Conditioning Regimen for Allogeneic Hematopoietic Stem-Cell Transplantation

NCT03513328 | Completed Phase 1 Results DMC FDA Drug

• 4 other identifiers: IRB201800798PEDS024OCR17838AWD05935
• Study Type: interventional
• Target: 6
• Locations: 1 country
• Sites: 1

Brief Summary

In this study, the investigators test 2 dose levels of thiotepa (5 mg/kg and 10 mg/kg) added to the backbone of targeted reduced dose IV busulfan, fludarabine and rabbit anti-thymocyte globulin (rATG) to determine the minimum effective dose required for reliable engraftment for subjects undergoing hematopoietic stem cell transplantation for non-malignant disease.

Conditions

Bone Marrow Failure Syndrome; Thalassemia; Sickle Cell Disease; Diamond Blackfan Anemia; Acquired Neutropenia in Newborn; Acquired Anemia Hemolytic; Acquired Thrombocytopenia; Hemophagocytic Lymphohistiocytoses; Wiskott-Aldrich Syndrome; Chronic Granulomatous Disease; Common Variable Immunodeficiency; X-linked Lymphoproliferative Disease; Severe Combined Immunodeficiency; Hurler Syndrome; Mannosidosis; Adrenoleukodystrophy

Keywords

human leukocyte antigen (HLA)

Outcome Measures

Primary Outcomes (1)

• Assessment of Minimum Effective Dose (MED) of Thiotepa

  Assess the MED of thiotepa in combination with reduced-dose busulfan, fludarabine and rATG required to achieve engraftment in \>90% subjects undergoing hematopoietic stem cell transplantation for non-malignant disorders.

  Day 42

Secondary Outcomes (7)

• Percentage of Subjects With Graft Rejection/Failure.

  Day 42; Day 365

• Percentage of Subjects Without Disease Recurrence Who Are Alive at 24 Months Post Transplant

  Month 24

• Percentage of Subjects Alive at 24 Months Post Transplant (OS)

  Month 24

• Evaluation of Transplant-related Mortality

  Month 12

• Number of Participants With Grade 2-4 Acute Graft-versus-host Disease (GVDH)

  Month 12

Study Arms (4)

Group A--Thiotepa single dose

EXPERIMENTAL

Fully matched 10/10 subjects with lower risk of graft failure. Subjects will undergo 10/10 HLA (human leukocyte antigen) matched bone marrow and peripheral blood transplant. Subjects receive combination of single daily dose thiotepa (5 mg/kg) added to the backbone of targeted reduced dose IV busulfan, fludarabine and rabbit anti-thymocyte globulin (rATG).

Drug: Thiotepa--single daily dose

Group A--Thiotepa escalated dose

EXPERIMENTAL

Fully matched 10/10 subjects with lower risk of graft failure. Subjects will undergo 10/10 HLA (human leukocyte antigen) matched bone marrow and peripheral blood transplant. Subjects receive combination of escalated dose of thiotepa (10 mg/kg) added to the backbone of targeted reduced dose IV busulfan, fludarabine and rabbit anti-thymocyte globulin (rATG).

Drug: Thiotepa--escalated dose

Group B--Thiotepa single dose

ACTIVE COMPARATOR

Subjects with higher risk of graft failure. Subjects will undergo transplant with \<10/10 bone marrow or peripheral blood match, or receiving cord blood transplant. Subjects receive combination of single daily dose thiotepa (5 mg/kg) added to the backbone of targeted reduced dose IV busulfan, fludarabine and rabbit anti-thymocyte globulin (rATG).

Drug: Thiotepa--single daily dose

Group B--Thiotepa escalated dose

ACTIVE COMPARATOR

Subjects with higher risk of graft failure. Subjects will undergo transplant with \<10/10 bone marrow or peripheral blood match, or receiving cord blood transplant. Subjects receive combination of escalated dose of thiotepa (10 mg/kg)added to the backbone of targeted reduced dose IV busulfan, fludarabine and rabbit anti-thymocyte globulin (rATG).

Drug: Thiotepa--escalated dose

Interventions

Thiotepa--single daily dose DRUG

Conditioning regimen for hematopoietic stem-cell transplant. Single daily IV dose of Thiotepa at 5 mg/kg.

