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Campath/Fludarabine/Melphalan Transplant Conditioning for Non-Malignant Diseases

Primary Purpose

Metabolic Disorders, Hematologic, Immune, or Bone Marrow Disorders, Hemoglobinopathies

Status
Recruiting
Phase
Phase 1
Locations
International
Study Type
Interventional
Intervention
Treatment Plan 1: Stratum 1
Treatment Plan 2: Strata 2, 3, or 4
GVHD Regimen A: UCB Recipients
GVHD Regimen B: BM Recipients
Sponsored by
Washington University School of Medicine
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Metabolic Disorders focused on measuring Bone marrow, Transplant, Transplantation, Hematopoietic, Umbilical cord, Related, Unrelated, Reduced, Non-myeloablative, Nonmyeloablative, Non-malignant, Nonmalignant

Eligibility Criteria

undefined - 20 Years (Child, Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Stratum 1: Patient must have non-malignant disorder, excluding thalassemia. Must be receiving a 8/8 HLA-matched bone marrow, related or unrelated Stratum 2: Patient must have thalassemia receiving 8/8 HLA-matched bone marrow or 5-8/8 HLA-matched UCB. Related or unrelated.

Stratum 3: Patient must have a hemoglobinopathy receiving 7/8 HLA-matched bone marrow or 5-8/8 HLA-matched UCB. Related or unrelated.

Stratum 4: Patient must have a non-malignant disorder (excluding hemoglobinopathy) receiving 7/8 HLA-matched bone marrow or 5-8/8 HLA-matched UCB. Related or unrelated.

All strata:

  • Recipient age < 21 years
  • Lansky/Karnofsky >/= 40
  • Adequate pulmonary, renal, liver, and other organ function as defined in protocol
  • Negative pregnancy test
  • Adequate total nucleated cell or CD34+ dose of product as defined in protocol
  • If sickle cell, Hemoglobin S <30%

Exclusion Criteria:

  • HIV positive
  • Invasive infection
  • Pregnancy/lactating

Sites / Locations

  • Phoenix Children's HospitalRecruiting
  • Children's Hospital of Orange CountyRecruiting
  • University of CaliforniaRecruiting
  • Yale School of MedicineRecruiting
  • George Washington University School of MedicineRecruiting
  • University of MiamiRecruiting
  • Miami Children's HospitalRecruiting
  • All Children's HospitalRecruiting
  • Children's Memorial Hospital
  • Indiana University School of MedicineRecruiting
  • St. Louis UniversityRecruiting
  • Washington University School of Medicine (in St. Louis)Recruiting
  • Hackensack University Medical Center
  • Columbia University Medical CenterRecruiting
  • Carolinas Medical CenterRecruiting
  • The University of Oklahoma
  • Texas Transplant InstituteRecruiting
  • University of CalgaryRecruiting

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Experimental

Experimental

Experimental

Experimental

Arm Label

Stratum 1

Stratum 2

Stratum 3

Stratum 4

Arm Description

Recipients with non-malignant disorders, excluding thalassemia. Related or unrelated 8/8 HLA-matched bone marrow

Recipient with transfusion dependent thalassemia. Related or unrelated. 8/8 HLA-matched bone marrow or 5-8/8 HLA-matched UCB

Recipient with hemoglobinopathy Related or unrelated. 7/8 HLA-matched bone marrow or 5-8/8 HLA-matched UCB

Recipient with non-malignant disorder, excluding hemoglobinopathy Related or unrelated. 7/8 HLA-matched bone marrow or 5-8/8 HLA-matched UCB

Outcomes

Primary Outcome Measures

Donor engraftment as measured by chimerism
Engraftment is measured in myeloid and lymphoid lineage cells
Major toxicities as graded by the CTC v4
Toxicity monitoring includes unanticipated side effects (new) and all severe irreversible toxicities Grade 3 and above unexpected Grade 4 and above - all toxicities that are possibly, probably or definitely related to protocol therapy All deaths irrespective of attribution

