilvex Plus Fludarabine BuFlu Versus Busilvex Plus Cyclophosphamide BuCy2 as Conditioning Regimens Prior AlloHSCT in Patients Age 40 and 65 Years With AML in Complete Remission
Status:
COMPLETED
Status Verified Date:
2023-03
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
GITMO-AMLR2
Brief Summary:
The purpose of this prospective phase III open-label randomized multicenter study is to evaluate whether Acute Myeloid Leukemia AML elderly patients in Complete Remission CR undergoing allogeneic hematopoietic stem cell transplantation after a reduce toxicity conditioning regimen IV BuFlu as compared to the conventional IV
BuCy2 program will experience
1 A lower transplant-related mortality TRM at 1 year after Hematopoietic Stem Cells Transplant HSCT
2 A similar anti-leukemic activity and a similar or better safety profile in terms of
Early andor late graft rejection
Hematopoietic and immunologic recovery
Chimerism
Toxicity and incidence of Veno-occlusive Disease VOD
Acute aGvHD and chronic graft-versus-host disease cGvHD
Cumulative incidence of TRM at 100 days and 2 years after transplant
Cumulative incidence of relapse by 1 and 2 years after transplant
Event-free EFS and overall survival OS by 1 and 2 years after transplant
BuCy2 program will experience
1 A lower transplant-related mortality TRM at 1 year after Hematopoietic Stem Cells Transplant HSCT
2 A similar anti-leukemic activity and a similar or better safety profile in terms of
Early andor late graft rejection
Hematopoietic and immunologic recovery
Chimerism
Toxicity and incidence of Veno-occlusive Disease VOD
Acute aGvHD and chronic graft-versus-host disease cGvHD
Cumulative incidence of TRM at 100 days and 2 years after transplant
Cumulative incidence of relapse by 1 and 2 years after transplant
Event-free EFS and overall survival OS by 1 and 2 years after transplant
Detailed Description:
Hematopoietic stem-cell transplantation HSCT is a potentially curative treatment modality for patients with Acute Myelogenous Leukemia AML
An effective conditioning regimen is based on the association of oral Busulfan 4 mgkg daily in 4 doses each of 1 mgkg on each of 4 successive days total dose 16 mgkg followed by CY 60 mgkg intravenously on each of 2 successive days BuCy2 The antileukemic activity of this latter program was tested and confirmed in most large randomized clinical trials conducted in AML and Chronic Myeloid Leukemia CML patients in which the BU-CY regimen was associated with survival and relapse probabilities that compare favourably with the CY-Total Body Irradiation TBI regimen The BuCy2 program is considered a golden standard preparative regimen for allogeneic transplantation in AML patients
Nonetheless for many years the treatment related toxicities of all these full myeloablative conditioning regimens has substantially limited the overall applicability of the transplant procedure to young patients with a good performance status PS The observation that allogeneic stem cell transplants have a potentially curative graft-versus-leukemia GVL effect in addition to the antileukemic action of myeloablative conditioning regimens was a major stimulus for the development of reduced-intensity conditioning RIC regimens aimed primarily at securing engraftment to provide the GVL effect while minimizing regimen-related toxicity
The observation that allogeneic stem cell transplants have a potentially curative graft-versus-leukemia GVL effect in addition to the antileukemic action of myeloablative conditioning regimens was a major stimulus for the development of reduced-intensity conditioning RIC regimens aimed primarily at securing engraftment to provide the GVL effect while minimizing regimen-related toxicity As a consequence reduced-intensity conditioning RIC regimens might give possibility to extend access to allogeneic transplantation to patients who would not have previously been considered reasonable candidates because of their age and for the presence of comorbidities However after a lot of initial enthusiasm it has become clear that a more intensive conditioning is associated with a reduced risk for relapse after HSCT Therefore while it is clear that RIC transplants have opened the way to using allogeneic SCT in patients several years older than the upper age limit of 60 the superiority of the RIC approach cannot be assumed even in this subgroup of patients This is why more recently investigators are looking for conditioning programs that while better tolerated still might retain a strong ability of inducing a direct ablation of the leukemic hematopoiesis This has led to the new concept of reduced toxicity rather than reduced intensity conditioning programs One of such a program is based on the association of a myeloablative dose of intravenous Busulfan 08 mgkgd for 4 days with Fludarabine 30 mgm2d for 4 days which has been reported as highly effective in patients with AML In elderly patients with this disease this program might lead to an overall outcome at least as good as that following conventional myeloablative programs such as those based on Cyclophosphamide combined to the same dose of IV Busulfan or the TBI In fact when compared to these latter programs the Busulfan Fludarabine regimen was found associated with lower non relapse mortality although a higher relapse rate was still documented but not in all published experiences In all outcomes for standard transplant regimens have generally improved and these newer myeloablative regimens of Fludarabine with full-dose intravenous Busulfan achieve 1 year TRM below 10 So based on these considerations protocol GITMO-AMLR2 has been designed to compare intravenous Busulfan plus Fludarabine BuFlu versus Busulfan IV Bu Busilvex plus Cyclophosphamide BuCy2 as conditioning regimens prior to allogeneic Hematopoietic Stem Cell Transplantation alloHSCT in patients aged between 40 and 65 years with Acute Myeloid Leukemia AML in Complete Remission CR
So based on these considerations protocol GITMO-AMLR2 has been designed to compare intravenous Busulfan plus Fludarabine BuFlu versus Busulfan IV Bu Busilvex plus Cyclophosphamide BuCy2 as conditioning regimens prior to allogeneic Hematopoietic Stem Cell Transplantation alloHSCT in patients aged between 40 and 65 years with Acute Myeloid Leukemia AML in Complete Remission CR