Group A--Thiotepa single dose; Group B--Thiotepa single dose

Thiotepa--escalated dose DRUG

Twice daily IV dose of Thiotepa at 5 mg/kg, twelve hours apart, 10mg/kg total.

Group A--Thiotepa escalated dose; Group B--Thiotepa escalated dose

Eligibility Criteria

• Age: 3 Months - 39 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• Diagnoses:
• Hemoglobinopathies (e.g. thalassemia or sickle cell disease),
• Cytopenias (e.g.Diamond-Blackfan anemia, congenital or acquired neutropenia, congenital or acquired thrombocytopenia, congenital or acquired anemia, and others, regardless clonality),
• Hemophagocytic lymphohistiocytosis,
• Primary immunodeficiencies (e.g. Wiscott Aldrich Syndrome, chronic granulomatous disease, common variable immune deficiency, X-linked lymphoproliferative disease, NK+ severe combined immune deficiencies),
• Metabolic disorders (Hurler's syndrome, mannosidosis, adrenal leuko-dystrophy)
• Other non-malignant disorders for which there is published evidence that HSCT (hematopoietic stem cell transplant) is a curative therapy.
• Donor Requirements
• Related or unrelated donor who is suitable and willing to donate bone marrow or peripheral blood stem cells. HLA typing should be done by high-resolution typing at A, B, C, DrB1 and DQ loci and the donor should be at a minimum ≥8/10 match (with one antigen/allele mismatch allowed at A, B, or C-loci and other at DQ loci).
• Cord blood units must be matched at a minimum of 6/8 antigens/alleles at A, B, C and DrB1 loci. High resolution typing at all loci is required. The minimum TNC dose pre-cryopreservation must be ≥3.7 x10\^7/kg of recipient's weight, if a single cord blood unit is used, or at least 2x10\^7/kg per unit, if two cord blood units are used. The mismatches cannot be at the same loci (e.g. double A mismatch).
• Haploidentical related stem cell donor who is suitable and willing to donate peripheral blood stem cells. T-cell depletion is required if haploidentical donors are used. Pharmacologic GVHD prophylaxis will not be used for T-cell depleted transplant recipients.
• Adequate organ function defined as:
• Cardiac: ejection fraction ≥55% or shortening fraction ≥30%
• creatinine clearance ≥70 ml/min/1.73m2
• Pulse oximetry \>95% on room air or FEV1/DLCO \>60%

You may not qualify if:

• Diagnoses that do not require myeloablative transplant for cure (e.g. NK- SCID patients), unless the subject previously did not engraft with non-myeloablative or reduced intensity conditioning transplant.
• Known or suspected sensitivity to chemotherapy or radiation (e.g Fanconi's anemia, Dyskeratosis congenita, Ligase IV deficiency, etc).
• Subjects with fast-progressing neurodegenerative disorders (e.g. Krabbe disease or adrenal leukodystrophy with Loes score of ≥10)
• Cytopenias with increased blasts (\>5%)
• Presence of anti-donor HLA antibodies (positive anti-donor HLA antibody is defined as a positive cross-match test of any titer (by complement-dependent cytotoxicity or flow cytometric testing) or the presence of anti-donor HLA antibody to the high expression loci HLA-A, B, C, DRB1 with mean fluorescence intensity (MFI)\>3000 by solid phase
• Prior allogeneic stem cell transplant, except for patients with immune deficiencies who underwent previous non-myeloablative or reduced intensity transplants.
• Haploidentical donor using in vivo T-cell depletion (e.g. post-transplant cyclophosphamide).
• Uncontrolled bacterial, viral, or fungal infection at the time of enrollment. Uncontrolled is defined as currently taking medication and with progression or no clinical improvement on adequate medical treatment.
• Seropositive for HIV
• Active Hepatitis B or C determined by a detectable viral load of HBV or HCV by PCR
• Bridging fibrosis or liver cirrhosis
• Females or males of childbearing potential who are unwilling or unable to use an acceptable method to avoid pregnancy for the entire study period and for at least 1 months after the end of conditioning
• Females who are pregnant or breastfeeding
• History of any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of protocol therapy or that might affect the interpretation of the results of the study or that puts the subject at high risk for treatment complications, in the opinion of the treating physician.
• Subjects demonstrating an inability to understand the study and comply with the study and/or follow-up procedures

Sponsors & Collaborators

• University of Florida: lead
• Live Like Bella Pediatric Cancer Research: collaborator

Study Sites (1)

UF Health Shands Children's Hospital

Gainesville, Florida, 32608, United States

Location

MeSH Terms

Conditions

Bone Marrow Failure Disorders; Thalassemia; Anemia, Sickle Cell; Anemia, Diamond-Blackfan; Anemia, Hemolytic; Lymphohistiocytosis, Hemophagocytic; Wiskott-Aldrich Syndrome; Granulomatous Disease, Chronic; Common Variable Immunodeficiency; Lymphoproliferative Disorders; Severe Combined Immunodeficiency; Mucopolysaccharidosis I; Mannosidase Deficiency Diseases; Adrenoleukodystrophy

Condition Hierarchy (Ancestors)

Bone Marrow Diseases; Hematologic Diseases; Hemic and Lymphatic Diseases; Anemia, Hemolytic, Congenital; Anemia; Hemoglobinopathies; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Anemia, Hypoplastic, Congenital; Anemia, Aplastic; Red-Cell Aplasia, Pure; Congenital Bone Marrow Failure Syndromes; Histiocytosis, Non-Langerhans-Cell; Histiocytosis; Lymphatic Diseases; Blood Coagulation Disorders, Inherited; Blood Coagulation Disorders; Lymphopenia; Leukopenia; Cytopenia; Hemorrhagic Disorders; Leukocyte Disorders; Genetic Diseases, X-Linked; Primary Immunodeficiency Diseases; Immunologic Deficiency Syndromes; Immune System Diseases; Phagocyte Bactericidal Dysfunction; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Immunoproliferative Disorders; Infant, Newborn, Diseases; DNA Repair-Deficiency Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Mucopolysaccharidoses; Carbohydrate Metabolism, Inborn Errors; Metabolism, Inborn Errors; Lysosomal Storage Diseases; Mucinoses; Connective Tissue Diseases; Skin and Connective Tissue Diseases; Brain Diseases, Metabolic, Inborn; Brain Diseases, Metabolic; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Hereditary Central Nervous System Demyelinating Diseases; Leukoencephalopathies; Demyelinating Diseases; X-Linked Intellectual Disability; Intellectual Disability; Neurobehavioral Manifestations; Neurologic Manifestations; Heredodegenerative Disorders, Nervous System; Peroxisomal Disorders; Adrenal Insufficiency; Adrenal Gland Diseases; Endocrine System Diseases

Limitations and Caveats

Due to change in clinical practice, only patients with HLA matched donors were enrolled in this trial. Study was closed prematurely due to lack of enrollment.

Results Point of Contact

• Title: Biljana Horn, MD
• Organization: University of Florida

biljana.horn@ufl.edu

352-273-9121

Study Officials

• Biljana Horn, MD

  University of Florida

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: The study builds in rules for escalation of thiotepa dose based on graft failure by day 42. Patients are stratified in two groups A (lower risk of graft failure) and B (higher risk of graft failure). Patients undergoing 10/10 HLA matched bone marrow and peripheral blood transplants are assigned to Group A, and patients receiving \<10/10 matched bone marrow or peripheral blood, or receiving cord blood, even if fully matched, are assigned to Group B. If criteria for thiotepa dose escalation are met first in Group A, which has a lower risk of graft failure, thiotepa dose will be escalated for all subjects (Groups A and B). If criteria for thiotepa dose escalation are met first in Group B, dose will be escalated only in Group B and Group A will continue enrolling patients at a lower dose level.

Study Record Dates

• First Submitted: April 19, 2018
• First Posted: May 1, 2018
• Study Start: June 15, 2018
• Primary Completion: February 17, 2022
• Study Completion: February 19, 2023
• Last Updated: September 15, 2023
• Results First Posted: September 15, 2023

Record last verified: 2023-09

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)