Ignite Creation Date:
2024-05-05 @ 4:51 PM
Last Modification Date:
2024-10-26 @ 9:24 AM
Study NCT ID:
NCT00326417
Status:
COMPLETED
Last Update Posted:
2021-10-28
First Post:
2006-05-12
Brief Title:
Fludarabine-based Conditioning for Severe Aplastic Anemia BMT CTN 0301
Sponsor:
Medical College of Wisconsin
Organization:
Medical College of Wisconsin
Study Overview
Official Title:
Fludarabine-based Conditioning for Allogeneic Marrow Transplantation From HLA-compatible Unrelated Donors in Severe Aplastic Anemia BMT CTN 0301
Status:
COMPLETED
Status Verified Date:
2021-10
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:
None
Brief Summary:
The purpose of the current study is to continue to optimize conditioning regimens in high-risk patients with severe aplastic anemia transplanted with marrow from HLA-compatible unrelated donors Specifically the study will determine whether the addition of fludarabine to the conditioning regimen previously described by Deeg et al will permit a reduction in the CY dose to a point where sustained hematopoietic engraftment and survival are maintained or improved while the frequency of major regimen-related toxicity RRT and early deaths is reduced
Detailed Description:
BACKGROUND
Aplastic anemia AA remains a life-threatening illness Treatment options include supportive care transfusions growth factors etc immunosuppression therapy and stem cell transplantation Only the latter two have favorably impacted the natural history of the disease The prognosis of AA patients particularly severe aplastic anemia SAA as defined by Camitta et al who fail to respond to immunosuppressive therapy IS or who relapse after an initial response to IS is poor Although many of these patients can be supported in the short term with growth factors transfusions and possibly rechallenged successfully with IS the cumulative morbidity and mortality from infection hemorrhage or transfusion-related complications is substantial
While allogeneic bone marrow transplantation is potentially curative in AA no more than 25 of patients have a human leukocyte antigen HLA-identical sibling donor Cyclophosphamide CY-antithymocyte globulin ATG has been recommended as the preparative regimen of choice in sibling donor transplants Results of bone marrow transplantation from alternative donors such as matched unrelated donors and mismatched related donors in AA patients who have failed IS have largely been unsatisfactory The cyclophosphamide-ATG conditioning regimen has proved inadequate in ensuring engraftment in allogeneic transplants from matched unrelated donors for AA This was the major reason why total body radiation TBI has been added to the conditioning regimen
Graft failure is a very serious and frequently life-threatening or fatal event following matched unrelated donor MUD allografts in aplastic anemia It is an immunologically mediated event Risk factors for graft failure include the use of HLA nonidentical or unrelated donors a poor marrow nucleated cell dose as well as prolonged transfusional support prior to BMT which increases the probability of patient sensitization to multiple antigens While some patients may achieve autologous hematopoietic recovery prolonged pancytopenia is common and infection-related morbidity and mortality are very substantial Reconditioning for a second allograft from the same or a different donor is frequently not successful While the addition of TBI and intensive pre-transplant conditioning has led to a sizable improvement in engraftment rates this has come with a price particularly in adult patients Transplant-related toxicity has been a major and frequent problem Radiation-induced pulmonary toxicity in particular has been common usually in the form of diffuse alveolar damage or diffuse interstitial pneumonitis In addition Graft Versus Host Disease GVHD-related morbidity and mortality in these patients have also been substantial
DESIGN NARRATIVE
The study is a prospective Phase III dose optimization study All patients are given a fixed dose of ATG either thymoglobulin 3 mgkg IV daily x 3 or ATGAM 30 mgkg IV daily x 3 on Days -4 to -2 Fludarabine 30 mgm2 IV daily x 4 on Days - 5 to -2 and TBI 200 cGy centigray from a linear accelerator at less than 20 cGymin on Day -1 The starting CY dose will be 150 mgkg 50 mgkg intravenously daily Days -4 to -2 and will be de-escalated depending on engraftment and toxicity The Phase I portion of the trial maximum of 24-27 patients tests each of four dose levels of CY for adequate safety and graft retention The Phase II portion of the trial refines the dose selection and allocates an additional 70 patients to the optimal dose at which two-year post-transplant survival will be assessed The combined enrollment in Phase I and II will total 94 patients
