Donor Stem Cell Transplant With Treosulfan, Fludarabine, and Thiotepa in Treating Patients With Non-malignant Disorders
Primary Purpose
Non-Neoplastic Hematologic and Lymphocytic Disorder
Status
Recruiting
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Thiotepa
Treosulfan
Fludarabine Phosphate
Rabbit Anti-Thymocyte Globulin
Allogeneic Hematopoietic Stem Cell Transplantation
Sponsored by
About this trial
This is an interventional treatment trial for Non-Neoplastic Hematologic and Lymphocytic Disorder
Eligibility Criteria
Inclusion Criteria:
- Patient with nonmalignant disease treatable by allogenic HCT
- Patient with a nonmalignant disease that is not clearly defined (a patient with a non-malignant disease HCT for whom a genetic mutation responsible for their non-malignant disease phenotype has not been identified) are eligible for the study following discussion with and approval by the protocol principal investigator (PI) (Dr. Lauri Burroughs)
- DONOR: Human leukocyte antigen (HLA)-identical related donor OR unrelated donor matched for HLA-A, B, C, DRB1 and DQB1 or mismatched for a single allele at HLA-A, B, C, or a single DQB1 antigen or allele mismatch by high resolution deoxyribonucleic acid (DNA) typing
DONOR: Bone marrow is the preferred cell source (when feasible). However, peripheral blood stem cells (PBSC) is also allowed and the PI may determine if PBSC is preferred for certain patients
- The recommended total nucleated cell count (TNC) for bone marrow grafts is >= 4.0 x 10^8 TNC/kg (actual recipient weight)
- The recommended CD34 cell count for PBSC grafts is >= 5 x 10^6 CD34/kg (actual recipient weight) and the recommended maximum CD34 cell count for PBSC grafts is 10 x 10^6 CD34/kg (actual recipient weight)
- DONOR: HLA-matched sibling bone marrow in combination with HLA-matched sibling umbilical cord blood if the HLA-matched sibling umbilical cord blood was collected and stored. The HLA-matched sibling bone marrow and cord blood would be matched for HLA-A, B, C, DRB1 and DQB1
Exclusion Criteria:
- Patients with idiopathic aplastic anemia and Fanconi anemia; patients with aplastic anemia associated with paroxysmal nocturnal hemoglobinuria (PNH) or inherited marrow failure syndromes (except Fanconi anemia) will be allowed
- Impaired cardiac function as evidenced by ejection fraction < 35% (or, if unable to obtain ejection fraction, shortening fraction of < 26%) or cardiac insufficiency requiring treatment or symptomatic coronary artery disease. Patients with a shortening fraction of < 26% may be enrolled if approved by a cardiologist
- Impaired pulmonary function as evidenced by carbon monoxide diffusing capability (DLCO) corrected < 50% of predicted (or, if unable to perform pulmonary function tests, then oxygen [O2] saturation < 92% on room air)
Impaired renal function as evidenced by:
- Estimated creatinine clearance < 60 mL/min/1.73m^2 using either the Chronic Kidney Disease Epidemiology Collaboration (CKD EPI) equation for adult patients (>= 18 years old), or the updated Schwartz formula for pediatric patients (< 18 years old). If the estimated creatinine clearance is < 60 mL/min/1.73m^2, then renal function must be measured by 24-hour creatinine clearance, Iothalamate, Iohexol or nuclear GFR and the patient is excluded if their measured creatinine clearance is < 50 mL/min/1.73 m^2, OR
- Serum creatinine > 2 x upper limit of normal, OR
- Dialysis dependent
- Evidence of synthetic dysfunction or severe cirrhosis requiring deferral of conditioning as recommended by a gastroenterology specialist
- Active infectious disease requiring deferral of conditioning as recommended by an infectious disease specialist
- Positive for HIV (human immunodeficiency virus)
- Females who are pregnant or breast-feeding
- Known hypersensitivity to treosulfan, fludarabine, and/or thiotepa
- DONOR: Donors deemed unable to undergo marrow harvesting of PBSC mobilization and leukapheresis
- DONOR: HIV-positive donors
- DONOR: Donors with active infectious hepatitis
- DONOR: Female donor with positive pregnancy test
- DONOR: Donors are excluded if the patient has an identified antibody against a donor-specific HLA locus as specified in standard practice
- DONOR: HLA-matched sibling cord blood units that have not passed donor screening for infectious disease markers as recommended by the National Marrow Donor Project (NMDP) will not be used unless a waiver is signed by the clinical attending allowing use of cord blood unit. Cord blood units are presumed to be cytomegalovirus (CMV) negative regardless of serologic testing due to passive transmission of maternal CMV antibodies
Sites / Locations
- Fred Hutch/University of Washington Cancer ConsortiumRecruiting
- Medical College of Wisconsin
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
Treatment (chemotherapy, transplant)
Arm Description
Patients receive thiotepa IV BID over 2 hours on day -7, treosulfan IV over 120 minutes on days -6 to -4, fludarabine phosphate IV over 60 minutes on days -6 to -2, and rabbit anti-thymocyte globulin IV over 4-6 hours on days -4 to -2. Patients then undergo allogeneic hematopoietic cell transplant via infusion on day 0.
