Aplastic AnemiaPhase 1NCT01267643
Alefacept in Patients With Relapsed/Refractory Aplastic Anemia
A Phase 1 study testing Alefacept in people with Aplastic Anemia, run by The Cleveland Clinic at 1 site in United States.
Trial 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%. Read more about this study
- Who is it for?
- Ages 18 years and olderHealthy volunteers can take part
- Conditions the study is for
- Aplastic Anemia
- What is being tested?
- Alefacept
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 4 participants
- Where
- 1 siteUnited States
- Study dates
- May 2011to 16 Apr 2013
- Phase
- Phase 1
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- Healthy volunteers accepted
- Adult, Older adult
Who may be able to join
- Fulfilled criteria for diagnosis of either moderate (mAA) or severe aplastic anemia (sAA) at the time of initial diagnosis defined per protocol.
- Patient with a history sAA must have had an incomplete response at least 3 months following treatment with ATG/CsA, or they must have relapsed following an initial response to treatment.
- Patient must not be receiving any cyclosporine or any other T cell immunosuppressive agents within 4 weeks of study entry.
- Patients must have organ function as defined below:
- total bilirubin within normal institutional limits (NV: 0.0-1.5 mg/dL)
- AST(SGOT)/ALT(SGPT) <2.5 X institutional upper limit of normal AST (NV: 7-40 U/L); ALT (NV: Male 5-50 U/L; Female 0-45 U/L)
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- creatinine within normal institutional limits (NV: Age 18 0.4-1.3 mg/dL; 19-99 years old 0.7-1.4 mg/dL) OR
- creatinine clearance >60 mL/min/1.73 m2 for patients with creatinine levels above institutional normal.
- Peripheral blood counts at the time of enrollment must include at least one of the following: Hgb <9 g/dL or red blood cell (RBC) transfusion dependence, ANC <1000/µl, or platelet count of <60,000/µL.
- Women of child-bearing potential and men must agree to use adequate contraception defined per protocol.
- Ability to understand and the willingness to sign a written informed consent document.
Who cannot join
- Patients may not be receiving any other investigational agents (other than hematopoietic growth factors) within 4 weeks of study entry.
- History of allergic reactions attributed to compounds of similar chemical or biologic composition to Alefacept.
- Current diagnosis of acute myeloid leukemia (AML), myelodysplastic syndromes (MDS), Fanconi's anemia, Dyskeratosis Congenita (DC) or other hereditary forms of AA.
- Psychiatric, addictive or any other disorder that compromises ability to give a truly informed consent.
- Age <18 years.
- ECOG performance status >2 (Karnofsky <60%, see Appendix A).
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- Malignancy other than non-melanoma skin cancer within the last 2 years.
- Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection (defined as uncontrolled infection requiring IV antibiotics, invasive fungal infection and progressive CMV viremia), symptomatic congestive heart failure (NYH class III and IV), unstable angina pectoris, or cardiac arrhythmia.
- Pregnant or breastfeeding women.
- HIV-positive patients on combination antiretroviral therapy.
- Patients who have previously received systemic chemotherapy and/ or radiation therapy.
- Patients who previously underwent allogeneic hematopoietic stem cell transplant.
Trial locations and contacts
1 site in 1 country.
United States1 site
Cleveland Clinic Taussig Cancer Institute, Case Comprehensive Cancer Center
Cleveland, Ohio, 44195
About this study
Official title: A Phase 1/2 Study of Alefacept, a CD2 Receptor Antagonist in Patients With Relapsed/Refractory Aplastic Anemia
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 (LFA3/CD58) 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 refractory/relapsed cases of AA.
Read the detailed description
OBJECTIVES:
- 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.
- 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, CD3+/CD4+ T cell, CD3+/CD8+, CD57+ natural killer cell count and CD4/CD8 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.
- Conditions
- Aplastic Anemia
- Being tested
- Alefacept
- Keywords
- Alefacept, Amevive, Aplastic Anemia, Moderate to Severe Aplastic Anemia
- Medical subject headings
- Anemia, Aplastic
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
AlefaceptDrug
Also called Amevieve
Dose Escalation Schedule
Level -1 5 mg IV once weekly
Level 1 7.5 mg IV once weekly
Level 2 10 mg IV once weekly
Level 3 12.5 mg IV once weekly
| Study group | Role | What they receive |
|---|---|---|
| Alefacept | Experimental | Not described Receives: Drug: Alefacept |
What is being measured
The primary outcome is the main question the study is designed to answer.
To measure the number of dose limiting toxicities (DLTs) as a determination of the maximum tolerable dose (MTD).
The dosing cohorts includes (Cohort -1= 5 mg IV weekly, Cohort 1= 7.5 mg IV weekly, Cohort 2= 10 mg IV weekly, and Cohort 3= 12.5 mg IV weekly). The MTD will be defined as the dose level that has maxiumum effectiveness with minimal toxicity.
Measured: Every 12 weeks
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.
Measured: Every 12 weeks
Secondary outcomes (1)
To analyze bood samples to evaluate for predictive markers for response to Alefacept with relapsed/ refractory AA and evaluate its effect on the PNH clone.
