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Phase I/II Pilot Study of Mixed Chimerism to Treat Hemoglobinopathies

Primary Purpose

Sickle Cell Disease

Status
Completed
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Enriched Hematopoetic Stem Cell Infusion
Sponsored by
Talaris Therapeutics Inc.
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Sickle Cell Disease focused on measuring Sickle Cell, Stem Cell, Tolerance, Bone Marrow Transplant, Total Body Irradiation (TBI), Apheresis, Aplastic Anemia, Hemoglobinopathies, Non Malignant

Eligibility Criteria

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

Inclusion Criteria:

The following criteria are established to identify subjects with sickle cell disease (SCD) who have a high predicted morbidity and are at risk for early mortality. Subjects with S/S disease, S/C disease, Hemoglobin H disease, Alpha Thalassemia Major, Thalassemia Major (also known as Cooley's anemia) or S/B* thalassemia and one or more of the following medical complications will be eligible:

  • History of impaired neurological function and/or findings on Magnetic Resonance Image (MRI)/Magnetic Resonance Angiogram (MRA) that are associated with sickle cell disease
  • More than 1 episode of acute chest syndrome with stage I or II pulmonary disease
  • Osteonecrosis involving ≥ 2 joints
  • Sickle cell nephropathy as evidenced by a glomerular filtration rate of 30% - 50% of the predicted normal
  • Alloimmunization that is sufficient to interfere with the efficacy of chronic transfusion therapy
  • Chronic or recurrent priapism
  • Major visual impairment in one or both eyes with bilateral proliferative retinopathy
  • Persistent disabling pain (≥ 2 episodes per year) despite trials of chronic transfusion and/or hydroxyurea at recommended doses for at least 6 months duration

Additional General Criteria:

Subjects must also meet all of the following general inclusion criteria:

  • Subjects must have a related donor (identical or mismatched for 1, 2 or 3 HLA- A, HLA-B or HLA-DR loci).
  • Subjects must have adequate cardiopulmonary function as documented by a left ventricular ejection fraction ≥ 50% (or within normal limits per Institutional criteria) or a left ventricular shortening fraction Within normal limits (WNL) per Institutional criteria, without inotropic support. If Ejection fraction is 40-50%, the patient may be considered for participation if cleared by a Cardiologist.
  • Subjects must have adequate pulmonary function as documented by Diffusing capacity of the lung for carbon monoxide (DLCO) and Forced expiratory volume in 1 second (FEV1)

    • 50% predicted for age and size. If DLCO and FEV1 are between 40-50%, patient may be considered for participation if cleared by a Pulmonologist.
  • Subjects must have adequate hepatic function as demonstrated by a serum albumin ≥ 3.0 mg/dL, and serum glutamic pyruvic transaminase (SGPT) or serum glutamic oxaloacetic transaminase (SGOT) ≤ 2.5 times the upper limit of normal.
  • Subjects must have adequate renal function as demonstrated by a serum creatinine ≤ 1.5 mg/dL. If serum creatinine is ≥ 1.5 mg/dL, then a creatinine clearance test must be done and the result 50% of normal.
  • Subjects or legal guardians must give written informed consent, and subjects must assent where age and intellectually appropriate.
  • There are no age limits for this protocol.

Exclusion Criteria:

  • Uncontrolled infection or severe concomitant diseases, which in the judgment of the Principal Investigator, could not tolerate transplantation.
  • Severe impairment of functional performance as evidenced by a Karnofsky (patients ≥16 years old) or Lansky (children <16 years old) score <70%
  • Stage III or IV sickle cell pulmonary disease
  • Renal insufficiency (GFR < 25% of predicted normal for age)
  • Subjects with a positive human immunodeficiency virus (HIV) antibody test result
  • Subjects who are pregnant, as indicated by a positive serum human chorionic gonadotrophin (HCG) test
  • Subjects of childbearing potential who are not practicing adequate contraception as defined by the investigator at the site
  • Subjects must not have had previous radiation therapy that would preclude total body irradiation (as determined by a radiation oncologist).