Outcomes
Primary Outcome Measures
Engraftment failure
Will be defined as donor CD3 chimerism < 5% at 1 year after transplant.
Secondary Outcome Measures
Overall survival
Event-free survival
Defined as death due to any cause, donor lymphocyte infusion, CD34 boost, second transplant, graft rejection or graft failure, or the development of myelodysplastic syndrome or leukemia following transplant (whichever event occurs first).
Transplant-related mortality
Incidence of grade II-IV acute graft-versus-host disease
Incidence of chronic graft-versus-host disease
Donor chimerism CD3 & CD33
Full Information
NCT ID
NCT03980769
First Posted
June 6, 2019
Last Updated
July 10, 2023
Sponsor
Fred Hutchinson Cancer Center
1. Study Identification
Unique Protocol Identification Number
NCT03980769
Brief Title
Donor Stem Cell Transplant With Treosulfan, Fludarabine, and Thiotepa in Treating Patients With Non-malignant Disorders
Official Title
Allogeneic Hematopoietic Cell Transplantation for Patients With Non-Malignant Disorders Using Treosulfan, Fludarabine, and Thiotepa
Study Type
Interventional
2. Study Status
Record Verification Date
July 2023
Overall Recruitment Status
Recruiting
Study Start Date
May 5, 2021 (Actual)
Primary Completion Date
July 1, 2027 (Anticipated)
Study Completion Date
July 1, 2027 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Fred Hutchinson Cancer Center
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
This phase II clinical trial studies how well treosulfan, thiotepa, fludarabine, and rabbit anti-thymocyte globulin (rATG) before donor stem cell transplantation works in treating patients with nonmalignant (non-cancerous) diseases. Hematopoietic cell transplantation has been shown to be curative for many patients with nonmalignant (non-cancerous) diseases such as primary immunodeficiency disorders, immune dysregulatory disorders, hemophagocytic lymphohistiocytosis, bone marrow failure syndromes, and hemoglobinopathies. Powerful chemotherapy drugs are often used to condition the patient before infusion of the new healthy donor cells. The purpose of the conditioning therapy is to destroy the patient's abnormal bone marrow which doesn't work properly in order to make way for the new healthy donor cells which functions normally. Although effective in curing the patient's disease, many hematopoietic cell transplantation regimens use intensive chemotherapy which can be quite toxic, have significant side effects, and can potentially be life-threatening. Investigators are investigating whether a new conditioning regimen that uses less intensive drugs (treosulfan, thiotepa, and fludarabine phosphate) results in new blood-forming cells (engraftment) of the new donor cells without increased toxicities in patients with nonmalignant (non-cancerous) diseases.
Detailed Description
OUTLINE:
Patients receive thiotepa intravenously (IV) twice daily (BID) over 2 hours on day -7, treosulfan IV over 120 minutes on days -6 to -4, fludarabine phosphate IV over 60 minutes on days -6 to -2, and rabbit anti-thymocyte globulin IV over 4-6 hours on days -4 to -2. Patients then undergo allogeneic hematopoietic cell transplant via infusion on day 0.