Secondary Outcome Measures

Time to neutrophil and platelet engraftment as measured by complete blood counts
Defined as an ANC >500/microliter and platelets >20,000 or 50,000/microliter depending on disorder
Incidence of acute graft-versus-host disease as measured by protocol grading scale
aGVHD - involving the skin, gut and liver. Classified according to grading described by Thomas et al. NEJM 1975; 292:895-902
Incidence of chronic graft-versus-host disease as measured by protocol grading scale
cGVHD classified per Schulman et al. Am J Med 69: 204-17, 1980.
Long-term donor engraftment by donor chimerism
Donor chimerism is determined by PCR analysis after cell separation into lymphoid and myeloid lineage cells using antibodies. Can also be detected by FISH analysis in the event of donor and recipient sex discrepancy.
Immune reconstitution by laboratory evaluations
Immune reconstitution detected by absolute numbers of T cell phenotypes, B cells and NK cells. T cell function determined by proliferative response to mitogens. B cell function determined by evaluating anti-tetanus antibody titers.
Overall and disease free survival
Overall survival is defined as survival with or without disease Event free survival is defined as disease free, severe GVHD free survival, monitoring quality of life and relevant parameters.

Full Information

First Posted
June 15, 2009
Last Updated
January 30, 2023
Sponsor
Washington University School of Medicine
Collaborators
St. Louis Children's Hospital
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1. Study Identification

Unique Protocol Identification Number
NCT00920972
Brief Title
Campath/Fludarabine/Melphalan Transplant Conditioning for Non-Malignant Diseases
Official Title
A Study of Hematopoietic Stem Cell Transplantation (HSCT) in Non-Malignant Disease Using a Reduced-Intensity Preparatory Regime
Study Type
Interventional

2. Study Status

Record Verification Date
January 2023
Overall Recruitment Status
Recruiting
Study Start Date
December 2001 (undefined)
Primary Completion Date
December 2026 (Anticipated)
Study Completion Date
December 2031 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Washington University School of Medicine
Collaborators
St. Louis Children's Hospital

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
The hypothesis for this study is that a preparative regimen that maximizes host immunosuppression without myeloablation will be well tolerated and sufficient for engraftment of donor hematopoietic cells. It is also to determine major toxicities from these conditioning regimens, within the first 100 days after transplantation.
Detailed Description
The study uses reduced intensity conditioning that is immune suppressive to achieve donor cell engraftment without exposure to radiation or high dose chemotherapy in children with non-malignant disorders. The intent is to minimize early and late regimen related toxicities in the context of a reduced intensity regimen. In addition to maximizing opportunity for donor cell engraftment, the trial seeks to minimize toxicities associated with transplant such as graft versus host disease and employs GVHD prophylaxis that seeks to decrease rates of acute and chronic GVHD in the setting of matched and mismatched donor stem cell transplants from marrow and cord blood sources.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Metabolic Disorders, Hematologic, Immune, or Bone Marrow Disorders, Hemoglobinopathies, Non-malignant Disorders
Keywords
Bone marrow, Transplant, Transplantation, Hematopoietic, Umbilical cord, Related, Unrelated, Reduced, Non-myeloablative, Nonmyeloablative, Non-malignant, Nonmalignant

