Anti-thymocyte Globulin and Cyclosporine as First-Line Therapy in Treating Patients With Severe Aplastic Anemia

• Sponsor: The Cleveland Clinic (Other)
• Overall Status: Completed
• CT.gov ID: NCT01231841
• Collaborator: (none)
• Enrollment: 20
• Location: 1
• Arm: 1
• Duration (Months): 69
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

RATIONALE: Immunosuppressive therapies, such as anti-thymocyte globulin and cyclosporine, may improve bone marrow function and increase blood cell counts. PURPOSE: This phase II trial is studying how well giving anti-thymocyte globulin together with cyclosporine as first-line therapy works in treating patients with severe aplastic anemia.

Condition or Disease	Intervention/Treatment	Phase
Aplastic Anemia	Drug: cyclosporine; Biological: anti-thymocyte globulin	Phase 2

Detailed Description

PRIMARY OBJECTIVES: To determine the response rate of r-ATG and CsA in the first line setting. SECONDARY OBJECTIVES: To determine the level of IS as assessed by Immuknow assay in responders and compare it to non-responders. OUTLINE:Patients receive anti-thymocyte globulin IV over 4-24 hours daily on days 1-5. Beginning on day 6, patients receive oral cyclosporine twice daily for 6 months followed by a taper. Treatment continues in the absence of disease progression or unacceptable toxicity.

Study Design

• Study Type: Interventional
• Actual Enrollment: 20 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Protocol for Prospective Phase II Study of Rabbit Antithymocyte Globulin (r-ATG/Thymoglobulin) and Cyclosporine (CsA) as a First Line Immunosuppressive (IS) Therapy for Severe Aplastic Anemia (sAA)
• Study Start Date: Mar 1, 2005
• Actual Primary Completion Date: Dec 1, 2010
• Actual Study Completion Date: Dec 1, 2010

Arms and Interventions

Arm	Intervention/Treatment
Experimental: rATG + Cyclosporine Patients receive anti-thymocyte globulin IV daily over 4-24 hours on days 1-5. Beginning on day 6, patients receive oral cyclosporine twice daily for 6 months followed by a taper. Treatment continues in the absence of disease progression or unacceptable toxicity	Drug: cyclosporine; Given orally; Other Names: 27-400 ciclosporin cyclosporin cyclosporin A CYSP Sandimmune ; Biological: anti-thymocyte globulin; Given IV; Other Names: ATG ATGAM lymphocyte immune globulin Thymoglobulin

Outcome Measures

Primary Outcome Measures

1. Patients Treated With Rabbit Antithymocyte Globulin (r-ATG/Thymoglobulin) and Cyclosporine (CsA) Achieving at Least a Partial Remission (PR) at 6 Months [At 6 months]

   Patients will be classified as responders if they have transfusion independence and meet two of the following three criteria: ANC greater than 500/mm3; platelet count greater than 20,000/mm3; and reticulocyte count greater than 40,000/mm3. Transfusion independence is defined as no need for transfusions for one month prior to response assessment.

Secondary Outcome Measures

1. Comparison of the Level of IS as Assessed by Immuknow Assay in Responders and Non-responders [Every 2 weeks for 3 months beginning on day 1 of therapy and then monthly (for a total of 6 months)]

2. Reduction of VB Repertoire Associated With r-ATG/CsA Combination [Every 4 weeks]

   We will perform molecular analysis of the TCR repertoire to identify "marker" immunodominant clone specimens using VB typing.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 12 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• All patients with sAA as defined by Camitta who are candidates for IS therapy; these criteria include bone marrow cellularity < 25% or 25-50% with < 30% of hematopoietic cells; it should also have two of the following three parameters: peripheral blood neutrophils < 0.5 x 10^{9/L, platelets < 20 x 10}9/L and reticulocytes < 60 x 10^9/L in anemic patients

• If cytogenetic testing has been done, it should show normal karyotype or be not informative

• Patients should be either unwilling or otherwise ineligible (age, comorbidities, lack of donor) for bone marrow transplantation as a therapeutic modality

• Not previously treated with ATG for sAA

• Patients must have ECOG performance status of 0, 1, or 2

• Vitamin B12 and folic acid deficiency must be ruled out by measurement of serum levels

• Patients must have had a bone marrow biopsy examination in the three months prior to enrolling in the study

• Must be able to provide informed consent

• Systemic and other hematologic causes of pancytopenia, based on clinical presentation, must have been ruled out

Exclusion Criteria:

• Patients with clinically evident congestive heart failure, serious cardiac arrhythmias; symptoms of coronary artery disease must be cleared by cardiology prior to therapy

• Patients who have had chemotherapy, radiotherapy, or immunotherapy or other investigational drug use within 3 weeks prior to study entry

• Pregnant women

• All females of childbearing potential must have a blood test or urine study within two weeks prior to induction registration to rule out pregnancy

• Women of childbearing potential are strongly advised to use an accepted and effective method of contraception