After completion of study treatment, patients are followed up at 1 year and then annually thereafter.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Non-Neoplastic Hematologic and Lymphocytic Disorder
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
40 (Anticipated)
8. Arms, Groups, and Interventions
Arm Title
Treatment (chemotherapy, transplant)
Arm Type
Experimental
Arm Description
Patients receive thiotepa IV BID over 2 hours on day -7, treosulfan IV over 120 minutes on days -6 to -4, fludarabine phosphate IV over 60 minutes on days -6 to -2, and rabbit anti-thymocyte globulin IV over 4-6 hours on days -4 to -2. Patients then undergo allogeneic hematopoietic cell transplant via infusion on day 0.
Intervention Type
Drug
Intervention Name(s)
Thiotepa
Other Intervention Name(s)
1,1',1"-phosphinothioylidynetrisaziridine, N,N', N''-Triethylenethiophosphoramid, Oncotiotepa, STEPA, Tepadina, TESPA, Tespamin, Tespamine, Thio-Tepa, Thiofosfamide, Thiofozil, Thiophosphamide, Thiophosphoramide, Thiotef, Tifosyl, TIO TEF, Triethylene thiophosphoramide, Triethylenethiophosphoramide, TSPA
Intervention Description
Given IV
Intervention Type
Drug
Intervention Name(s)
Treosulfan
Other Intervention Name(s)
(S-(R*,R*))-1,2,3,4-butanetetrol, 1,4-dimethanesulfonate, [R-(R*,S*)]-, 299-75-2, 39069, Dihydroxybusulfan, Ovastat, Treosulphan, Tresulfon
Intervention Description
Given IV
Intervention Type
Drug
Intervention Name(s)
Fludarabine Phosphate
Other Intervention Name(s)
2-F-ara-AMP, 312887, 328002, 75607-67-9, 9H-Purin-6-amine, 2-fluoro-9-(5-O-phosphono-.beta.-D-arabinofuranosyl)-, Beneflur, Fludara, Fludarabine-5'-Monophosphate
Intervention Description
Given IV
Intervention Type
Biological
Intervention Name(s)
Rabbit Anti-Thymocyte Globulin
Intervention Description
Given IV
Intervention Type
Procedure
Intervention Name(s)
Allogeneic Hematopoietic Stem Cell Transplantation
Other Intervention Name(s)
Allogeneic Hematopoietic Cell Transplantation, Allogeneic Stem Cell Transplantation, HSC, HSCT
Intervention Description
Undergo HCT via infusion
Primary Outcome Measure Information:
Title
Engraftment failure
Description
Will be defined as donor CD3 chimerism < 5% at 1 year after transplant.
Time Frame
1 year after transplant
Secondary Outcome Measure Information:
Title
Overall survival
Time Frame
At 1 year post-transplant
Title
Event-free survival
Description
Defined as death due to any cause, donor lymphocyte infusion, CD34 boost, second transplant, graft rejection or graft failure, or the development of myelodysplastic syndrome or leukemia following transplant (whichever event occurs first).
Time Frame
At 1 year post-transplant
Title
Transplant-related mortality
Time Frame
At day 100 after transplant
Title
Incidence of grade II-IV acute graft-versus-host disease
Time Frame
At day 100 after transplant
Title
Incidence of chronic graft-versus-host disease
Time Frame
At 1 year after transplant
Title
Donor chimerism CD3 & CD33
Time Frame
At 1 year after transplant
10. Eligibility
Sex
All
Maximum Age & Unit of Time
50 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Patient with nonmalignant disease treatable by allogenic HCT
Patient with a nonmalignant disease that is not clearly defined (a patient with a non-malignant disease for whom genetic testing has been done and a genetic mutation responsible for their non-malignant disease phenotype has not been identified) are eligible for the study following discussion with and approval by the protocol principal investigator (PI) (Dr. Lauri Burroughs)
Age < 50 years
DONOR: Human leukocyte antigen (HLA)-identical related donor OR unrelated donor matched for HLA-A, B, C, DRB1 and DQB1 or mismatched for a single allele at HLA-A, B, C, or a single DQB1 antigen or allele mismatch by high resolution deoxyribonucleic acid (DNA) typing
DONOR: Bone marrow is the preferred cell source (when feasible). However, peripheral blood stem cells (PBSC) is also allowed and the PI may determine if PBSC is preferred for certain patients
The recommended total nucleated cell count (TNC) for bone marrow grafts is >= 4.0 x 10^8 TNC/kg (actual recipient weight)
