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Allogeneic Mixed Chimerism Stem Cell Transplant Using Campath for Hemoglobinopathies & Bone Marrow Failure Syndromes

Primary Purpose

Sickle Cell Anemia, Severe Aplastic Anemia, Paroxysmal Nocturnal Hemoglobinuria (PNH)

Status
Completed
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Campath, Chemo and/or TBI Allo SCT
Sponsored by
David Rizzieri, MD
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Sickle Cell Anemia focused on measuring sickle cell anemia, severe aplastic anemia

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria: Patients must have their clinical material reviewed at the transplanting institution and the diagnosis confirmed Performance status must be Cancer and Leukemia Group B (CALGB) Performance Status (PS) 0, 1, or 2. Patients must have a 5/6 to 6/6 HLA matched family member donor who is evaluated and deemed able to provide PBSCs and/or marrow by the transplant team. Donor must have < 50% Hemoglobin S (HgS) on hemoglobin electrophoresis. Cytomegalovirus (CMV) status of the donor will be assessed, but not used as an exclusion criterion. Patients must meet the following laboratory parameters unless due to disease status as determined by the treating physician: bilirubin and hepatic transaminases and creatinine must be reviewed by the transplantation center and deemed acceptable. HIV antibody negative. hematocrit, white cell count, platelet counts and hematologic status will be reviewed by the treating physician before patient is deemed acceptable. Patient must agree to use some form of adequate birth control during the periods that they receive chemotherapy and any post-chemotherapy medications related to the transplant. Patients must also have a resting multiple gated acquisition scan (MUGA) or echocardiogram and Pulmonary Function Tests (PFTs) with Diffusing Capacity of the Lung for Carbon Monoxide (DLCO) performed before transplant. Recommended minimum standards include an Ejection Fraction (EF) greater than 40% and DLCO greater than 40% for this less toxic regimen. Appropriate cardiology or pulmonary consultations should be considered if the patient has severe cardiac or lung disease at the initiation of therapy. I) Hemoglobinopathies: (a)Sickle Cell Anemia having history of one or more of the following despite treatment with standard therapies such as hydroxyurea: i) 2 or more episodes of acute chest syndrome since age 13 years ii) pulmonary hypertension as measured by tricuspid regurgitant jet velocity of greater than 2.5m/s iii) 2 or more painful crisis per year requiring medical care and analgesia in excess of what is needed at baseline. iv) history of cerebrovascular accident (b)Thalassemia major: Those eligible will have either cardiac or hepatic sequela of thalassemia as documented by biopsy or functional studies. For those with hepatic damage, this would be an increase in size by 50% of the liver or a doubling of the total bilirubin, aspartate transaminase (AST), alanine aminotransferase (ALT), or alkaline phosphatase. To be eligible for transplant due to cardiac damage, there must be evidence of left ventricular dysfunction as measured by MUGA scan or echocardiography. II) Bone marrow failure Disorders Severe Aplastic Anemia: Cytopenia consisting of at least 2 of the following 3: absolute neutrophil count less than 500/μL, platelet count less than 20,000/μL, and reticulocyte count less than 50,000/μL. Paroxysmal nocturnal hemoglobinuria (PNH): Patients must have a history of either life-threatening thrombosis, cytopenia, transfusion dependence or recurrent, debilitating hemolytic crisis Pure red cell aplasia: Patients must be transfusion dependent. Exclusion Criteria: pregnant or lactating women, patients with other major medical or psychiatric illnesses which the treating or transplant physician feels could seriously compromise compliance to this protocol patients with known history of allergies to murine protein

Sites / Locations

  • Florida Hospital Cancer Institute
  • Duke Cancer Institute

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Experimental

Arm Label

Campath SCT for hemoglobinopathies

Campath SCT for Bone Marrow Failure

Arm Description

Campath, Chemo and/or TBI Allo SCT

Campath, Chemo and/or TBI Allo SCT

Outcomes

Primary Outcome Measures

Number of Patients With Neutrophil Engraftment
Number of patients with neutrophil engraftment: Absolute Neutrophil Count (ANC) > 500/μL and hemoglobin level remaining above 10 g/dL without transfusion support, with tests showing at least 2.5% donor cells present. Primary graft failure is defined as absence of establishment of adequate donor hematopoiesis by day 42 with bone marrow cellularity < 5%, peripheral White Blood Count (WBC) < 500/μL, peripheral ANC < 100/μL, and/or platelets < 10,000/μL by day 120 with absence of megakaryocytes in the bone marrow (in the absence of disease relapse).
Number of Patients With Platelet Engraftment
Number of patients with platelet engraftment - Platelets > 20,000/μL and hemoglobin level remaining above 10 g/dL without transfusion support, with tests showing at least 2.5% donor cells present. Primary graft failure is defined as absence of establishment of adequate donor hematopoiesis by day 42 with bone marrow cellularity < 5%, peripheral White Blood Count (WBC) < 500/μL, peripheral ANC < 100/μL, and/or platelets < 10,000/μL by day 120 with absence of megakaryocytes in the bone marrow (in the absence of disease relapse).
Number of Patients With Grade 3-4 Acute Graft Versus Host Disease (GVHD)
Number of patients with Grade 3-4 acute Graft Versus Host Disease (GVHD). GVHD will be monitored at least two times per week through day 45, then weekly through day 60 and graded by 2 persons at each institution, to ensure internal consistency in grading.
Number of Participants With Grade 3-4 Unexpected Adverse Events
An unexpected adverse event is one that differs in the nature, severity, or frequency from (a) the research procedures that are described in the protocol-related documents, (such as the IRB-approved research protocol and informed consent document) as expected, and/or (b) the characteristics of the subject population being studied.
Number of Participants With Transplant-related Mortality
Number of patients who died due to transplant-related complications