Sites / Locations

  • University of Louisville
  • Duke University Medical Center
  • St. Christopher's Hospital for Children

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Experimental

Experimental

Experimental

Experimental

Arm Label

Sickle Cell Disease

Non-Malignant Disorders

Aplastic Anemia

Sickle Cell Disease : Extended Protocol

Arm Description

Recipients treated with an enriched hematopoetic stem cell infusion

Recipients treated with an enriched hematopoetic stem cell infusion

Recipients treated with an enriched hematopoetic stem cell infusion

Recipients treated with an enriched hematopoetic stem cell infusion and Campath 1H conditioning

Outcomes

Primary Outcome Measures

Level of Donor Chimerism from Enriched Hematopoietic Stem Cell Engraftment
Tests are done at key time points to monitor for donor chimerism by evaluating presence of bone marrow-derived hematopoietic stem cells.

Secondary Outcome Measures

Full Information

First Posted
October 20, 2008
Last Updated
October 6, 2020
Sponsor
Talaris Therapeutics Inc.
Collaborators
Duke University, St. Christopher's Hospital for Children, The Western Pennsylvania Hospital, University of Florida, Medical College of Pennsylvania Hospital, Hahnemann University Hospital
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1. Study Identification

Unique Protocol Identification Number
NCT00777231
Brief Title
Phase I/II Pilot Study of Mixed Chimerism to Treat Hemoglobinopathies
Official Title
Phase I/II Pilot Study of Mixed Chimerism to Treat Hemoglobinopathies
Study Type
Interventional

2. Study Status

Record Verification Date
October 2020
Overall Recruitment Status
Completed
Study Start Date
January 2005 (undefined)
Primary Completion Date
August 2010 (Actual)
Study Completion Date
August 2013 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Talaris Therapeutics Inc.
Collaborators
Duke University, St. Christopher's Hospital for Children, The Western Pennsylvania Hospital, University of Florida, Medical College of Pennsylvania Hospital, Hahnemann University Hospital

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
The goal of this research study is to establish chimerism and avoid graft-versus-host disease in patients with Hemoglobinopathies to halt disease progression.
Detailed Description
Hematopoietic stem cell transplantation (HSCT) is emerging as a therapeutic alternative for patients with sickle cell disease. Conventional HSCT therapy has been limited to extremely high-risk hemoglobinopathy patients. Those patients who may be difficult to identify before end-organ damage develops. Also, conventional HSCT is only available to the minority of candidates who have Histocompatibility Leukocyte Antigen (HLA) identical siblings to donate bone marrow or mobilized peripheral blood stem cells. This study proposes two important improvements over conventional HSCT: Donor peripheral blood or bone marrow will be processed via a new technology, which will deplete mature immune cells while enriching hematopoietic stem cells (HSC) and graft facilitating cells (FC). A reduced intensity recipient conditioning regimen will be used to promote mixed allogeneic chimerism, as opposed to full donor chimerism, following HSCT. These two elements may significantly improve the benefit:risk ratio of HSCT for patients with hemoglobinopathies. Stem cell transplantation may become a more feasible option for patients that do not have HLA-identical siblings that can donate stem cells. Also, transplantation may be offered to patients earlier in the disease progression, before end-organ damage occurs.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Sickle Cell Disease
Keywords
Sickle Cell, Stem Cell, Tolerance, Bone Marrow Transplant, Total Body Irradiation (TBI), Apheresis, Aplastic Anemia, Hemoglobinopathies, Non Malignant

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Single Group Assignment
Model Description
No control group used, single group for each of four different disease groups
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
9 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Sickle Cell Disease
Arm Type
Experimental
Arm Description
Recipients treated with an enriched hematopoetic stem cell infusion
Arm Title
Non-Malignant Disorders
Arm Type
Experimental
Arm Description
Recipients treated with an enriched hematopoetic stem cell infusion
Arm Title
Aplastic Anemia
Arm Type
Experimental
Arm Description
Recipients treated with an enriched hematopoetic stem cell infusion
Arm Title
Sickle Cell Disease : Extended Protocol
Arm Type
Experimental
Arm Description
Recipients treated with an enriched hematopoetic stem cell infusion and Campath 1H conditioning
Intervention Type
Biological
Intervention Name(s)
Enriched Hematopoetic Stem Cell Infusion
Intervention Description
Enriched Hematopoetic Stem Cell Infusion
Primary Outcome Measure Information:
Title
Level of Donor Chimerism from Enriched Hematopoietic Stem Cell Engraftment
Description
Tests are done at key time points to monitor for donor chimerism by evaluating presence of bone marrow-derived hematopoietic stem cells.
Time Frame
From one month to three years