The study is a prospective single-arm Phase III dose-selection and evaluation study The study will seek the optimal dose level of CY based on assessments of graft failure toxicity and early death during 100 days of follow-up post-transplant A brief synopsis is given below
Phase I - Test Each Dose for Adequate Safety and Graft Retention
1 Proceed from the highest dose 150 mgkg CY to the lowest dose 0 mgkg CY treating a minimum of six patients at each dose
2 Evaluate the 100-Day outcomes for toxicity death and graft failure on each patient enrolled at the current dose or until stopping criteria are met
3 If there are three or more graft failures at the current dose the current dose and all lower doses are closed to further enrollment
4 If there are five or more severe regimen-related toxicities andor early deaths at the current dose the current dose is closed to further enrollment and the next lower dose is tested
5 Dose de-escalation ceases once all four doses are tested or closed to further enrollment
Phase II - Refine Dose Selection and Allocate Patients to the Optimal Dose
1 Treat each newly enrolled patient at the most desirable of the dose levels remaining open to enrollment This can involve de-escalation escalation or no change in dose
2 As each patient completes the observation period evaluate the 100-Day outcomes for graft failure toxicity andor early death for this patient or until stopping criteria are met
3 If there are excess according to the criteria in Table 58 graft failures that patients dose and all lower doses are closed to further enrollment
4 If there are excess according to the criteria in Table 58 toxicities andor early deaths that patients dose is closed to further enrollment
5 Re-evaluate the desirability of the current dose level based on the 100-Day outcomes for toxicity andor early death and graft failure
6 Repeat steps 1-5 until 54 patients are enrolled in Phase II or all dose levels are closed to further enrollment
Dosage Levels for CY
3 Days Day -4 -3 -2 Dose of 50 mgkgday total dose of 150 mgkg dose level 3
2 Days Day -3 -2 Dose of 50 mgkgday total dose of 100 mgkg dose level 2
1 Day Day -2 Dose of 50 mgkgday total dose of 50 mgkg dose level 1
0 Days None No dose no total dose dose level 0
There may be wait periods between enrollment of successive patients andor cohorts for endpoint assessment Under these circumstances the final decision about waiting versus treating the patient off study will be made at the local transplant center
Aplastic anemia AA remains a life-threatening illness Treatment options include supportive care transfusions growth factors etc immunosuppression therapy and stem cell transplantation Only the latter two have favorably impacted the natural history of the disease The prognosis of AA patients particularly severe aplastic anemia SAA as defined by Camitta et al who fail to respond to immunosuppressive therapy IS or who relapse after an initial response to IS is poor Although many of these patients can be supported in the short term with growth factors transfusions and possibly rechallenged successfully with IS the cumulative morbidity and mortality from infection hemorrhage or transfusion-related complications is substantial
While allogeneic bone marrow transplantation is potentially curative in AA no more than 25 of patients have a human leukocyte antigen HLA-identical sibling donor Cyclophosphamide CY-antithymocyte globulin ATG has been recommended as the preparative regimen of choice in sibling donor transplants Results of bone marrow transplantation from alternative donors such as matched unrelated donors and mismatched related donors in AA patients who have failed IS have largely been unsatisfactory The cyclophosphamide-ATG conditioning regimen has proved inadequate in ensuring engraftment in allogeneic transplants from matched unrelated donors for AA This was the major reason why total body radiation TBI has been added to the conditioning regimen
