Ignite Creation Date:
2024-05-05 @ 11:08 PM
Last Modification Date:
2024-10-26 @ 10:29 AM
Study NCT ID:
NCT01267643
Status:
TERMINATED
Last Update Posted:
2018-01-26
First Post:
2010-12-20
Brief Title:
Alefacept in Patients With RelapsedRefractory Aplastic Anemia
Sponsor:
The Cleveland Clinic
Organization:
The Cleveland Clinic
Study Overview
Official Title:
A Phase 12 Study of Alefacept a CD2 Receptor Antagonist in Patients With RelapsedRefractory Aplastic Anemia
Status:
TERMINATED
Status Verified Date:
2018-01
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Study drug not available at this time
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
Aplastic Anemia AA is an autoimmune hematologic stem cell disease mediated by activated T-lymphocytes that leads to pancytopenia The disease related morbidity and mortality if left untreated can approach 90 For over 30 years anti-thymocyte globulin ATG in combination with cyclosporine CsA remains the standard therapy However the treatment response with ATG is at best between 50-60 with a sizeable number of partial responses Treatment with ATG is also associated with significant toxicity and high relapse rate that can be as high as 45 Since the prognosis in refractory and relapsed AA remains poor there is a need for less toxic novel immunosuppressive agents that can improve response rates and remission duration in refractory and relapsed AA
Alefacept is a human recombinant dimeric fusion protein composed of the terminal portion of leukocyte functioning antigen-3 LFA3CD58 and the Fc portion of human IgG1 It prevents co-stimulatory signals between antigen presenting cells and memory T cells by competitive inhibition of CD2 in T cells induces selective apoptosis of CD4 and CD8 memory effector T cells by interaction between the Fc portion of IgG1 and the FcyIII in NK cells and possibly direct ligation of CD2 molecules on T cells that subsequently result in the alteration in T cell agonist signaling It has been used successfully in the treatment of other T cell mediated disorders particularly psoriasis and steroid refractory graft versus host disease GVHD with minimal side effects In a case of liver transplant associated AA similar to transfusion associated AA which is fatal in most patients Alefacept induced remission after patient did not respond to ATG and other immunosuppressants The investigators hypothesize that the LFA3-CD2 co-stimulatory pathway play an important role in the immune pathogenesis of AA and treatment with Alefacept can help treat refractoryrelapsed cases of AA
Alefacept is a human recombinant dimeric fusion protein composed of the terminal portion of leukocyte functioning antigen-3 LFA3CD58 and the Fc portion of human IgG1 It prevents co-stimulatory signals between antigen presenting cells and memory T cells by competitive inhibition of CD2 in T cells induces selective apoptosis of CD4 and CD8 memory effector T cells by interaction between the Fc portion of IgG1 and the FcyIII in NK cells and possibly direct ligation of CD2 molecules on T cells that subsequently result in the alteration in T cell agonist signaling It has been used successfully in the treatment of other T cell mediated disorders particularly psoriasis and steroid refractory graft versus host disease GVHD with minimal side effects In a case of liver transplant associated AA similar to transfusion associated AA which is fatal in most patients Alefacept induced remission after patient did not respond to ATG and other immunosuppressants The investigators hypothesize that the LFA3-CD2 co-stimulatory pathway play an important role in the immune pathogenesis of AA and treatment with Alefacept can help treat refractoryrelapsed cases of AA
Detailed Description:
OBJECTIVES
1 Primary Objective
To define the safety tolerability dose-limiting toxicities DLT of alefacept in relapsed refractory aplastic anemia AA
To evaluate the efficacy of alefacept in refractory relapsed AA by determining overall response rates ORR which includes complete remission CR and partial remission PR rates
2 Secondary Objective
To evaluate for predictive markers for response to Alefacept with relapsed refractory AA and evaluate its effect on the PNH clone The effects of alefacept in major populations of lymphocytes will be evaluated The absolute numbers of various T cell populations including CD3 T cell CD3CD4 T cell CD3CD8 CD57 natural killer cell count and CD4CD8 ratio will be measured as part of an immunodeficiency panel by flow cytometry The functional properties of T cells will be evaluated by measuring markers of T cell activation and cytokine production The saturation of CD2 receptors with alefacept will be determined Occupied CD2 will not be detectable by competing antibody in-vitro The expression of CD2 within lymphocytes will be measured prior to the initiation of therapy and every 2 weeks prior to and 30 minutes after the administration of alefacept The presence of a Paroxysmal Nocturnal Hemoglobinuria PNH clone in patients with AA has been shown to correlate with increased response to immunosuppression25
OUTLINE This is an open-label single center study Patients will receive intravenous Alefacept once weekly for a total of 12 weeks in the absence of disease progression or unacceptable toxicity After completion of the 12 week treatment patients will go through a 12 week observation period After completion of the study patients will be followed periodically The dose defined in the Phase 1 study will be used for the subsequent Phase 2 study Four bone marrow biopsies will be taken at screening week 13 week 24 and the end of study
1 Primary Objective
To define the safety tolerability dose-limiting toxicities DLT of alefacept in relapsed refractory aplastic anemia AA
To evaluate the efficacy of alefacept in refractory relapsed AA by determining overall response rates ORR which includes complete remission CR and partial remission PR rates
2 Secondary Objective
To evaluate for predictive markers for response to Alefacept with relapsed refractory AA and evaluate its effect on the PNH clone The effects of alefacept in major populations of lymphocytes will be evaluated The absolute numbers of various T cell populations including CD3 T cell CD3CD4 T cell CD3CD8 CD57 natural killer cell count and CD4CD8 ratio will be measured as part of an immunodeficiency panel by flow cytometry The functional properties of T cells will be evaluated by measuring markers of T cell activation and cytokine production The saturation of CD2 receptors with alefacept will be determined Occupied CD2 will not be detectable by competing antibody in-vitro The expression of CD2 within lymphocytes will be measured prior to the initiation of therapy and every 2 weeks prior to and 30 minutes after the administration of alefacept The presence of a Paroxysmal Nocturnal Hemoglobinuria PNH clone in patients with AA has been shown to correlate with increased response to immunosuppression25
OUTLINE This is an open-label single center study Patients will receive intravenous Alefacept once weekly for a total of 12 weeks in the absence of disease progression or unacceptable toxicity After completion of the 12 week treatment patients will go through a 12 week observation period After completion of the study patients will be followed periodically The dose defined in the Phase 1 study will be used for the subsequent Phase 2 study Four bone marrow biopsies will be taken at screening week 13 week 24 and the end of study
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 |
|---|---|---|---|
| CASE 5Z10 | OTHER | Case Comprehensive Cancer Center | None |