Alemtuzumab to Treat Severe Aplastic Anemia

• ClinicalTrials.gov Identifier: NCT00195624
• Recruitment Status: Active, not recruiting
• First Posted: September 19, 2005
• Results First Posted: August 2, 2019
• Last Update Posted: August 2, 2019
• Sponsor: National Heart, Lung, and Blood Institute (NHLBI)
• Information provided by (Responsible Party): National Institutes of Health Clinical Center (CC) ( National Heart, Lung, and Blood Institute (NHLBI) )

Tracking Information

• First Submitted Date: September 16, 2005
• First Posted Date: September 19, 2005
• Results First Submitted Date: July 11, 2019
• Results First Posted Date: August 2, 2019
• Last Update Posted Date: August 2, 2019
• Study Start Date: September 15, 2005
• Actual Primary Completion Date: April 14, 2014 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: July 11, 2019)

Hematological Response Rate at 6 Months [ Time Frame: 6 months ]

Hematological response is defined as no longer satisfying blood count criteria for Severe Aplastic Anemia. Patients were classified as responders if they met two of the following three criteria: ANC greater than 500/ mm'; platelet count greater than 20,000/mm3; and reticulocyte count greater than 40,000/mm3 (60,000/mm3 after January 1993).

• Original Primary Outcome Measures: Not Provided
• Change History: Complete list of historical versions of study NCT00195624 on ClinicalTrials.gov Archive Site
• Current Secondary Outcome Measures: Not Provided
• Original Secondary Outcome Measures: Not Provided
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Alemtuzumab to Treat Severe Aplastic Anemia
• Official Title: A Pilot Study of Alemtuzumab (Campath) in Patients With Relapsed or Refractory Severe Aplastic Anemia

Brief Summary

This study will evaluate the safety and usefulness of a new immunosuppressive drug, alemtuzumab (Campath ), in patients with severe aplastic anemia (SAA). SAA is a rare and serious blood disorder in which the bone marrow stops making red blood cells, white blood cells and platelets. Alemtuzumab is a monoclonal antibody that attaches to and kills white blood cells called lymphocytes. In certain types of aplastic anemia, lymphocytes are responsible for the destruction of stem cells in the bone marrow, leading to a decrease in blood counts. Because alemtuzumab destroys lymphocytes, it may be effective in treating aplastic anemia. Alemtuzumab is currently approved to treat chronic lymphocytic leukemia and is also helpful in other conditions that require immunosuppression, such as rheumatoid arthritis and immune cytopenias.

Patients 2 years of age and older with severe aplastic anemia whose disease does not respond to immunosuppressive therapy or has recurred following immunosuppressive therapy may be eligible for this study. Participants undergo the following tests and procedures:

• Pretreatment evaluation: Patients have a medical history, physical examination, blood tests, electrocardiogram (EKG), echocardiogram, 24-hour Holter monitor (continuous 24-hour monitoring of electrical activity of the heart), bone marrow biopsy (withdrawal through a needle of a small sample of bone marrow for analysis).
• Placement of a central line, if needed: An intravenous line (tube) is placed into a major vein in the patient's chest. It can stay in the body for the entire treatment period and be used to give chemotherapy or other medications, including antibiotics and blood transfusions, if needed, and to withdraw blood samples.
• Alemtuzumab therapy: Patients are admitted to the NIH Clinical Center for the first few injections for close monitoring of side effects. After receiving an initial small test dose, patients begin the first of ten daily injections under the skin, each lasting about 2 hours. Once patients tolerate the infusions with minimal or no side effects, they may be given the remaining infusions on an outpatient basis. Patients who relapse after their initial response to alemtuzumab are given cyclosporine to see if this drug will boost their immune response.
• Patients receive transfusions, growth factors, and antibiotic therapy, as needed.
• Infection therapy: Patients are given aerosolized pentamidine to protect against lung infections and valacyclovir to protect against herpes infections.
• A blood test is done and vital signs are measured every day while patients receive alemtuzumab.
• Patients have an echocardiogram and 24-hour Holter monitor after the last dose of alemtuzumab.
• Blood tests are done weekly for the first 3 months after alemtuzumab administration, then every other week until 6 months.

Patients return to the NIH for follow-up visits 1 month, 3 months, 6 months, and yearly for 5 years after the last dose of alemtuzumab for the following tests and evaluations:

• Blood test
• Repeat echocardiogram at 3-month visit
• Repeat bone marrow biopsy 6 months and 12 months after alemtuzumab, then as clinically indicated for 5 years.

Detailed Description

Hematopoietic stem cell destruction in many human bone marrow failure syndromes is now recognized to be secondary to immune mechanisms. Severe aplastic anemia (SAA) is a life-threatening blood disease which can be effectively treated with immunosuppressive drug regimens. However, a significant minority of patients with SAA fail to respond to a single course of horse antithymocyte globulin and cyclosporine, and other patients experience relapse, especially on discontinuation of therapy. Pancytopenia secondary to refractory or relapsed aplastic anemia has a poor prognosis, with death usually resulting from infectious complications. Alemtuzumab (Campath ) is a humanized IgG1 monoclonal antibody directed against the CD52 protein; CD52 is expressed on all lymphocytes and monocytes. Alemtuzumab (Campath ) produces profound and persistent lymphopenia. The antibody has been used to treat a wide range of autoimmune diseases, lymphoid malignancies, and in solid organ and hematopoietic stem cell transplantation. In our limited experience with alemtuzumab for the treatment of SAA refractory to horse antithymocyte globulin, meaningful hematologic responses have been observed and toxicity has been modest.