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
220 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Stratum 1
Arm Type
Experimental
Arm Description
Recipients with non-malignant disorders, excluding thalassemia. Related or unrelated 8/8 HLA-matched bone marrow
Arm Title
Stratum 2
Arm Type
Experimental
Arm Description
Recipient with transfusion dependent thalassemia. Related or unrelated. 8/8 HLA-matched bone marrow or 5-8/8 HLA-matched UCB
Arm Title
Stratum 3
Arm Type
Experimental
Arm Description
Recipient with hemoglobinopathy Related or unrelated. 7/8 HLA-matched bone marrow or 5-8/8 HLA-matched UCB
Arm Title
Stratum 4
Arm Type
Experimental
Arm Description
Recipient with non-malignant disorder, excluding hemoglobinopathy Related or unrelated. 7/8 HLA-matched bone marrow or 5-8/8 HLA-matched UCB
Intervention Type
Drug
Intervention Name(s)
Treatment Plan 1: Stratum 1
Intervention Description
Day -50 to -21: Hydroxyurea 30mg/kg PO q day Day -22: Campath-1H 3 mg IV or SQ... Day -21: Campath-1H 10 mg IV or SQ... Day -20: Campath-1H 15 mg IV or SQ... Day -19: Campath-1H 20 mg IV or SQ... Day -8: Fludarabine 30mg/m2 IV... Day -7: Fludarabine 30mg/m2 IV... Day -6: Fludarabine 30mg/m2 IV... Day -5: Fludarabine 30mg/m2 IV... Day -4: Fludarabine 30mg/m2 IV... Day -3: Melphalan 140 mg/m2 IV... (dose modifications for patients <10 kgs) Procedure/Surgery: Hematopoietic stem cell infusion on Day 0...
Intervention Type
Drug
Intervention Name(s)
Treatment Plan 2: Strata 2, 3, or 4
Intervention Description
Day -50 to -21: Hydroxyurea 30mg/kg PO q day… Day -22: Campath-1H 3 mg IV or SQ... Day -21: Campath-1H 10 mg IV or SQ... Day -20: Campath-1H 15 mg IV or SQ... Day -19: Campath-1H 20 mg IV or SQ... Day -8: Fludarabine 30mg/m2 IV... Day -7: Fludarabine 30mg/m2 IV... Day -6: Fludarabine 30mg/m2 IV... Day -5: Fludarabine 30mg/m2 IV... Day -4: Fludarabine 30mg/m2 IV... Day -4: Thiotepa 8mg/kg IV… Day -3: Melphalan 140 mg/m2 IV... (dose modifications for patients <10 kgs) Procedure/Surgery: Hematopoietic stem cell infusion on day 0...
Intervention Type
Drug
Intervention Name(s)
GVHD Regimen A: UCB Recipients
Intervention Description
Day -3: Begin Tacrolimus or cyclosporine Begin MMF Day -1: Abatacept 10mg/kg IV Day +5: Abatacept 10mg/kg IV Day +14: Abatacept 10mg/kg IV Day +28: Abatacept 10mg/kg IV Day +60: Abatacept 10mg/kg IV Day +100: Abatacept 10mg/kg IV
Intervention Type
Drug
Intervention Name(s)
GVHD Regimen B: BM Recipients
Intervention Description
Day -3: Begin Tacrolimus or cyclosporine Begin MMF Day -1: Abatacept 10mg/kg IV Day +1: Methotrexate 7.5mg/m2 IV Day +3: Methotrexate 7.5mg/m2 IV Day +5: Abatacept 10mg/kg IV Day +6: Methotrexate 7.5mg/m2 IV Day +14: Abatacept 10mg/kg IV Day +28: Abatacept 10mg/kg IV Day +60: Abatacept 10mg/kg IV Day +100: Abatacept 10mg/kg IV Day +180: Abatacept 10mg/kg IV Day +270: Abatacept 10mg/kg IV Day +365: Abatacept 10mg/kg IV
Primary Outcome Measure Information:
Title
Donor engraftment as measured by chimerism
Description
Engraftment is measured in myeloid and lymphoid lineage cells
Time Frame
100 days post-transplant
Title
Major toxicities as graded by the CTC v4
Description
Toxicity monitoring includes unanticipated side effects (new) and all severe irreversible toxicities Grade 3 and above unexpected Grade 4 and above - all toxicities that are possibly, probably or definitely related to protocol therapy All deaths irrespective of attribution
Time Frame
100 days post-transplant
Secondary Outcome Measure Information:
Title
Time to neutrophil and platelet engraftment as measured by complete blood counts
Description
Defined as an ANC >500/microliter and platelets >20,000 or 50,000/microliter depending on disorder
Time Frame
Post transplant
Title
Incidence of acute graft-versus-host disease as measured by protocol grading scale
Description
aGVHD - involving the skin, gut and liver. Classified according to grading described by Thomas et al. NEJM 1975; 292:895-902
Time Frame
100 days post-transplant
Title
Incidence of chronic graft-versus-host disease as measured by protocol grading scale
Description
cGVHD classified per Schulman et al. Am J Med 69: 204-17, 1980.
Time Frame
2 years post-transplant
Title
Long-term donor engraftment by donor chimerism
Description
Donor chimerism is determined by PCR analysis after cell separation into lymphoid and myeloid lineage cells using antibodies. Can also be detected by FISH analysis in the event of donor and recipient sex discrepancy.
Time Frame
2 years post-transplant
Title
Immune reconstitution by laboratory evaluations
Description
Immune reconstitution detected by absolute numbers of T cell phenotypes, B cells and NK cells. T cell function determined by proliferative response to mitogens. B cell function determined by evaluating anti-tetanus antibody titers.
Time Frame
1 year post-transplant
Title
Overall and disease free survival
Description
Overall survival is defined as survival with or without disease Event free survival is defined as disease free, severe GVHD free survival, monitoring quality of life and relevant parameters.
Time Frame
2 years post-transplant

