Conditioning Regimen for Allogeneic Hematopoietic Stem-Ce... | NCT03513328

NCT03513328

ID	Type	Description
PEDS024	Other Identifier	UF Health
OCR17838	Other Identifier	Universiy of Florida
AWD05935	Other Grant/Funding Number	Live Like Bella Pediatric Cancer Research

Status Module

Name	Class
Live Like Bella Pediatric Cancer Research	OTHER

Description Module

Arms/Interventions Module

Arm Groups

Label	Type	Description	Intervention Names
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).

Interventions

Name	Type	Description	Arm Group Labels	Other Names
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

Measure	Description	Time Frame
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

Measure	Description	Time Frame
Percentage of Subjects With Graft Rejection/Failure.	Percentage of all subjects who initiated conditioning regimen and have sustained engraftment failure.	Day 42; Day 365
Percentage of Subjects Without Disease Recurrence Who Are Alive at 24 Months Post Transplant

Eligibility Module

Eligibility Criteria

Inclusion Criteria:

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%
- LFTs < 3 x ULN, Total bilirubin <3 mg/dl (unless due to non-hepatic cause (e.g. Gilbert's syndrome or hemolysis)
Lansky/Karnofsky score ≥60%
Written informed consent obtained from the subject or parental/guardian permission ± child's assent per institutional guidelines
Women of childbearing potential (WOCBP) must be using an adequate method of contraception to avoid pregnancy for at least 1 month after completion of conditioning. WOCBP include any woman who has experienced menarche and who has not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or who is not post-menopausal. Post-menopause is defined as:
- Amenorrhea that has lasted for ≥ 12 consecutive months without another cause, or
- For women with irregular menstrual periods who are taking hormone replacement therapy (HRT), a documented serum follicle-stimulating hormone (FSH) level of greater than 35 mIU/mL.
- Males with female partners of childbearing potential must agree to use physician-approved contraceptive methods (e.g., abstinence, condoms, or vasectomy) for at least one month after completion of conditioning.

Exclusion Criteria:

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

Name	Affiliation	Role
Biljana Horn, MD	University of Florida	Principal Investigator

Facility	Status	City	State	ZIP	Country	Contacts
UF Health Shands Children's Hospital		Gainesville	Florida	32608	United States

Results Section

Participant Flow Module

Arm/Group Information

ID	Title	Description
FG000	Group A--Thiotepa Single Dose	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). Thiotepa--single daily dose: Conditioning regimen for hematopoietic stem-cell transplant. Single daily IV dose of Thiotepa at 5 mg/kg.

Baseline Characteristics Module

Outcome Measures Module

Adverse Events Module

More Info Module

Type	Includes Protocol	Includes SAP	Includes ICF	Document Label	Document Date	Document Uploaded Date	Document File Name
Prot_SAP	Yes	Yes	No	Study Protocol and Statistical Analysis Plan	Jul 19, 2020

Arm/Group Information

ID	Title	Description
BG000	Group A--Thiotepa Single Dose	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). Thiotepa--single daily dose: Conditioning regimen for hematopoietic stem-cell transplant. Single daily IV dose of Thiotepa at 5 mg/kg.
BG001	Group A--Thiotepa Escalated Dose	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). Thiotepa--escalated dose: Twice daily IV dose of Thiotepa at 5 mg/kg, twelve hours apart, 10mg/kg total.
BG002	Group B--Thiotepa Single Dose	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). Thiotepa--single daily dose: Conditioning regimen for hematopoietic stem-cell transplant. Single daily IV dose of Thiotepa at 5 mg/kg.
BG003	Group B--Thiotepa Escalated Dose	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). Thiotepa--escalated dose: Twice daily IV dose of Thiotepa at 5 mg/kg, twelve hours apart, 10mg/kg total.
BG004	Total	Total of all reporting groups

Units	Counts
Participants	BG0006 BG0010 BG0020 BG0030 BG0046

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

Primary

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.

MED dose of thiotepa in group A was determined to be 5 mg/kg in combination with Fludarabine and rATG. All six patients engrafted by day 42 using this dose. No subsequent escalation was done.

Posted

Number

mg/kg

Day 42

ID	Title	Description
OG000	Group A--Thiotepa Single Dose	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). Thiotepa--single daily dose: Conditioning regimen for hematopoietic stem-cell transplant. Single daily IV dose of Thiotepa at 5 mg/kg.
OG001	Group A--Thiotepa Escalated Dose	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). Thiotepa--escalated dose: Twice daily IV dose of Thiotepa at 5 mg/kg, twelve hours apart, 10mg/kg total.
OG002	Group B--Thiotepa Single Dose	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). Thiotepa--single daily dose: Conditioning regimen for hematopoietic stem-cell transplant. Single daily IV dose of Thiotepa at 5 mg/kg.
OG003	Group B--Thiotepa Escalated Dose	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). Thiotepa--escalated dose: Twice daily IV dose of Thiotepa at 5 mg/kg, twelve hours apart, 10mg/kg total.

Units	Counts
Participants	OG0006 OG0010 OG0020 OG003

Title

Denominators

Categories

Title	Measurements
	OG0005

Secondary

Percentage of Subjects With Graft Rejection/Failure.

Percentage of all subjects who initiated conditioning regimen and have sustained engraftment failure.

Risk of rejection was determined in Group A. None of the patients rejected the graft = 0% (95% CI 0-46%) either at Day 42 or Day 365

Posted

Number

Percentage of participants

Day 42; Day 365

ID	Title	Description
OG000	Group A--Thiotepa Single Dose	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). Thiotepa--single daily dose: Conditioning regimen for hematopoietic stem-cell transplant. Single daily IV dose of Thiotepa at 5 mg/kg.
OG001	Group A--Thiotepa Escalated Dose	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). Thiotepa--escalated dose: Twice daily IV dose of Thiotepa at 5 mg/kg, twelve hours apart, 10mg/kg total.

Secondary

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

Percentage of subjects who initiated conditioning regimen and are without evidence of underlying disease (DFS).

At 24 month OS and DFS was 100% (95% CI 54-100%) in group A, the OS and DFS could not have been evaluated for group B due to lack of enrollment

Posted

Number

95% Confidence Interval

Percentage of patients

Month 24

ID	Title	Description
OG000	Group A--Thiotepa Single Dose	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). Thiotepa--single daily dose: Conditioning regimen for hematopoietic stem-cell transplant. Single daily IV dose of Thiotepa at 5 mg/kg.
OG001	Group A--Thiotepa Escalated Dose	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). Thiotepa--escalated dose: Twice daily IV dose of Thiotepa at 5 mg/kg, twelve hours apart, 10mg/kg total.

Secondary

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

Percentage of subjects who initiated conditioning regimen and are alive at 24 months post transplant (OS).

At 24 month OS and DFS was 100% (95% CI 54-100%) in group A, the OS and DFS could not have been evaluated for group B due to lack of enrollment

Posted

Number

95% Confidence Interval

Percentage of patients

Month 24

ID	Title	Description
OG000	Group A--Thiotepa Single Dose	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). Thiotepa--single daily dose: Conditioning regimen for hematopoietic stem-cell transplant. Single daily IV dose of Thiotepa at 5 mg/kg.
OG001	Group A--Thiotepa Escalated Dose	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). Thiotepa--escalated dose: Twice daily IV dose of Thiotepa at 5 mg/kg, twelve hours apart, 10mg/kg total.

Secondary

Evaluation of Transplant-related Mortality

Percentage of subjects who initiated conditioning regimen and who died due to a cause unrelated to the underlying disease.

Transplant related mortality at 12 months post transplant was 0% (95% CI 0-46%) in Group A. Transplant-related mortality could not have been evaluated for group B due to lack of enrollment

Posted

Number

95% Confidence Interval

Percentage of patients

Month 12

ID	Title	Description
OG000	Group A--Thiotepa Single Dose	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). Thiotepa--single daily dose: Conditioning regimen for hematopoietic stem-cell transplant. Single daily IV dose of Thiotepa at 5 mg/kg.
OG001	Group A--Thiotepa Escalated Dose	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). Thiotepa--escalated dose: Twice daily IV dose of Thiotepa at 5 mg/kg, twelve hours apart, 10mg/kg total.

Secondary

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

Graft-versus host disease symptoms measured using Modified Glucksberg Staging Criteria. (Scale 0-4; with 4 being most severe)

1 of 6 patients developed GVHD grade 2-4.

Posted

Number

Number of patients

Month 12

ID	Title	Description
OG000	Group A--Thiotepa Single Dose	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). Thiotepa--single daily dose: Conditioning regimen for hematopoietic stem-cell transplant. Single daily IV dose of Thiotepa at 5 mg/kg.
OG001	Group A--Thiotepa Escalated Dose	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). Thiotepa--escalated dose: Twice daily IV dose of Thiotepa at 5 mg/kg, twelve hours apart, 10mg/kg total.
OG002

Secondary

Percentage of Participants With Chronic Graft-versus-host Disease (cGVHD)

Measures the frequency of chronic graft-vs-host disease in Group A participants

cGVHD in 2 of 6 participants

Posted

Number

95% Confidence Interval

Percentage of patients

Month 24

ID	Title	Description
OG000	Group A--Thiotepa Single Dose	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). Thiotepa--single daily dose: Conditioning regimen for hematopoietic stem-cell transplant. Single daily IV dose of Thiotepa at 5 mg/kg.
OG001	Group A--Thiotepa Escalated Dose	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). Thiotepa--escalated dose: Twice daily IV dose of Thiotepa at 5 mg/kg, twelve hours apart, 10mg/kg total.
OG002

Secondary

Percentage of Participants With Transplant-related Complications

Complications gathered via CIBMTR (Center for International Blood & Marrow Transplant Research) post-transplant form was tabulated and described by treatment received.

Percentages of patient at risk for complications during first 2 years post transplant

Posted

Number

95% Confidence Interval

Percentage of patients

24 months

ID	Title	Description
OG000	Group A--Thiotepa Single Dose	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). Thiotepa--single daily dose: Conditioning regimen for hematopoietic stem-cell transplant. Single daily IV dose of Thiotepa at 5 mg/kg.
OG001	Group A--Thiotepa Escalated Dose	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). Thiotepa--escalated dose: Twice daily IV dose of Thiotepa at 5 mg/kg, twelve hours apart, 10mg/kg total.

Arm/Groups

ID	Title	Description	Deaths (At Risk)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	Group A--Thiotepa Single Dose	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). Thiotepa--single daily dose: Conditioning regimen for hematopoietic stem-cell transplant. Single daily IV dose of Thiotepa at 5 mg/kg.	6	6	6	6
EG001	Group A--Thiotepa Escalated Dose	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). Thiotepa--escalated dose: Twice daily IV dose of Thiotepa at 5 mg/kg, twelve hours apart, 10mg/kg total.	0	0	0	0
EG002	Group B--Thiotepa Single Dose	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). Thiotepa--single daily dose: Conditioning regimen for hematopoietic stem-cell transplant. Single daily IV dose of Thiotepa at 5 mg/kg.	0	0	0	0
EG003	Group B--Thiotepa Escalated Dose	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). Thiotepa--escalated dose: Twice daily IV dose of Thiotepa at 5 mg/kg, twelve hours apart, 10mg/kg total.	0	0	0	0

Other Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Mucositis	Gastrointestinal disorders	CTCAE (4.0)	Systematic Assessment	EG0003 events3 affected6 at risk EG0010 events0 affected0 at risk EG0020 events0 affected0 at risk EG0030 events0 affected0 at risk
Salmonella Bacteremia	Infections and infestations	CTCAE (4.0)	Systematic Assessment	EG0001 events1 affected6 at risk EG0010 events0 affected0 at risk EG0020 events0 affected0 at risk EG003
Coag Negative Staph Bacteremia	Infections and infestations	CTCAE (4.0)	Systematic Assessment	EG0001 events1 affected6 at risk EG0010 events0 affected0 at risk EG0020 events0 affected0 at risk EG003
Haemorrhagic Cystitis	Renal and urinary disorders	CTCAE (4.0)	Systematic Assessment	EG0001 events1 affected6 at risk EG0010 events0 affected0 at risk EG0020 events0 affected0 at risk EG003
Deep Vein Thrombosis	Vascular disorders	CTCAE (4.0)	Systematic Assessment	EG0001 events1 affected6 at risk EG0010 events0 affected0 at risk EG0020 events0 affected0 at risk EG003
Fever and joint pain	Immune system disorders	CTCAE (4.0)	Systematic Assessment	EG0001 events1 affected6 at risk EG0010 events0 affected0 at risk EG0020 events0 affected0 at risk EG003
Respiratory Distress secondary to mucositis	Respiratory, thoracic and mediastinal disorders	CTCAE (4.0)	Systematic Assessment	EG0001 events1 affected6 at risk EG0010 events0 affected0 at risk EG0020 events0 affected0 at risk EG003
Tranaminitis	Investigations	CTCAE (4.0)	Systematic Assessment	EG0001 events1 affected6 at risk EG0010 events0 affected0 at risk EG0020 events0 affected0 at risk EG003
Dehydration	Gastrointestinal disorders	CTCAE (4.0)	Systematic Assessment	EG0001 events1 affected6 at risk EG0010 events0 affected0 at risk EG0020 events0 affected0 at risk EG003

