Alefacept in Patients With Relapsed/Refractory Aplastic Anemia

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Brief Title

Alefacept in Patients With Relapsed/Refractory Aplastic Anemia

Official Title

A Phase 1/2 Study of Alefacept, a CD2 Receptor Antagonist in Patients With Relapsed/Refractory Aplastic Anemia

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 (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:

        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 Phase

Phase 1

Study Type

Interventional


Primary Outcome

To measure the number of dose limiting toxicities (DLTs) as a determination of the maximum tolerable dose (MTD).

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.

Condition

Aplastic Anemia

Intervention

Alefacept

Study Arms / Comparison Groups

 Alefacept
Description:  

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

4

Start Date

May 2011

Completion Date

April 16, 2013

Primary Completion Date

December 16, 2011

Eligibility Criteria

        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.
      

Gender

All

Ages

18 Years - N/A

Accepts Healthy Volunteers

Accepts Healthy Volunteers

Contacts

Ramon V. Tiu, M.D., , 

Location Countries

United States

Location Countries

United States

Administrative Informations


NCT ID

NCT01267643

Organization ID

CASE5Z10

Secondary IDs

CASE 5Z10

Responsible Party

Sponsor

Study Sponsor

The Cleveland Clinic

Collaborators

 Astellas Pharma US, Inc.

Study Sponsor

Ramon V. Tiu, M.D., Principal Investigator, Cleveland Clinic Taussig Cancer Center, Case Comprehensive Cancer Center


Verification Date

January 2018