The recommended CD34 cell count for PBSC grafts is >= 5 x 10^6 CD34/kg (actual recipient weight) and the recommended maximum CD34 cell count for PBSC grafts is 10 x 10^6 CD34/kg (actual recipient weight)
DONOR: HLA-matched sibling bone marrow in combination with HLA-matched sibling umbilical cord blood if the HLA-matched sibling umbilical cord blood was collected and stored. The HLA-matched sibling bone marrow and cord blood would be matched for HLA-A, B, C, DRB1 and DQB1
Exclusion Criteria:
Patients with idiopathic aplastic anemia and Fanconi anemia; patients with aplastic anemia associated with paroxysmal nocturnal hemoglobinuria (PNH) or inherited marrow failure syndromes (except Fanconi anemia) will be allowed
Impaired cardiac function as evidenced by ejection fraction < 35% (or, if unable to obtain ejection fraction, shortening fraction of < 26%) or cardiac insufficiency requiring treatment or symptomatic coronary artery disease. Patients with a shortening fraction of < 26% may be enrolled if approved by a cardiologist
Impaired pulmonary function as evidenced by carbon monoxide diffusing capability (DLCO) corrected < 50% of predicted (or, if unable to perform pulmonary function tests, then oxygen [O2] saturation < 92% on room air)
Impaired renal function as evidenced by:
Estimated creatinine clearance < 60 mL/min/1.73m^2 using either the Chronic Kidney Disease Epidemiology Collaboration (CKD EPI) equation for adult patients (>= 18 years old), or the updated Schwartz formula for pediatric patients (< 18 years old). If the estimated creatinine clearance is < 60 mL/min/1.73m^2, then renal function must be measured by 24-hour creatinine clearance, Iothalamate, Iohexol or nuclear GFR and the patient is excluded if their measured creatinine clearance is < 50 mL/min/1.73 m^2, OR
Serum creatinine > 2 x upper limit of normal, OR
Dialysis dependent
Evidence of synthetic dysfunction or severe cirrhosis requiring deferral of conditioning as recommended by a gastroenterology specialist
Active infectious disease requiring deferral of conditioning as recommended by an infectious disease specialist
Positive for HIV (human immunodeficiency virus)
Females who are pregnant or breast-feeding
Known hypersensitivity to treosulfan, fludarabine, and/or thiotepa
DONOR: Donors deemed unable to undergo marrow harvesting of PBSC mobilization and leukapheresis
DONOR: HIV-positive donors
DONOR: Donors with active infectious hepatitis
DONOR: Female donor with positive pregnancy test
DONOR: Donors are excluded if the patient has an identified antibody against a donor-specific HLA locus as specified in standard practice
DONOR: HLA-matched sibling cord blood units that have not passed donor screening for infectious disease markers as recommended by the National Marrow Donor Project (NMDP) will not be used unless a waiver is signed by the clinical attending allowing use of cord blood unit. Cord blood units are presumed to be cytomegalovirus (CMV) negative regardless of serologic testing due to passive transmission of maternal CMV antibodies
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Lauri Burroughs
Phone
206-667-2396
Email
lburroug@fredhutch.org
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Lauri Burroughs
Organizational Affiliation
Fred Hutch/University of Washington Cancer Consortium
Official's Role
Principal Investigator
Facility Information:
Facility Name
Fred Hutch/University of Washington Cancer Consortium
City
Seattle
State/Province
Washington
ZIP/Postal Code
98109
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Lauri Burroughs
Phone
206-667-2396
Email
lburroug@fredhutch.org
First Name & Middle Initial & Last Name & Degree
Lauri Burroughs
Facility Name
Medical College of Wisconsin
City
Milwaukee
State/Province
Wisconsin
ZIP/Postal Code
53226
Country
United States
Individual Site Status
Withdrawn
12. IPD Sharing Statement
Plan to Share IPD
No
Learn more about this trial
Donor Stem Cell Transplant With Treosulfan, Fludarabine, and Thiotepa in Treating Patients With Non-malignant Disorders
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