• Patients who have medical, psychological, or social conditions that may interfere with the patient's participation in the study or evaluation of the study results

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Cleveland Clinic Taussig Cancer Institute, Case Comprehensive Cancer Center	Cleveland	Ohio	United States	44195

Sponsors and Collaborators

• The Cleveland Clinic

Investigators

• Principal Investigator: Jaroslaw Maciejewski, Cleveland Clinic Taussig Cancer Institute, Case Comprehensive Cancer Center

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: The Cleveland Clinic
• ClinicalTrials.gov Identifier: NCT01231841
• Other Study ID Numbers: CCF7922; NCI-2010-01365
• First Posted: Nov 1, 2010
• Last Update Posted: Feb 22, 2018
• Last Verified: Jan 1, 2018

• Additional relevant MeSH terms: Anemia; Anemia, Aplastic; Cyclosporine; Cyclosporins; Thymoglobulin; Antilymphocyte Serum; Immunoglobulins

Study Results

Participant Flow

Recruitment Details	Patients with severe aplastic anemia were recruited over a period of four years (2005-2009) in the hematology clinic at the Cleveland Clinic, a hospital in Cleveland, Ohio.

Arm/Group Title	Rabbit Antithymocyte Globulin (r-ATG/Thymoglobulin)
Arm/Group Description	Patients received rabbit anti-thymocyte globulin IV daily over 4-24 hours on days 1-5 (3.5 mg/kg/day). Beginning on day 6, patients received oral cyclosporine twice daily (5 mg/kg/day) for a period of 6 months and then tapered.
Period Title: Overall Study
STARTED	20
COMPLETED	20
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	rATG
Arm/Group Description	Patients receive anti-thymocyte globulin IV daily over 4-24 hours on days 1-5. Beginning on day 6, patients receive oral cyclosporine twice daily for 6 months followed by a taper. Treatment continues in the absence of disease progression or unacceptable toxicity
Overall Participants	20
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	14 70%
>=65 years	6 30%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	51.95 (18.43)
Sex: Female, Male (Count of Participants)
Female	7 35%
Male	13 65%
Region of Enrollment (participants) [Number]
United States	20 100%

Outcome Measures

1. Primary Outcome

Title	Patients Treated With Rabbit Antithymocyte Globulin (r-ATG/Thymoglobulin) and Cyclosporine (CsA) Achieving at Least a Partial Remission (PR) at 6 Months
Description	Patients will be classified as responders if they have transfusion independence and meet two of the following three criteria: ANC greater than 500/mm3; platelet count greater than 20,000/mm3; and reticulocyte count greater than 40,000/mm3. Transfusion independence is defined as no need for transfusions for one month prior to response assessment.
Time Frame	At 6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Rabbit Antithymocyte Globulin (r-ATG/Thymoglobulin)
Arm/Group Description	Patients received rabbit anti-thymocyte globulin IV daily over 4-24 hours on days 1-5 (3.5 mg/kg/day). Beginning on day 6, patients received oral cyclosporine twice daily (5 mg/kg/day) for a period of 6 months and then tapered.
Measure Participants	20
Number [participants]	9 45%

2. Secondary Outcome

Title	Comparison of the Level of IS as Assessed by Immuknow Assay in Responders and Non-responders
Time Frame	Every 2 weeks for 3 months beginning on day 1 of therapy and then monthly (for a total of 6 months)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

3. Secondary Outcome

Title	Reduction of VB Repertoire Associated With r-ATG/CsA Combination
Description	We will perform molecular analysis of the TCR repertoire to identify "marker" immunodominant clone specimens using VB typing.
Time Frame	Every 4 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

Adverse Events

Adverse Event Reporting Description	The endpoints of this study evaluated response only. As such, data on non-serious adverse events were not collected or reported for any patients on this trial. Data regarding serious adverse events were collected and reported according to FDA and IRB policies and regulations.
Arm/Group Title	rATG
Arm/Group Description	Patients receive anti-thymocyte globulin IV daily over 4-24 hours on days 1-5. Beginning on day 6, patients receive oral cyclosporine twice daily for 6 months followed by a taper. Treatment continues in the absence of disease progression or unacceptable toxicity
All Cause Mortality
	rATG
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	rATG
	Affected / at Risk (%)	# Events
Total	11/20 (55%)
Blood and lymphatic system disorders
febrile neutropenia	3/20 (15%)	4
Gastrointestinal disorders
gastrointestinal bleed	1/20 (5%)	1
General disorders
headache	1/20 (5%)	1
Immune system disorders
serum sickness	2/20 (10%)	2
Infections and infestations
colitis	2/20 (10%)	2
pneumonia	1/20 (5%)	2
sepsis	4/20 (20%)	4
urinary tract infection	1/20 (5%)	2
Musculoskeletal and connective tissue disorders
chest pain	2/20 (10%)	2
compression fractures	1/20 (5%)	1
Other (Not Including Serious) Adverse Events
	rATG
	Affected / at Risk (%)	# Events
Total	0/0 (NaN)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.