10. Eligibility

Sex
All
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: The following criteria are established to identify subjects with sickle cell disease (SCD) who have a high predicted morbidity and are at risk for early mortality. Subjects with S/S disease, S/C disease, Hemoglobin H disease, Alpha Thalassemia Major, Thalassemia Major (also known as Cooley's anemia) or S/B* thalassemia and one or more of the following medical complications will be eligible: History of impaired neurological function and/or findings on Magnetic Resonance Image (MRI)/Magnetic Resonance Angiogram (MRA) that are associated with sickle cell disease More than 1 episode of acute chest syndrome with stage I or II pulmonary disease Osteonecrosis involving ≥ 2 joints Sickle cell nephropathy as evidenced by a glomerular filtration rate of 30% - 50% of the predicted normal Alloimmunization that is sufficient to interfere with the efficacy of chronic transfusion therapy Chronic or recurrent priapism Major visual impairment in one or both eyes with bilateral proliferative retinopathy Persistent disabling pain (≥ 2 episodes per year) despite trials of chronic transfusion and/or hydroxyurea at recommended doses for at least 6 months duration Additional General Criteria: Subjects must also meet all of the following general inclusion criteria: Subjects must have a related donor (identical or mismatched for 1, 2 or 3 HLA- A, HLA-B or HLA-DR loci). Subjects must have adequate cardiopulmonary function as documented by a left ventricular ejection fraction ≥ 50% (or within normal limits per Institutional criteria) or a left ventricular shortening fraction Within normal limits (WNL) per Institutional criteria, without inotropic support. If Ejection fraction is 40-50%, the patient may be considered for participation if cleared by a Cardiologist. Subjects must have adequate pulmonary function as documented by Diffusing capacity of the lung for carbon monoxide (DLCO) and Forced expiratory volume in 1 second (FEV1) 50% predicted for age and size. If DLCO and FEV1 are between 40-50%, patient may be considered for participation if cleared by a Pulmonologist. Subjects must have adequate hepatic function as demonstrated by a serum albumin ≥ 3.0 mg/dL, and serum glutamic pyruvic transaminase (SGPT) or serum glutamic oxaloacetic transaminase (SGOT) ≤ 2.5 times the upper limit of normal. Subjects must have adequate renal function as demonstrated by a serum creatinine ≤ 1.5 mg/dL. If serum creatinine is ≥ 1.5 mg/dL, then a creatinine clearance test must be done and the result 50% of normal. Subjects or legal guardians must give written informed consent, and subjects must assent where age and intellectually appropriate. There are no age limits for this protocol. Exclusion Criteria: Uncontrolled infection or severe concomitant diseases, which in the judgment of the Principal Investigator, could not tolerate transplantation. Severe impairment of functional performance as evidenced by a Karnofsky (patients ≥16 years old) or Lansky (children <16 years old) score <70% Stage III or IV sickle cell pulmonary disease Renal insufficiency (GFR < 25% of predicted normal for age) Subjects with a positive human immunodeficiency virus (HIV) antibody test result Subjects who are pregnant, as indicated by a positive serum human chorionic gonadotrophin (HCG) test Subjects of childbearing potential who are not practicing adequate contraception as defined by the investigator at the site Subjects must not have had previous radiation therapy that would preclude total body irradiation (as determined by a radiation oncologist).
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Suzanne T Ildstad, M.D.
Organizational Affiliation
Talaris Therapeutics Inc.
Official's Role
Study Director
Facility Information:
Facility Name
University of Louisville
City
Louisville
State/Province
Kentucky
ZIP/Postal Code
40202
Country
United States
Facility Name
Duke University Medical Center
City
Durham
State/Province
North Carolina
ZIP/Postal Code
27705
Country
United States
Facility Name
St. Christopher's Hospital for Children
City
Pittsburgh
State/Province
Pennsylvania
ZIP/Postal Code
19134
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
Undecided

Learn more about this trial

Phase I/II Pilot Study of Mixed Chimerism to Treat Hemoglobinopathies

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