Alemtuzumab to Treat Severe Aplastic Anemia

Tracking Information
First Submitted Date ICMJE	September 16, 2005
First Posted Date ICMJE	September 19, 2005
Last Update Posted Date	October 11, 2018
Study Start Date ICMJE	September 15, 2005
Actual Primary Completion Date	April 14, 2014 (Final data collection date for primary outcome measure)
Current Primary Outcome Measures ICMJE; (submitted: October 3, 2018)	The primary endpoint for either trial (relapsed SAA or refractory SAA) will be the response rate at 6 months. [ Time Frame: 6 months ]; Response rate at 6 months
Original Primary Outcome Measures ICMJE	Not Provided
Change History	Complete list of historical versions of study NCT00195624 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures ICMJE; (submitted: October 3, 2018)	Six secondary endpoints will be evaluated for the study:(a) robustness of hematologic recovery with reticulocyte or platelet count L 50,000/LL at 6 months; (b) relapse; (c) response rates at 3 months; (d) clonal evolution to PNH, myelodysplas... [ Time Frame: 3 months to 5 year ]
Original Secondary Outcome Measures ICMJE	Not Provided
Current Other Outcome Measures ICMJE	Not Provided
Original Other Outcome Measures ICMJE	Not Provided
Descriptive Information
Brief Title ICMJE	Alemtuzumab to Treat Severe Aplastic Anemia
Official Title ICMJE	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 ICMJE	Interventional
Study Phase	Phase 2
Study Design ICMJE	Allocation: Non-Randomized; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
Condition ICMJE	Severe Aplastic Anemia, Refractory; Severe Aplastic Anemia, Relapse
Intervention ICMJE	Drug: 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: Drug: Alemtuzumab (Campath ); Experimental: 2 Subjects diagnosed with refractory severe aplastic anemia Intervention: Drug: 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.
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
Recruitment Information
Recruitment Status ICMJE	Active, not recruiting
Actual Enrollment ICMJE; (submitted: January 22, 2015)	47
Original Enrollment ICMJE; (submitted: September 16, 2005)	62
Estimated Study Completion Date	October 15, 2018
Actual Primary Completion Date	April 14, 2014 (Final data collection date for primary outcome measure)
Eligibility Criteria ICMJE	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 ICMJE	Contact information is only displayed when the study is recruiting subjects
Listed Location Countries ICMJE	United States
Removed Location Countries
Administrative Information
NCT Number ICMJE	NCT00195624
Other Study ID Numbers ICMJE	050242; 05-H-0242
Has Data Monitoring Committee	Not Provided
U.S. FDA-regulated Product	Studies a U.S. FDA-regulated Drug Product: Yes
IPD Sharing Statement	Not Provided
Responsible Party	National Institutes of Health Clinical Center (CC) ( National Heart, Lung, and Blood Institute (NHLBI) )
Study Sponsor ICMJE	National Heart, Lung, and Blood Institute (NHLBI)
Collaborators ICMJE	National Cancer Institute (NCI)
Investigators ICMJE	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	September 28, 2018
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP