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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT00920972
Recruitment Status : Recruiting
First Posted : June 16, 2009
Last Update Posted : May 20, 2020
Sponsor:
Collaborator:
St. Louis Children's Hospital
Information provided by (Responsible Party):
Washington University School of Medicine

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.

Condition or disease Intervention/treatment Phase
Metabolic Disorders Hematologic, Immune, or Bone Marrow Disorders Hemoglobinopathies Non-malignant Disorders Drug: Treatment Plan 1: Stratum 1 Drug: Treatment Plan 2: Strata 2, 3, or 4 Drug: GVHD Regimen A: UCB Recipients Drug: GVHD Regimen B: BM Recipients Phase 1 Phase 2

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 220 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Study of Hematopoietic Stem Cell Transplantation (HSCT) in Non-Malignant Disease Using a Reduced-Intensity Preparatory Regime
Study Start Date : December 2001
Estimated Primary Completion Date : December 2026
Estimated Study Completion Date : December 2031

Arm Intervention/treatment
Experimental: Stratum 1
Recipients with non-malignant disorders, excluding thalassemia. Related or unrelated 8/8 HLA-matched bone marrow
Drug: Treatment Plan 1: Stratum 1
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...

Drug: GVHD Regimen B: BM Recipients
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

Experimental: Stratum 2
Recipient with transfusion dependent thalassemia. Related or unrelated. 8/8 HLA-matched bone marrow or 5-8/8 HLA-matched UCB
Drug: Treatment Plan 2: Strata 2, 3, or 4
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...

Drug: GVHD Regimen A: UCB Recipients
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

Drug: GVHD Regimen B: BM Recipients
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

Experimental: Stratum 3
Recipient with hemoglobinopathy Related or unrelated. 7/8 HLA-matched bone marrow or 5-8/8 HLA-matched UCB
Drug: Treatment Plan 2: Strata 2, 3, or 4
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...

Drug: GVHD Regimen A: UCB Recipients
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

Drug: GVHD Regimen B: BM Recipients
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

Experimental: Stratum 4
Recipient with non-malignant disorder, excluding hemoglobinopathy Related or unrelated. 7/8 HLA-matched bone marrow or 5-8/8 HLA-matched UCB
Drug: Treatment Plan 2: Strata 2, 3, or 4
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...

Drug: GVHD Regimen A: UCB Recipients
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

Drug: GVHD Regimen B: BM Recipients
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 Measures :
  1. Donor engraftment as measured by chimerism [ Time Frame: 100 days post-transplant ]
    Engraftment is measured in myeloid and lymphoid lineage cells

  2. Major toxicities as graded by the CTC v4 [ Time Frame: 100 days post-transplant ]
    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 :
  1. Time to neutrophil and platelet engraftment as measured by complete blood counts [ Time Frame: Post transplant ]
    Defined as an ANC >500/microliter and platelets >20,000 or 50,000/microliter depending on disorder

  2. Incidence of acute graft-versus-host disease as measured by protocol grading scale [ Time Frame: 100 days post-transplant ]
    aGVHD - involving the skin, gut and liver. Classified according to grading described by Thomas et al. NEJM 1975; 292:895-902

  3. Incidence of chronic graft-versus-host disease as measured by protocol grading scale [ Time Frame: 2 years post-transplant ]
    cGVHD classified per Schulman et al. Am J Med 69: 204-17, 1980.

  4. Long-term donor engraftment by donor chimerism [ Time Frame: 2 years post-transplant ]
    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.

  5. Immune reconstitution by laboratory evaluations [ Time Frame: 1 year post-transplant ]
    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.

  6. Overall and disease free survival [ Time Frame: 2 years post-transplant ]
    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.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   up to 20 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00920972


Contacts
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Contact: Lisa Murray, MA, CCRP 3144544240 murraylm@wustl.edu

Locations
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Sponsors and Collaborators
Washington University School of Medicine
St. Louis Children's Hospital
Investigators
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Principal Investigator: Shalini Shenoy, MD Washington University School of Medicine (in St. Louis)
Publications of Results:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Washington University School of Medicine
ClinicalTrials.gov Identifier: NCT00920972    
Other Study ID Numbers: 201110144
First Posted: June 16, 2009    Key Record Dates
Last Update Posted: May 20, 2020
Last Verified: May 2020
Keywords provided by Washington University School of Medicine:
Bone marrow
Transplant
Transplantation
Hematopoietic
Umbilical cord
Related
Unrelated
Reduced
Non-myeloablative
Nonmyeloablative
Non-malignant
Nonmalignant
Additional relevant MeSH terms:
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Hemoglobinopathies
Bone Marrow Diseases
Metabolic Diseases
Disease
Pathologic Processes
Hematologic Diseases
Genetic Diseases, Inborn