Measured: Every 2 weeks for the first 4 weeks, then monthly after that
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted28 Dec 2010 (estimated)
- Study startMay 2011
- Primary completion16 Dec 2011
- Study completion16 Apr 2013
Why it stopped: Study drug not available at this time
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Aplastic AnemiaStudies of the same condition, open and under way.
- More trials run by The Cleveland ClinicThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 4 participants (actual)
Sponsor and investigators
- Lead sponsor
- The Cleveland Clinic
- Sponsor type
- University, hospital or other
- Collaborators
- Astellas Pharma US, Inc.
- Responsible party
- Sponsor
- Investigators
- Ramon V. Tiu, M.D., Principal investigator, Cleveland Clinic Taussig Cancer Center, Case Comprehensive Cancer Center
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01267643
- Sponsor's protocol ID
- CASE5Z10
- Other IDs
- CASE 5Z10
- Status last verified
- Jan 2018
- First submitted
- 20 Dec 2010
- Last updated
- 26 Jan 2018
- Results posted
- No
- Data monitoring committee
- Yes
Study at a glance
From the registry record, last updated by the sponsor on 26 Jan 2018. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Phase 1/2 Study of Alefacept, a CD2 Receptor Antagonist in Patients With Relapsed/Refractory Aplastic Anemia
- ClinicalTrials.gov ID
- NCT01267643
- Acronym / sponsor ID
- CASE5Z10
- Conditions
- Aplastic Anemia
- Keywords
- Alefacept, Amevive, Aplastic Anemia, Moderate to Severe Aplastic Anemia
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: Study drug not available at this time
- Enrolment
- 4 participants (actual)
- Lead sponsor
- The Cleveland ClinicUniversity, hospital or other
- Collaborators
- Astellas Pharma US, Inc.
- Study start
- May 2011
- Primary completion
- 16 Dec 2011 (actual)
- Study completion
- 16 Apr 2013 (actual)
- First posted
- 28 Dec 2010 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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 (LFA3/CD58) 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 refractory/relapsed cases of AA.
Detailed description
OBJECTIVES:
- 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.
- 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, CD3+/CD4+ T cell, CD3+/CD8+, CD57+ natural killer cell count and CD4/CD8 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 design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Alefacept | Experimental | Drug: Alefacept |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (11 listed)
- Fulfilled criteria for diagnosis of either moderate (mAA) or severe aplastic anemia (sAA) at the time of initial diagnosis defined per protocol.
- Patient with a history sAA must have had an incomplete response at least 3 months following treatment with ATG/CsA, or they must have relapsed following an initial response to treatment.
- Patient must not be receiving any cyclosporine or any other T cell immunosuppressive agents within 4 weeks of study entry.
- Patients must have organ function as defined below:
- Peripheral blood counts at the time of enrollment must include at least one of the following: Hgb <9 g/dL or red blood cell (RBC) transfusion dependence, ANC <1000/µl, or platelet count of <60,000/µL.
Key exclusion criteria (12 listed)
- Patients may not be receiving any other investigational agents (other than hematopoietic growth factors) within 4 weeks of study entry.
- History of allergic reactions attributed to compounds of similar chemical or biologic composition to Alefacept.
- Current diagnosis of acute myeloid leukemia (AML), myelodysplastic syndromes (MDS), Fanconi's anemia, Dyskeratosis Congenita (DC) or other hereditary forms of AA.
- Psychiatric, addictive or any other disorder that compromises ability to give a truly informed consent.
- Age <18 years.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| AlefaceptAlso: AmevieveDose Escalation Schedule Level -1 5 mg IV once weekly Level 1 7.5 mg IV once weekly Level 2 10 mg IV once weekly Level 3 12.5 mg IV once weekly | Drug | Alefacept |
Primary outcome
To measure the number of dose limiting toxicities (DLTs) as a determination of the maximum tolerable dose (MTD).
Time frame: Every 12 weeks
The dosing cohorts includes (Cohort -1= 5 mg IV weekly, Cohort 1= 7.5 mg IV weekly, Cohort 2= 10 mg IV weekly, and Cohort 3= 12.5 mg IV weekly). The MTD will be defined as the dose level that has maxiumum effectiveness with minimal toxicity.
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.
Time frame: Every 12 weeks
1 secondary outcome
To analyze bood samples to evaluate for predictive markers for response to Alefacept with relapsed/ refractory AA and evaluate its effect on the PNH clone.
Time frame: Every 2 weeks for the first 4 weeks, then monthly after that
Results and safety
The study was stopped early (reason given: Study drug not available at this time). Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 26 Jan 2018.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Ramon V. Tiu, M.D. principal investigator
Cleveland Clinic Taussig Cancer Center, Case Comprehensive Cancer Center
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing Alefacept in people with Aplastic Anemia, run by The Cleveland Clinic at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 11 inclusion and 12 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: stopped early, as of the sponsor's last update on 26 Jan 2018. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study was stopped early (reason given: Study drug not available at this time). Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
To measure the number of dose limiting toxicities (DLTs) as a determination of the maximum tolerable dose (MTD). (time frame: Every 12 weeks). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 26 Jan 2018.