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

A Study of Hematopoietic Stem Cell Transplantation (HSCT) in Non-Malignant Disease Using a Reduced-Intensity Preparatory Regime

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.

Study Overview

• Status: Recruiting
• Conditions: Hemoglobinopathies; Metabolic Disorders; Hematologic, Immune, or Bone Marrow Disorders; Non-malignant Disorders
• Intervention / Treatment: Drug: Treatment Plan 1: Stratum 1; Drug: GVHD Regimen B: BM Recipients; Drug: Treatment Plan 2: Strata 2, 3, or 4; Drug: GVHD Regimen A: UCB Recipients

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.

• Study Type: Interventional
• Enrollment (Anticipated): 220
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Stephanie Hyde, CCRP; Phone Number: 3142861180; Email: stephanie.day@wustl.edu

Study Locations

• Canada
  • Calgary, Canada
    • Recruiting
    • University of Calgary
    • Contact: Gregory Guilcher, MD
• United States
  • Arizona
    • Phoenix, Arizona, United States, 85016
      • Recruiting
      • Phoenix Children's Hospital
  • California
    • Orange, California, United States, 92868
      • Recruiting
      • Children's Hospital of Orange County
      • Contact: David Buchbinder, MD
      • Principal Investigator: David Buchbinder, MD
    • San Diego, California, United States, 92123
      • Recruiting
      • University of California
  • Connecticut
    • New Haven, Connecticut, United States, 06510
      • Recruiting
      • Yale School of Medicine
  • District of Columbia
    • Washington, District of Columbia, United States, 20010
      • Recruiting
      • George Washington University School of Medicine
  • Florida
    • Miami, Florida, United States, 33136
      • Recruiting
      • University of Miami
      • Principal Investigator: Edward Dela Ziga, MD
    • Miami, Florida, United States, 33155
      • Recruiting
      • Miami Children's Hospital
      • Principal Investigator: Kamar Godder, MD
    • Saint Petersburg, Florida, United States, 33701
      • Recruiting
      • All Children's Hospital
  • Illinois
    • Chicago, Illinois, United States, 60614
      • Completed
      • Children's Memorial Hospital
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Recruiting
      • Indiana University School of Medicine
      • Principal Investigator: Scott Goebel, MD
  • Missouri
    • Saint Louis, Missouri, United States, 63104
      • Recruiting
      • St. Louis University
      • Contact: Deepika Bhatla, MD
    • Saint Louis, Missouri, United States, 63110
      • Recruiting
      • Washington University School of Medicine (in St. Louis)
      • Contact: Stephanie Hyde, CCRP; Phone Number: 3142861180; Email: stephanie.day@wustl.edu
  • New Jersey
    • Hackensack, New Jersey, United States, 07601
      • Completed
      • Hackensack University Medical Center
  • New York
    • New York, New York, United States, 10032
      • Recruiting
      • Columbia University Medical Center
      • Contact: Monica Bhatia, MD
  • North Carolina
    • Charlotte, North Carolina, United States, 28232
      • Recruiting
      • Carolinas Medical Center
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73104
      • Completed
      • The University of Oklahoma
  • Texas
    • San Antonio, Texas, United States, 78229
      • Recruiting
      • Texas Transplant Institute

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 20 years (ADULT, CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NON_RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

4

Arms and Interventions

Participant Group / 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: 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; 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
EXPERIMENTAL: Stratum 3; Recipient with hemoglobinopathy Related or unrelated. 7/8 HLA-matched bone marrow or 5-8/8 HLA-matched UCB	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; 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
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: 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; 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Donor engraftment as measured by chimerism	Engraftment is measured in myeloid and lymphoid lineage cells	100 days post-transplant
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	100 days post-transplant

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	Post transplant
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	100 days post-transplant
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.	2 years post-transplant
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.	2 years post-transplant
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.	1 year post-transplant
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.	2 years post-transplant

Collaborators and Investigators

• Sponsor: Washington University School of Medicine
• Collaborators: St. Louis Children's Hospital
• Investigators: Principal Investigator: Shalini Shenoy, MD, Washington University School of Medicine (in St. Louis)

Publications and helpful links

General Publications

• 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.
• 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.
• 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start: December 1, 2001
• Primary Completion (ANTICIPATED): December 1, 2026
• Study Completion (ANTICIPATED): December 1, 2031

Study Registration Dates

• First Submitted: June 15, 2009
• First Submitted That Met QC Criteria: June 15, 2009
• First Posted (ESTIMATE): June 16, 2009

Study Record Updates

• Last Update Posted (ACTUAL): January 31, 2023
• Last Update Submitted That Met QC Criteria: January 30, 2023
• Last Verified: January 1, 2023

More Information

Terms related to this study

• Keywords: Transplantation; Transplant; Hematopoietic; Bone marrow; Umbilical cord; Nonmyeloablative; Non-malignant; Reduced; Unrelated; Related; Non-myeloablative; Nonmalignant
• Additional Relevant MeSH Terms: Pathologic Processes; Hematologic Diseases; Genetic Diseases, Inborn; Disease; Bone Marrow Diseases; Metabolic Diseases; Hemoglobinopathies
• Other Study ID Numbers: 201110144