Alefacept in Patients With Relapsed/Refractory Aplastic Anemia

NCT01267643 | Terminated Phase 1 DMC

• 2 other identifiers: CASE5Z10CASE 5Z10
• Study Type: interventional
• Target: 4
• Locations: 1 country
• Sites: 1

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.

Conditions

Aplastic Anemia

Keywords

Alefacept; Amevive; Aplastic Anemia; Moderate to Severe Aplastic Anemia

Outcome Measures

Primary Outcomes (2)

• 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.

  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.

  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.

  Every 2 weeks for the first 4 weeks, then monthly after that

Study Arms (1)

Alefacept

EXPERIMENTAL

Drug: Alefacept

Interventions

Alefacept DRUG

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

Also known as: Amevieve

Alefacept

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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)
• 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.

You may not qualify if:

• 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).
• 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.

Sponsors & Collaborators

• The Cleveland Clinic: lead
• Astellas Pharma US, Inc.: collaborator

Study Sites (1)

Cleveland Clinic Taussig Cancer Institute, Case Comprehensive Cancer Center

Cleveland, Ohio, 44195, United States

Location

MeSH Terms

Conditions

Anemia, Aplastic

Interventions

Alefacept

Condition Hierarchy (Ancestors)

Anemia; Hematologic Diseases; Hemic and Lymphatic Diseases; Bone Marrow Failure Disorders; Bone Marrow Diseases

Intervention Hierarchy (Ancestors)

CD58 Antigens; Membrane Glycoproteins; Glycoproteins; Glycoconjugates; Carbohydrates; Immunoglobulin G; Immunoglobulin Isotypes; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Membrane Proteins; Recombinant Fusion Proteins; Recombinant Proteins

Study Officials

• Ramon V. Tiu, M.D.

  Cleveland Clinic Taussig Cancer Center, Case Comprehensive Cancer Center

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 20, 2010
• First Posted: December 28, 2010
• Study Start: May 1, 2011
• Primary Completion: December 16, 2011
• Study Completion: April 16, 2013
• Last Updated: January 26, 2018

Record last verified: 2018-01

Locations

US (1)