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

Hemoglobinopathies Clinical Trial

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT00920972
• Other study ID #: 201110144
• Status: Recruiting
• Phase: Phase 1/Phase 2
• Start date: December 2001
• Est. completion date: December 2031

Study information

• Verified date: April 2024
• Source: Washington University School of Medicine
• Contact: Stephanie Hyde, CCRP
• Phone: 3142861180
• Email: stephanie.day[@]wustl.edu
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 220
• Est. completion date: December 2031
• Est. primary completion date: December 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A to 20 Years

Eligibility

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

Related Conditions & MeSH terms

• Bone Marrow Diseases
• Hematologic, Immune, or Bone Marrow Disorders
• Hemoglobinopathies
• Metabolic Diseases
• Metabolic Disorders
• Non-malignant Disorders

Intervention

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...
• 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...
• 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
• 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

Locations

Country	Name	City	State
Canada	University of Calgary	Calgary
United States	Carolinas Medical Center	Charlotte	North Carolina
United States	Children's Memorial Hospital	Chicago	Illinois
United States	Hackensack University Medical Center	Hackensack	New Jersey
United States	Indiana University School of Medicine	Indianapolis	Indiana
United States	Miami Children's Hospital	Miami	Florida
United States	University of Miami	Miami	Florida
United States	Yale School of Medicine	New Haven	Connecticut
United States	Columbia University Medical Center	New York	New York
United States	The University of Oklahoma	Oklahoma City	Oklahoma
United States	Children's Hospital of Orange County	Orange	California
United States	Phoenix Children's Hospital	Phoenix	Arizona
United States	St. Louis University	Saint Louis	Missouri
United States	Washington University School of Medicine (in St. Louis)	Saint Louis	Missouri
United States	All Children's Hospital	Saint Petersburg	Florida
United States	Texas Transplant Institute	San Antonio	Texas
United States	University of California	San Diego	California
United States	George Washington University School of Medicine	Washington	District of Columbia

Sponsors (2)

Lead Sponsor	Collaborator
Washington University School of Medicine	St. Louis Children's Hospital

Countries where clinical trial is conducted

United States,  Canada, 

References & Publications (4)

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 syn — View 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( — View 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. — View 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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Donor engraftment as measured by chimerism	Engraftment is measured in myeloid and lymphoid lineage cells	100 days post-transplant
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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