The principal objective of this trial is the evaluation of one year transplant-related mortality TRM of AML patients undergoing allogeneic hematopoietic stem cell transplantation after a reduced toxicity conditioning regimen IVBuFlu as compared to the conventional IV BuCy2 program
To this purpose in the IV BuCy2 arm reference TRM was assumed to be 25 range 16-50 while in the IV BuFlu arm and an estimated 125 TRM is assumed range 0-30 The study is designed to demonstrate a relative risk reduction of 50 For the event-driven two-sided test an alpha-level probability of 005 type I error and a power of 80 type II error02 has been considered The ratio between the numbers of patients included in each arm is set equal to 11 The resulting required sample size is 240 120 patients in each arm Sample size estimation is based on the intention-to-treat principle
The accrual time is 25 years and an additional follow-up of 2 years is planned after the last patient entry in the study and before the final analysis
An effective conditioning regimen is based on the association of oral Busulfan 4 mgkg daily in 4 doses each of 1 mgkg on each of 4 successive days total dose 16 mgkg followed by CY 60 mgkg intravenously on each of 2 successive days BuCy2 The antileukemic activity of this latter program was tested and confirmed in most large randomized clinical trials conducted in AML and Chronic Myeloid Leukemia CML patients in which the BU-CY regimen was associated with survival and relapse probabilities that compare favourably with the CY-Total Body Irradiation TBI regimen The BuCy2 program is considered a golden standard preparative regimen for allogeneic transplantation in AML patients
Nonetheless for many years the treatment related toxicities of all these full myeloablative conditioning regimens has substantially limited the overall applicability of the transplant procedure to young patients with a good performance status PS The observation that allogeneic stem cell transplants have a potentially curative graft-versus-leukemia GVL effect in addition to the antileukemic action of myeloablative conditioning regimens was a major stimulus for the development of reduced-intensity conditioning RIC regimens aimed primarily at securing engraftment to provide the GVL effect while minimizing regimen-related toxicity
The observation that allogeneic stem cell transplants have a potentially curative graft-versus-leukemia GVL effect in addition to the antileukemic action of myeloablative conditioning regimens was a major stimulus for the development of reduced-intensity conditioning RIC regimens aimed primarily at securing engraftment to provide the GVL effect while minimizing regimen-related toxicity As a consequence reduced-intensity conditioning RIC regimens might give possibility to extend access to allogeneic transplantation to patients who would not have previously been considered reasonable candidates because of their age and for the presence of comorbidities However after a lot of initial enthusiasm it has become clear that a more intensive conditioning is associated with a reduced risk for relapse after HSCT Therefore while it is clear that RIC transplants have opened the way to using allogeneic SCT in patients several years older than the upper age limit of 60 the superiority of the RIC approach cannot be assumed even in this subgroup of patients This is why more recently investigators are looking for conditioning programs that while better tolerated still might retain a strong ability of inducing a direct ablation of the leukemic hematopoiesis This has led to the new concept of reduced toxicity rather than reduced intensity conditioning programs One of such a program is based on the association of a myeloablative dose of intravenous Busulfan 08 mgkgd for 4 days with Fludarabine 30 mgm2d for 4 days which has been reported as highly effective in patients with AML In elderly patients with this disease this program might lead to an overall outcome at least as good as that following conventional myeloablative programs such as those based on Cyclophosphamide combined to the same dose of IV Busulfan or the TBI In fact when compared to these latter programs the Busulfan Fludarabine regimen was found associated with lower non relapse mortality although a higher relapse rate was still documented but not in all published experiences In all outcomes for standard transplant regimens have generally improved and these newer myeloablative regimens of Fludarabine with full-dose intravenous Busulfan achieve 1 year TRM below 10 So based on these considerations protocol GITMO-AMLR2 has been designed to compare intravenous Busulfan plus Fludarabine BuFlu versus Busulfan IV Bu Busilvex plus Cyclophosphamide BuCy2 as conditioning regimens prior to allogeneic Hematopoietic Stem Cell Transplantation alloHSCT in patients aged between 40 and 65 years with Acute Myeloid Leukemia AML in Complete Remission CR
So based on these considerations protocol GITMO-AMLR2 has been designed to compare intravenous Busulfan plus Fludarabine BuFlu versus Busulfan IV Bu Busilvex plus Cyclophosphamide BuCy2 as conditioning regimens prior to allogeneic Hematopoietic Stem Cell Transplantation alloHSCT in patients aged between 40 and 65 years with Acute Myeloid Leukemia AML in Complete Remission CR
The principal objective of this trial is the evaluation of one year transplant-related mortality TRM of AML patients undergoing allogeneic hematopoietic stem cell transplantation after a reduced toxicity conditioning regimen IVBuFlu as compared to the conventional IV BuCy2 program
To this purpose in the IV BuCy2 arm reference TRM was assumed to be 25 range 16-50 while in the IV BuFlu arm and an estimated 125 TRM is assumed range 0-30 The study is designed to demonstrate a relative risk reduction of 50 For the event-driven two-sided test an alpha-level probability of 005 type I error and a power of 80 type II error02 has been considered The ratio between the numbers of patients included in each arm is set equal to 11 The resulting required sample size is 240 120 patients in each arm Sample size estimation is based on the intention-to-treat principle
The accrual time is 25 years and an additional follow-up of 2 years is planned after the last patient entry in the study and before the final analysis
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None