Secondary Outcome Measures

Overall Survival
Number of patients alive 2 years after transplant

Full Information

First Posted
December 10, 1999
Last Updated
November 19, 2014
Sponsor
David Rizzieri, MD
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1. Study Identification

Unique Protocol Identification Number
NCT00004143
Brief Title
Allogeneic Mixed Chimerism Stem Cell Transplant Using Campath for Hemoglobinopathies & Bone Marrow Failure Syndromes
Official Title
Allogeneic Mixed Chimerism Stem Cell Transplantation Utilizing In Vivo and In Vitro Campath for Hemoglobinopathies and Bone Marrow Failure Syndromes
Study Type
Interventional

2. Study Status

Record Verification Date
November 2014
Overall Recruitment Status
Completed
Study Start Date
September 1999 (undefined)
Primary Completion Date
May 2008 (Actual)
Study Completion Date
June 2009 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
David Rizzieri, MD

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
RATIONALE: Although used primarily to treat malignant disorders of the blood, allogeneic stem cell transplantation can also cure a variety of non-cancerous, inherited or acquired disorders of the blood. Unfortunately, the conventional approach to allogeneic stem cell transplantation is a risky procedure. For some non-cancerous conditions, the risks of this procedure outweigh the potential benefits. This protocol is designed to test a new approach to allogeneic stem cell transplantation. It is hoped that this approach will be better suited for patients with non-cancerous blood and bone marrow disorders.
Detailed Description
OBJECTIVES: Primary Objective(s): Evaluate the feasibility in terms of mortality, occurrence of acute graft versus host disease, and grades 3-4/4 toxicity of in vivo and in vitro Campath coupled with concomitantly administered nonmyeloablative fludarabine, cyclophosphamide and total body irradiation (TBI) followed by Human Leukocyte Antigen (HLA) 5-6/6 matched family member allo peripheral blood stem cell transplant (PBSCT). Evaluate the engraftment rate of HLA 5-6/6 matched family member patients who receive in vivo Campath followed by concomitantly administered fludarabine, cyclophosphamide and total body irradiation (TBI) as a conditioning regimen with Campath-treated peripheral blood stem cells (in vitro and in vivo exposure). Secondary Objective(s): Evaluate the response rate and survival of patients who receive a non-myeloablative conditioning regimen of in vivo Campath followed by concomitantly administered fludarabine, cyclophosphamide and total body irradiation (TBI) with Campath-treated peripheral blood stem cells. Evaluate the recovery of immune function post engraftment with this regimen.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Sickle Cell Anemia, Severe Aplastic Anemia, Paroxysmal Nocturnal Hemoglobinuria (PNH), Pure Red Cell Aplasia
Keywords
sickle cell anemia, severe aplastic anemia

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
2 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Campath SCT for hemoglobinopathies
Arm Type
Experimental
Arm Description
Campath, Chemo and/or TBI Allo SCT
Arm Title
Campath SCT for Bone Marrow Failure
Arm Type
Experimental
Arm Description
Campath, Chemo and/or TBI Allo SCT
Intervention Type
Drug
Intervention Name(s)
Campath, Chemo and/or TBI Allo SCT
Other Intervention Name(s)
Alemtuzumab, Allogeneic Hematopoietic Stem Cell Transplant
Intervention Description
Allogeneic PBSC/marrow will be collected/harvested from the donor after granulocyte colony-stimulating factor (G-CSF) priming. The allogeneic PBSCs will be infused as per current institutional practice.
Primary Outcome Measure Information:
Title
Number of Patients With Neutrophil Engraftment
Description
Number of patients with neutrophil engraftment: Absolute Neutrophil Count (ANC) > 500/μL and hemoglobin level remaining above 10 g/dL without transfusion support, with tests showing at least 2.5% donor cells present. Primary graft failure is defined as absence of establishment of adequate donor hematopoiesis by day 42 with bone marrow cellularity < 5%, peripheral White Blood Count (WBC) < 500/μL, peripheral ANC < 100/μL, and/or platelets < 10,000/μL by day 120 with absence of megakaryocytes in the bone marrow (in the absence of disease relapse).
Time Frame
1 year post transplant
Title
Number of Patients With Platelet Engraftment
Description
Number of patients with platelet engraftment - Platelets > 20,000/μL and hemoglobin level remaining above 10 g/dL without transfusion support, with tests showing at least 2.5% donor cells present. Primary graft failure is defined as absence of establishment of adequate donor hematopoiesis by day 42 with bone marrow cellularity < 5%, peripheral White Blood Count (WBC) < 500/μL, peripheral ANC < 100/μL, and/or platelets < 10,000/μL by day 120 with absence of megakaryocytes in the bone marrow (in the absence of disease relapse).
Time Frame
1 year post transplant
Title
Number of Patients With Grade 3-4 Acute Graft Versus Host Disease (GVHD)
Description
Number of patients with Grade 3-4 acute Graft Versus Host Disease (GVHD). GVHD will be monitored at least two times per week through day 45, then weekly through day 60 and graded by 2 persons at each institution, to ensure internal consistency in grading.
Time Frame
60 days post transplant
Title
Number of Participants With Grade 3-4 Unexpected Adverse Events
Description
An unexpected adverse event is one that differs in the nature, severity, or frequency from (a) the research procedures that are described in the protocol-related documents, (such as the IRB-approved research protocol and informed consent document) as expected, and/or (b) the characteristics of the subject population being studied.
Time Frame
45 days post transplant
Title
Number of Participants With Transplant-related Mortality
Description
Number of patients who died due to transplant-related complications
Time Frame
100 days
Secondary Outcome Measure Information:
Title
Overall Survival
Description
Number of patients alive 2 years after transplant
Time Frame
2 years

