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Phase I/II Pilot Study of Mixed Chimerism to Treat Inherited Metabolic Disorders

Primary Purpose

Hurler Syndrome (MPS I), Hurler-Scheie Syndrome, Hunter Syndrome (MPS II)

Status
Terminated
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
hematopoietic 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 Hurler Syndrome (MPS I) focused on measuring hematopoietic stem cell Tx, chimerism, leukodystrophy

Eligibility Criteria

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

Inclusion criteria:

  1. Patients must have a confirmed diagnosis of inherited metabolic disorder / inborn error of metabolism. Diagnosis should be confirmed by appropriate test(s) (enzyme and/or mutation analysis) before study entry. Patients must not be eligible for myeloablative chemotherapy as a preparative regimen for transplant due to age, co-morbidities or organ dysfunction.

    Inborn errors of metabolism / Inherited Metabolic Disorders (IMD) eligible for this study include the following:

    • Hurler Syndrome (MPS I)
    • Hurler-Scheie Syndrome with early neurologic involvement and/or sensitization to ERT
    • Hunter Syndrome (MPS II)
    • Sanfilippo Syndrome (MPS III)
    • Krabbe Disease (Globoid Leukodystrophy)
    • Metachromatic Leukodystrophy (MLD)
    • Adrenoleukodystrophy (ALD and AMN)
    • Sandhoff Disease
    • Tay Sachs Disease
    • Pelizaeus Merzbacher (PMD)
    • Niemann-Pick Disease
    • Alpha-mannosidosis
  2. Patients must have adequate function of other organ systems as measured by:

    • Creatinine less than or equal to 2.0 mg/dl and creatinine clearance ≥60 cc/min/1.73m2. Newborns must have a creatinine clearance ≥ 25 cc/min. For babies less than or equal to 3 months of age, the raw value on glomerular filtration rate (GFR) must be ≥ 1 cc/kg/min.
    • Hepatic transaminases (ALT/AST) 2.5 x normal, bilirubin <2.0mg/dl
    • Normal cardiac function by echocardiogram or radionuclide scan (ejection fraction or shortening fraction >80% of normal value for age)
    • Pulmonary function tests (PFTs) demonstrating forced expiratory volume at one second (FEV1) of ≥50% of predicted for age. If child is too young or unable to perform PFTs, crying vital capacity result of >50% of normal value for age or resting pulse oximeter >92% on room air or clearance by pulmonologist will be required.
  3. Patient must have a related donor (identical or mismatched for 1, 2 or 3 Human Leukocyte Antigen (HLA)-A, -B or -DR loci).
  4. Patient, and parent, or legal guardian must have given written informed consent according to FDA guidelines.
  5. Patients must have a minimum life expectancy of at least 6 months.
  6. Female patients of childbearing potential cannot be pregnant or lactating/breast-feeding and must be either surgically sterile, postmenopausal (no menses for the previous 12 months), or must be practicing an effective method of birth control as determined by the investigator (e.g., oral contraceptives, double barrier methods, hormonal injectable or implanted contraceptives, tubal ligation, or partner with vasectomy).
  7. There is no upper or lower age limit for this study.

Exclusion Criteria

  1. Patients with uncontrolled seizures, apnea, evidence of recurrent or uncontrolled aspiration, or need for chronic mechanical ventilation.
  2. Patients with allogeneic stem cell transplant with cytoreductive therapy in the past 6 months.
  3. Subjects must not have had previous radiation therapy that would preclude total body irradiation (TBI) (as determined by radiation therapist)
  4. Uncontrolled infection or severe concomitant diseases, which in the judgment of the Principal Investigator, could not tolerate reduced intensity transplantation.
  5. Subjects with a positive human immunodeficiency virus (HIV) antibody test result
  6. Subjects who are pregnant, as indicated by a positive serum human chorionic gonadotropin (HCG) test
  7. Subjects whose only donor is pregnant at the time of intended transplant
  8. Subjects of childbearing potential who are not practicing adequate contraception as defined by the investigator at the site
  9. Jehovah's witnesses being unwilling to be transfused
  10. Patients that have any comorbid condition which, in the view of the Principal Investigators, renders the patient at too high a risk from treatment complications and regimen related morbidity/mortality.
  11. Lack of related donors

Sites / Locations

  • Duke University Medical Center

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Inherited Metabolic Disorder Patients

Arm Description

Recipients are treated with hematopoietic stem cell infusion from living donors

Outcomes

Primary Outcome Measures

Production of missing enzyme at levels greater than or equal to 10% of normal

Secondary Outcome Measures

Enriched Hematopoetic Stem Cell Engraftment

Full Information

First Posted
June 10, 2011
Last Updated
April 10, 2023
Sponsor
Talaris Therapeutics Inc.
Collaborators
Duke University
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1. Study Identification

Unique Protocol Identification Number
NCT01372228
Brief Title
Phase I/II Pilot Study of Mixed Chimerism to Treat Inherited Metabolic Disorders
Official Title
Phase I/II Pilot Study of Mixed Chimerism to Treat Inherited Metabolic Disorders
Study Type
Interventional

2. Study Status

Record Verification Date
April 2023
Overall Recruitment Status
Terminated
Why Stopped
company did not pursue this indication
Study Start Date
April 2011 (Actual)
Primary Completion Date
April 2016 (Actual)
Study Completion Date
April 2016 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Talaris Therapeutics Inc.
Collaborators
Duke University