Graft failure is a very serious and frequently life-threatening or fatal event following matched unrelated donor MUD allografts in aplastic anemia It is an immunologically mediated event Risk factors for graft failure include the use of HLA nonidentical or unrelated donors a poor marrow nucleated cell dose as well as prolonged transfusional support prior to BMT which increases the probability of patient sensitization to multiple antigens While some patients may achieve autologous hematopoietic recovery prolonged pancytopenia is common and infection-related morbidity and mortality are very substantial Reconditioning for a second allograft from the same or a different donor is frequently not successful While the addition of TBI and intensive pre-transplant conditioning has led to a sizable improvement in engraftment rates this has come with a price particularly in adult patients Transplant-related toxicity has been a major and frequent problem Radiation-induced pulmonary toxicity in particular has been common usually in the form of diffuse alveolar damage or diffuse interstitial pneumonitis In addition Graft Versus Host Disease GVHD-related morbidity and mortality in these patients have also been substantial
DESIGN NARRATIVE
The study is a prospective Phase III dose optimization study All patients are given a fixed dose of ATG either thymoglobulin 3 mgkg IV daily x 3 or ATGAM 30 mgkg IV daily x 3 on Days -4 to -2 Fludarabine 30 mgm2 IV daily x 4 on Days - 5 to -2 and TBI 200 cGy centigray from a linear accelerator at less than 20 cGymin on Day -1 The starting CY dose will be 150 mgkg 50 mgkg intravenously daily Days -4 to -2 and will be de-escalated depending on engraftment and toxicity The Phase I portion of the trial maximum of 24-27 patients tests each of four dose levels of CY for adequate safety and graft retention The Phase II portion of the trial refines the dose selection and allocates an additional 70 patients to the optimal dose at which two-year post-transplant survival will be assessed The combined enrollment in Phase I and II will total 94 patients
The study is a prospective single-arm Phase III dose-selection and evaluation study The study will seek the optimal dose level of CY based on assessments of graft failure toxicity and early death during 100 days of follow-up post-transplant A brief synopsis is given below
Phase I - Test Each Dose for Adequate Safety and Graft Retention
1 Proceed from the highest dose 150 mgkg CY to the lowest dose 0 mgkg CY treating a minimum of six patients at each dose
2 Evaluate the 100-Day outcomes for toxicity death and graft failure on each patient enrolled at the current dose or until stopping criteria are met
3 If there are three or more graft failures at the current dose the current dose and all lower doses are closed to further enrollment
4 If there are five or more severe regimen-related toxicities andor early deaths at the current dose the current dose is closed to further enrollment and the next lower dose is tested
5 Dose de-escalation ceases once all four doses are tested or closed to further enrollment
Phase II - Refine Dose Selection and Allocate Patients to the Optimal Dose
1 Treat each newly enrolled patient at the most desirable of the dose levels remaining open to enrollment This can involve de-escalation escalation or no change in dose
2 As each patient completes the observation period evaluate the 100-Day outcomes for graft failure toxicity andor early death for this patient or until stopping criteria are met
3 If there are excess according to the criteria in Table 58 graft failures that patients dose and all lower doses are closed to further enrollment
4 If there are excess according to the criteria in Table 58 toxicities andor early deaths that patients dose is closed to further enrollment
5 Re-evaluate the desirability of the current dose level based on the 100-Day outcomes for toxicity andor early death and graft failure
6 Repeat steps 1-5 until 54 patients are enrolled in Phase II or all dose levels are closed to further enrollment
Dosage Levels for CY
3 Days Day -4 -3 -2 Dose of 50 mgkgday total dose of 150 mgkg dose level 3
2 Days Day -3 -2 Dose of 50 mgkgday total dose of 100 mgkg dose level 2
1 Day Day -2 Dose of 50 mgkgday total dose of 50 mgkg dose level 1
0 Days None No dose no total dose dose level 0
There may be wait periods between enrollment of successive patients andor cohorts for endpoint assessment Under these circumstances the final decision about waiting versus treating the patient off study will be made at the local transplant center
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
Secondary IDs
| Secondary ID | Type | Domain | Link |
|---|---|---|---|
| 5U24CA076518 | NIH | None | httpsreporternihgovquickSearch5U24CA076518 |
| U01HL069294 | NIH | None | None |
| 5U01HL069294-05 | NIH | None | None |