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Patients must have their clinical material reviewed at the transplanting institution and the diagnosis confirmed Performance status must be Cancer and Leukemia Group B (CALGB) Performance Status (PS) 0, 1, or 2. Patients must have a 5/6 to 6/6 HLA matched family member donor who is evaluated and deemed able to provide PBSCs and/or marrow by the transplant team. Donor must have < 50% Hemoglobin S (HgS) on hemoglobin electrophoresis. Cytomegalovirus (CMV) status of the donor will be assessed, but not used as an exclusion criterion. Patients must meet the following laboratory parameters unless due to disease status as determined by the treating physician: bilirubin and hepatic transaminases and creatinine must be reviewed by the transplantation center and deemed acceptable. HIV antibody negative. hematocrit, white cell count, platelet counts and hematologic status will be reviewed by the treating physician before patient is deemed acceptable. Patient must agree to use some form of adequate birth control during the periods that they receive chemotherapy and any post-chemotherapy medications related to the transplant. Patients must also have a resting multiple gated acquisition scan (MUGA) or echocardiogram and Pulmonary Function Tests (PFTs) with Diffusing Capacity of the Lung for Carbon Monoxide (DLCO) performed before transplant. Recommended minimum standards include an Ejection Fraction (EF) greater than 40% and DLCO greater than 40% for this less toxic regimen. Appropriate cardiology or pulmonary consultations should be considered if the patient has severe cardiac or lung disease at the initiation of therapy. I) Hemoglobinopathies: (a)Sickle Cell Anemia having history of one or more of the following despite treatment with standard therapies such as hydroxyurea: i) 2 or more episodes of acute chest syndrome since age 13 years ii) pulmonary hypertension as measured by tricuspid regurgitant jet velocity of greater than 2.5m/s iii) 2 or more painful crisis per year requiring medical care and analgesia in excess of what is needed at baseline. iv) history of cerebrovascular accident (b)Thalassemia major: Those eligible will have either cardiac or hepatic sequela of thalassemia as documented by biopsy or functional studies. For those with hepatic damage, this would be an increase in size by 50% of the liver or a doubling of the total bilirubin, aspartate transaminase (AST), alanine aminotransferase (ALT), or alkaline phosphatase. To be eligible for transplant due to cardiac damage, there must be evidence of left ventricular dysfunction as measured by MUGA scan or echocardiography. II) Bone marrow failure Disorders Severe Aplastic Anemia: Cytopenia consisting of at least 2 of the following 3: absolute neutrophil count less than 500/μL, platelet count less than 20,000/μL, and reticulocyte count less than 50,000/μL. Paroxysmal nocturnal hemoglobinuria (PNH): Patients must have a history of either life-threatening thrombosis, cytopenia, transfusion dependence or recurrent, debilitating hemolytic crisis Pure red cell aplasia: Patients must be transfusion dependent. Exclusion Criteria: pregnant or lactating women, patients with other major medical or psychiatric illnesses which the treating or transplant physician feels could seriously compromise compliance to this protocol patients with known history of allergies to murine protein
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
David A. Rizzieri, MD
Organizational Affiliation
Duke Cancer Institute
Official's Role
Study Chair
First Name & Middle Initial & Last Name & Degree
Mitchell Horwitz, MD
Organizational Affiliation
Duke University
Official's Role
Principal Investigator
Facility Information:
Facility Name
Florida Hospital Cancer Institute
City
Orlando
State/Province
Florida
ZIP/Postal Code
32804
Country
United States
Facility Name
Duke Cancer Institute
City
Durham
State/Province
North Carolina
ZIP/Postal Code
27710
Country
United States

12. IPD Sharing Statement

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Allogeneic Mixed Chimerism Stem Cell Transplant Using Campath for Hemoglobinopathies & Bone Marrow Failure Syndromes

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