Ancestor Terms

ID	Term
D001855	Bone Marrow Diseases
D006402	Hematologic Diseases
D006425	Hemic and Lymphatic Diseases
D000745	Anemia, Hemolytic, Congenital
D000740	Anemia
D006453	Hemoglobinopathies
D030342	Genetic Diseases, Inborn
D009358	Congenital, Hereditary, and Neonatal Diseases and Abnormalities
D029502	Anemia, Hypoplastic, Congenital
D000741	Anemia, Aplastic
D012010	Red-Cell Aplasia, Pure
D000080984	Congenital Bone Marrow Failure Syndromes
D015616	Histiocytosis, Non-Langerhans-Cell
D015614	Histiocytosis
D008206	Lymphatic Diseases
D025861	Blood Coagulation Disorders, Inherited
D001778	Blood Coagulation Disorders
D008231	Lymphopenia
D007970	Leukopenia
D000095542	Cytopenia
D006474	Hemorrhagic Disorders
D007960	Leukocyte Disorders
D040181	Genetic Diseases, X-Linked
D000081207	Primary Immunodeficiency Diseases
D007153	Immunologic Deficiency Syndromes
D007154	Immune System Diseases
D010585	Phagocyte Bactericidal Dysfunction
D002908	Chronic Disease
D020969	Disease Attributes
D010335	Pathologic Processes
D013568	Pathological Conditions, Signs and Symptoms
D007160	Immunoproliferative Disorders
D007232	Infant, Newborn, Diseases
D049914	DNA Repair-Deficiency Disorders
D008659	Metabolic Diseases
D009750	Nutritional and Metabolic Diseases
D009083	Mucopolysaccharidoses
D002239	Carbohydrate Metabolism, Inborn Errors
D008661	Metabolism, Inborn Errors
D016464	Lysosomal Storage Diseases
D017520	Mucinoses
D003240	Connective Tissue Diseases
D017437	Skin and Connective Tissue Diseases
D020739	Brain Diseases, Metabolic, Inborn
D001928	Brain Diseases, Metabolic
D001927	Brain Diseases
D002493	Central Nervous System Diseases
D009422	Nervous System Diseases
D020279	Hereditary Central Nervous System Demyelinating Diseases
D056784	Leukoencephalopathies
D003711	Demyelinating Diseases
D038901	X-Linked Intellectual Disability
D008607	Intellectual Disability
D019954	Neurobehavioral Manifestations
D009461	Neurologic Manifestations
D020271	Heredodegenerative Disorders, Nervous System
D018901	Peroxisomal Disorders
D000309	Adrenal Insufficiency
D000307	Adrenal Gland Diseases
D004700	Endocrine System Diseases

ID	Term
D000080983	Bone Marrow Failure Disorders
D013789	Thalassemia
D000755	Anemia, Sickle Cell
D029503	Anemia, Diamond-Blackfan
D000743	Anemia, Hemolytic
D051359	Lymphohistiocytosis, Hemophagocytic
D014923	Wiskott-Aldrich Syndrome
D006105	Granulomatous Disease, Chronic
D017074	Common Variable Immunodeficiency
D008232	Lymphoproliferative Disorders
D016511	Severe Combined Immunodeficiency
D008059	Mucopolysaccharidosis I
D044904	Mannosidase Deficiency Diseases
D000326	Adrenoleukodystrophy