Alefacept in Patients With Relapsed/Refractory Aplastic Anemia

January 24, 2018 updated by: The Cleveland Clinic

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.

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Terminated

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

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, 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 Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Actual)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
4

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Ohio
      • Cleveland, Ohio, United States, 44195
        • Cleveland Clinic Taussig Cancer institute, Case Comprehensive Cancer Center

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

14 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  1. Fulfilled criteria for diagnosis of either moderate (mAA) or severe aplastic anemia (sAA) at the time of initial diagnosis defined per protocol.
  2. 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.
  3. Patient must not be receiving any cyclosporine or any other T cell immunosuppressive agents within 4 weeks of study entry.

  4. 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)
    • 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.
  5. 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.
  6. Women of child-bearing potential and men must agree to use adequate contraception defined per protocol.
  7. Ability to understand and the willingness to sign a written informed consent document.

Exclusion Criteria:

  1. Patients may not be receiving any other investigational agents (other than hematopoietic growth factors) within 4 weeks of study entry.
  2. History of allergic reactions attributed to compounds of similar chemical or biologic composition to Alefacept.
  3. Current diagnosis of acute myeloid leukemia (AML), myelodysplastic syndromes (MDS), Fanconi's anemia, Dyskeratosis Congenita (DC) or other hereditary forms of AA.
  4. Psychiatric, addictive or any other disorder that compromises ability to give a truly informed consent.
  5. Age <18 years.
  6. ECOG performance status >2 (Karnofsky <60%, see Appendix A).
  7. Malignancy other than non-melanoma skin cancer within the last 2 years.
  8. 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.
  9. Pregnant or breastfeeding women.
  10. HIV-positive patients on combination antiretroviral therapy.
  11. Patients who have previously received systemic chemotherapy and/ or radiation therapy.
  12. Patients who previously underwent allogeneic hematopoietic stem cell transplant.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
Experimental: Alefacept
Drug: Alefacept

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

Other Names:
  • Amevieve

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
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.
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.
Time Frame: Every 12 weeks
Every 12 weeks

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Time Frame
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
Every 2 weeks for the first 4 weeks, then monthly after that

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
The Cleveland Clinic

Collaborators

Collaborators

An organization other than the sponsor that provides support for a clinical study. This support may include activities related to funding, design, implementation, data analysis, or reporting.
Astellas Pharma US, Inc.

Investigators

Investigators

A researcher involved in a clinical study. Related terms include site principal investigator, site sub-investigator, study chair, study director, and study principal investigator.
  • Principal Investigator: Ramon V. Tiu, M.D., Cleveland Clinic Taussig Cancer Center, Case Comprehensive Cancer Center

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
May 1, 2011

Primary Completion (Actual)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
December 16, 2011

Study Completion (Actual)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
April 16, 2013

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
December 20, 2010

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
December 27, 2010

First Posted (Estimate)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
December 28, 2010

Study Record Updates

Last Update Posted (Actual)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
January 26, 2018

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
January 24, 2018

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
January 1, 2018

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • CASE5Z10
  • CASE 5Z10 (Other Identifier: Case Comprehensive Cancer Center)

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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