10. Eligibility

Sex
All
Maximum Age & Unit of Time
20 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Stratum 1: Patient must have non-malignant disorder, excluding thalassemia. Must be receiving a 8/8 HLA-matched bone marrow, related or unrelated Stratum 2: Patient must have thalassemia receiving 8/8 HLA-matched bone marrow or 5-8/8 HLA-matched UCB. Related or unrelated. Stratum 3: Patient must have a hemoglobinopathy receiving 7/8 HLA-matched bone marrow or 5-8/8 HLA-matched UCB. Related or unrelated. Stratum 4: Patient must have a non-malignant disorder (excluding hemoglobinopathy) receiving 7/8 HLA-matched bone marrow or 5-8/8 HLA-matched UCB. Related or unrelated. All strata: Recipient age < 21 years Lansky/Karnofsky >/= 40 Adequate pulmonary, renal, liver, and other organ function as defined in protocol Negative pregnancy test Adequate total nucleated cell or CD34+ dose of product as defined in protocol If sickle cell, Hemoglobin S <30% Exclusion Criteria: HIV positive Invasive infection Pregnancy/lactating
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Stephanie Hyde, CCRP
Phone
3142861180
Email
stephanie.day@wustl.edu
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Shalini Shenoy, MD
Organizational Affiliation
Washington University School of Medicine (in St. Louis)
Official's Role
Principal Investigator
Facility Information:
Facility Name
Phoenix Children's Hospital
City
Phoenix
State/Province
Arizona
ZIP/Postal Code
85016
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Roberta Adams, MD
Facility Name
Children's Hospital of Orange County
City
Orange
State/Province
California
ZIP/Postal Code
92868
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
David Buchbinder, MD
First Name & Middle Initial & Last Name & Degree
David Buchbinder, MD
Facility Name
University of California
City
San Diego
State/Province
California
ZIP/Postal Code
92123
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Eric Anderson, MD
Facility Name
Yale School of Medicine
City
New Haven
State/Province
Connecticut
ZIP/Postal Code
06510
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Niketa Shah, MD
First Name & Middle Initial & Last Name & Degree
Niketa Shah, MD
Facility Name
George Washington University School of Medicine
City
Washington
State/Province
District of Columbia
ZIP/Postal Code
20010
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
David Jacobsohn, MD
Facility Name
University of Miami
City
Miami
State/Province
Florida
ZIP/Postal Code
33136
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Edward Dela Ziga, MD
Facility Name
Miami Children's Hospital
City
Miami
State/Province
Florida
ZIP/Postal Code
33155
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Kamar Godder, MD
Facility Name
All Children's Hospital
City
Saint Petersburg
State/Province
Florida
ZIP/Postal Code
33701
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Gregory Hale, MD
Facility Name
Children's Memorial Hospital
City
Chicago
State/Province
Illinois
ZIP/Postal Code
60614
Country
United States
Individual Site Status
Completed
Facility Name
Indiana University School of Medicine
City
Indianapolis
State/Province
Indiana
ZIP/Postal Code
46202
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Scott Goebel, MD
Facility Name
St. Louis University
City
Saint Louis
State/Province
Missouri
ZIP/Postal Code
63104
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Deepika Bhatla, MD
First Name & Middle Initial & Last Name & Degree
Deepika Bhatla, MD
Facility Name
Washington University School of Medicine (in St. Louis)
City
Saint Louis
State/Province
Missouri
ZIP/Postal Code
63110
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Shalini Shenoy, MD
Phone
314-454-6018
Email
shalinishenoy@wustl.edu
First Name & Middle Initial & Last Name & Degree
Stephanie Hyde, CCRP
Phone
3142861180
Email
stephanie.day@wustl.edu
Facility Name
Hackensack University Medical Center
City
Hackensack
State/Province
New Jersey
ZIP/Postal Code
07601
Country
United States
Individual Site Status
Completed
Facility Name
Columbia University Medical Center
City
New York
State/Province
New York
ZIP/Postal Code
10032
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Monica Bhatia, MD
First Name & Middle Initial & Last Name & Degree
Monica Bhatia, MD
Facility Name
Carolinas Medical Center
City
Charlotte
State/Province
North Carolina
ZIP/Postal Code
28232
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Michael Kent, MD
Facility Name
The University of Oklahoma
City
Oklahoma City
State/Province
Oklahoma
ZIP/Postal Code
73104
Country
United States
Individual Site Status
Completed
Facility Name
Texas Transplant Institute
City
San Antonio
State/Province
Texas
ZIP/Postal Code
78229
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Troy Quigg, MD
Facility Name
University of Calgary
City
Calgary
Country
Canada
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Gregory Guilcher, MD
First Name & Middle Initial & Last Name & Degree
Gregory Guilcher, MD