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 (GVHD) in patients with inherited metabolic disorders.
Detailed Description
The objective for the study is to establish chimerism following reduced intensity conditioning with no grade III/IV GVHD. The primary endpoint we will follow is production of the missing enzyme at ≥ 10% of the normal level at day 180 post-transplant in > 90% of patients.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Hurler Syndrome (MPS I), Hurler-Scheie Syndrome, Hunter Syndrome (MPS II), Sanfilippo Syndrome (MPS III), Krabbe Disease (Globoid Leukodystrophy), Metachromatic Leukodystrophy (MLD), Adrenoleukodystrophy (ALD and AMN), Sandhoff Disease, Tay Sachs Disease, Pelizaeus Merzbacher (PMD), Niemann-Pick Disease, Alpha-mannosidosis
Keywords
hematopoietic stem cell Tx, chimerism, leukodystrophy

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
3 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Inherited Metabolic Disorder Patients
Arm Type
Experimental
Arm Description
Recipients are treated with hematopoietic stem cell infusion from living donors
Intervention Type
Biological
Intervention Name(s)
hematopoietic stem cell infusion
Intervention Description
Enriched hematopoetic stem cell infusion
Primary Outcome Measure Information:
Title
Production of missing enzyme at levels greater than or equal to 10% of normal
Time Frame
Day 180 post transplant to three years
Secondary Outcome Measure Information:
Title
Enriched Hematopoetic Stem Cell Engraftment
Time Frame
One month to three years

10. Eligibility

Sex
All
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion criteria: Patients must have a confirmed diagnosis of inherited metabolic disorder / inborn error of metabolism. Diagnosis should be confirmed by appropriate test(s) (enzyme and/or mutation analysis) before study entry. Patients must not be eligible for myeloablative chemotherapy as a preparative regimen for transplant due to age, co-morbidities or organ dysfunction. Inborn errors of metabolism / Inherited Metabolic Disorders (IMD) eligible for this study include the following: Hurler Syndrome (MPS I) Hurler-Scheie Syndrome with early neurologic involvement and/or sensitization to ERT Hunter Syndrome (MPS II) Sanfilippo Syndrome (MPS III) Krabbe Disease (Globoid Leukodystrophy) Metachromatic Leukodystrophy (MLD) Adrenoleukodystrophy (ALD and AMN) Sandhoff Disease Tay Sachs Disease Pelizaeus Merzbacher (PMD) Niemann-Pick Disease Alpha-mannosidosis Patients must have adequate function of other organ systems as measured by: Creatinine less than or equal to 2.0 mg/dl and creatinine clearance ≥60 cc/min/1.73m2. Newborns must have a creatinine clearance ≥ 25 cc/min. For babies less than or equal to 3 months of age, the raw value on glomerular filtration rate (GFR) must be ≥ 1 cc/kg/min. Hepatic transaminases (ALT/AST) 2.5 x normal, bilirubin <2.0mg/dl Normal cardiac function by echocardiogram or radionuclide scan (ejection fraction or shortening fraction >80% of normal value for age) Pulmonary function tests (PFTs) demonstrating forced expiratory volume at one second (FEV1) of ≥50% of predicted for age. If child is too young or unable to perform PFTs, crying vital capacity result of >50% of normal value for age or resting pulse oximeter >92% on room air or clearance by pulmonologist will be required. Patient must have a related donor (identical or mismatched for 1, 2 or 3 Human Leukocyte Antigen (HLA)-A, -B or -DR loci). Patient, and parent, or legal guardian must have given written informed consent according to FDA guidelines. Patients must have a minimum life expectancy of at least 6 months. Female patients of childbearing potential cannot be pregnant or lactating/breast-feeding and must be either surgically sterile, postmenopausal (no menses for the previous 12 months), or must be practicing an effective method of birth control as determined by the investigator (e.g., oral contraceptives, double barrier methods, hormonal injectable or implanted contraceptives, tubal ligation, or partner with vasectomy). There is no upper or lower age limit for this study. Exclusion Criteria Patients with uncontrolled seizures, apnea, evidence of recurrent or uncontrolled aspiration, or need for chronic mechanical ventilation. Patients with allogeneic stem cell transplant with cytoreductive therapy in the past 6 months. Subjects must not have had previous radiation therapy that would preclude total body irradiation (TBI) (as determined by radiation therapist) Uncontrolled infection or severe concomitant diseases, which in the judgment of the Principal Investigator, could not tolerate reduced intensity transplantation. Subjects with a positive human immunodeficiency virus (HIV) antibody test result Subjects who are pregnant, as indicated by a positive serum human chorionic gonadotropin (HCG) test Subjects whose only donor is pregnant at the time of intended transplant Subjects of childbearing potential who are not practicing adequate contraception as defined by the investigator at the site Jehovah's witnesses being unwilling to be transfused Patients that have any comorbid condition which, in the view of the Principal Investigators, renders the patient at too high a risk from treatment complications and regimen related morbidity/mortality. Lack of related donors
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Suzanne T Ildstad, MD
Organizational Affiliation
Talaris Therapeutics Inc.
Official's Role
Study Director
Facility Information:
Facility Name
Duke University Medical Center
City
Durham
State/Province
North Carolina
ZIP/Postal Code
27705
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 Inherited Metabolic Disorders

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