We therefore propose a non-randomized pilot phase II study of this humanized monoclonal antibody in SAA relapsed or refractory to ATG. Commercially available alemtuzumab (Campath ) will be administered at 10 mg per day subcutaneously for 10 days total.

The primary end point of the study is the response rate at 6 months, defined as no longer satisfying blood count criteria for SAA.

Relapse, robustness of the hematopoietic recovery at 3 and 6 months, 3 months responses, survival, and clonal evolution to myelodysplasia and acute leukemia will be secondary end points.

• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Non-Randomized; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Severe Aplastic Anemia, Refractory
• Severe Aplastic Anemia, Relapse

Intervention

• Biological: Alemtuzumab (Campath )
  Campath administered at a dose of 10/mg/day for 10 days
• Drug: Cyclosporine
  Subjects who relapse after initial response to alemtuzumab therapy will have cyclosporine added to the regimen after the 6 month visit. Dosing will be based on ideal body weight and will be adjusted to maintain a target level of 200 - 400 ng /ml.

Study Arms

• Experimental: 1
  Subjects diagnosed with relapsed severe aplastic anemia
  Intervention: Biological: Alemtuzumab (Campath )
• Experimental: 2
  Subjects diagnosed with refractory severe aplastic anemia
  Intervention: Biological: Alemtuzumab (Campath )
• Experimental: Relapse
  Subjects who relapse after initial response to alemtuzumab therapy will have cyclosporine added to the regimen after the 6 month visit.
  Intervention: Drug: Cyclosporine

Publications *

• Young NS, Barrett AJ. The treatment of severe acquired aplastic anemia. Blood. 1995 Jun 15;85(12):3367-77. Review.
• Young NS, Maciejewski J. The pathophysiology of acquired aplastic anemia. N Engl J Med. 1997 May 8;336(19):1365-72. Review.
• Zoumbos NC, Gascón P, Djeu JY, Trost SR, Young NS. Circulating activated suppressor T lymphocytes in aplastic anemia. N Engl J Med. 1985 Jan 31;312(5):257-65.
• Pang Y, Xiao HW, Zhang H, Liu ZH, Li L, Gao Y, Li HB, Jiang ZJ, Tan H, Lin JR, Du X, Weng JY, Nie DN, Lin DJ, Zhang XZ, Liu QF, Xu DR, Chen HJ, Ge XH, Wang XY, Xiao Y. Allogeneic Bone Marrow-Derived Mesenchymal Stromal Cells Expanded In Vitro for Treatment of Aplastic Anemia: A Multicenter Phase II Trial. Stem Cells Transl Med. 2017 Jul;6(7):1569-1575. doi: 10.1002/sctm.16-0227. Epub 2017 May 15. Erratum in: Stem Cells Transl Med. 2017 Oct;6(10 ):1949.
• Scheinberg P, Nunez O, Weinstein B, Scheinberg P, Wu CO, Young NS. Activity of alemtuzumab monotherapy in treatment-naive, relapsed, and refractory severe acquired aplastic anemia. Blood. 2012 Jan 12;119(2):345-54. doi: 10.1182/blood-2011-05-352328. Epub 2011 Nov 8.

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: January 22, 2015): 47
• Original Enrollment (submitted: September 16, 2005): 62
• Estimated Study Completion Date: October 2, 2019
• Actual Primary Completion Date: April 14, 2014 (Final data collection date for primary outcome measure)

Eligibility Criteria

• INCLUSION CRITERIA:

Relapsed severe aplastic anemia after initial hematologic response to a prior course of h-ATG or r-ATG based immunosuppression

Or

Refractory severe aplastic anemia not responding to both horse-ATG and rabbit ATG-based immunosuppression

The criteria for severe aplastic anemia are two of the three criteria:

• Absolute neutrophil count less than or equal to 500 /mm(3)
• Platelets to less than or equal to 20,000/mm(3)
• Absolute reticulocyte count less than 60,000 /microL

Age greater than or equal to 2 years old and greater than 12 kg

Prospective subjects or their parent(s)/responsible guardian(s) must be able to comprehend and be willing to sign an informed consent.

EXCLUSION CRITERIA:

Known Diagnosis of Fanconi's anemia

Evidence of a clonal disorder on cytogenetics. In the refractory disease setting, prospective subjects with super severe neutropenia (ANC less than 200 /microL) will not be excluded if results of cytogenetics are not available or pending.

Infection not adequately responding to appropriate therapy

HIV positivity

Failure to discontinue the herbal supplements Echinacea purpurea or Usnea barbata (Old Man's Beard) within 2 weeks of enrollment

Moribund status or concurrent hepatic, renal, cardiac, neurologic, pulmonary, infectious, or metabolic disease of such severity that it would preclude the patient's ability to tolerate protocol therapy, or that death within 7-10 days is likely

Previous hypersensitivity to alemtuzumab or its components

Potential subjects with cancer who are on active chemotherapeutic treatment or who take drugs with hematological effects will not be eligible

Current pregnancy, or unwilling to take oral contraceptives or refrain from pregnancy if of childbearing potential

Not able to understand the investigational nature of the study or give informed consent

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 2 Years to 110 Years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT00195624
• Other Study ID Numbers: 050242; 05-H-0242
• Has Data Monitoring Committee: Not Provided

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

• IPD Sharing Statement: Not Provided
• Responsible Party: National Institutes of Health Clinical Center (CC) ( National Heart, Lung, and Blood Institute (NHLBI) )
• Study Sponsor: National Heart, Lung, and Blood Institute (NHLBI)
• Collaborators: Not Provided

Investigators

• Principal Investigator: Neal S Young, M.D.; National Heart, Lung, and Blood Institute (NHLBI)

• PRS Account: National Institutes of Health Clinical Center (CC)
• Verification Date: October 11, 2018