12. IPD Sharing Statement

Citations:
PubMed Identifier
18500373
Citation
Bhatla D, Davies SM, Shenoy S, Harris RE, Crockett M, Shoultz L, Smolarek T, Bleesing J, Hansen M, Jodele S, Jordan M, Filipovich AH, Mehta PA. Reduced-intensity conditioning is effective and safe for transplantation of patients with Shwachman-Diamond syndrome. Bone Marrow Transplant. 2008 Aug;42(3):159-65. doi: 10.1038/bmt.2008.151. Epub 2008 May 26.
Results Reference
result
PubMed Identifier
18026148
Citation
Hansen MD, Filipovich AH, Davies SM, Mehta P, Bleesing J, Jodele S, Hayashi R, Barnes Y, Shenoy S. Allogeneic hematopoietic cell transplantation (HCT) in Hurler's syndrome using a reduced intensity preparative regimen. Bone Marrow Transplant. 2008 Feb;41(4):349-53. doi: 10.1038/sj.bmt.1705926. Epub 2007 Nov 19.
Results Reference
result
PubMed Identifier
16990602
Citation
Rao A, Kamani N, Filipovich A, Lee SM, Davies SM, Dalal J, Shenoy S. Successful bone marrow transplantation for IPEX syndrome after reduced-intensity conditioning. Blood. 2007 Jan 1;109(1):383-5. doi: 10.1182/blood-2006-05-025072. Epub 2006 Sep 21.
Results Reference
result
PubMed Identifier
15592491
Citation
Shenoy S, Grossman WJ, DiPersio J, Yu LC, Wilson D, Barnes YJ, Mohanakumar T, Rao A, Hayashi RJ. A novel reduced-intensity stem cell transplant regimen for nonmalignant disorders. Bone Marrow Transplant. 2005 Feb;35(4):345-52. doi: 10.1038/sj.bmt.1704795.
Results Reference
result
PubMed Identifier
26348869
Citation
King AA, Kamani N, Bunin N, Sahdev I, Brochstein J, Hayashi RJ, Grimley M, Abraham A, Dioguardi J, Chan KW, Douglas D, Adams R, Andreansky M, Anderson E, Gilman A, Chaudhury S, Yu L, Dalal J, Hale G, Cuvelier G, Jain A, Krajewski J, Gillio A, Kasow KA, Delgado D, Hanson E, Murray L, Shenoy S. Successful matched sibling donor marrow transplantation following reduced intensity conditioning in children with hemoglobinopathies. Am J Hematol. 2015 Dec;90(12):1093-8. doi: 10.1002/ajh.24183. Epub 2015 Oct 6.
Results Reference
derived

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Campath/Fludarabine/Melphalan Transplant Conditioning for Non-Malignant Diseases

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