Reduced Intensity Conditioning for Umbilical Cord Blood Transplant in Pediatric Patients With Non-Malignant Disorders

• Sponsor: Duke University (Other)
• Overall Status: Completed
• CT.gov ID: NCT00744692
• Collaborator: (none)
• Enrollment: 22
• Location: 1
• Arm: 1
• Duration (Months): 66
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

The primary objective is to determine the feasibility of attaining acceptable rates of donor cell engraftment (>25% donor chimerism at 180 days) following reduced intensity conditioning (RIC) regimens in pediatric patients < 21 years receiving cord blood transplantation for non-malignant disorders.

Condition or Disease	Intervention/Treatment	Phase
Non Malignant Disorders; Immunodeficiencies; Congenital Marrow Failures; Hemoglobinopathies; Inborn Errors of Metabolism; Sickle Cell; Thalassemia; Lysosomal Storage Disease	Biological: Unrelated Umbilical Cord Blood Transplant; Drug: Reduced Intensity Conditioning	Phase 1

Detailed Description

Myeloablative doses of chemotherapy and/or radiation therapy are employed with the primary purpose of eradicating malignant cells. Additionally, these regimens exert varying degree of immunosuppression/immunoablation that aids in reducing the likelihood of rejection by host hematopoietic cells. However, myeloablative /immunoablative regimens have also been associated with significant regimen related toxicity (RRT) and regimen related mortality (RRM) that may cause death in up to 20% of patients and significantly higher rate of severe organ dysfunction or failure. While most of these RRT occur typically in the first 100 days [ e.g. VOD (veno occlusive disease), pulmonary or intracranial hemorrhage, multiorgan failure (MOF)], there are significant long term toxicities of TBI and/or chemotherapy including growth impairment, gonadal dysfunction/failure, hypothyroidism, cataracts, neurocognitive impairment, and second malignancies.

The primary objective is to determine the feasibility of attaining acceptable rates of donor cell engraftment (>25% donor chimerism at 180 days) following reduced intensity conditioning (RIC) regimens in pediatric patients < 21 years receiving cord blood transplantation for non-malignant disorders.

The secondary objectives are:

• To describe the pace of neutrophil and platelet recovery

• To evaluate the pace of immune reconstitution.

• To determine the treatment related mortality, overall survival and disease free survival by days 100 and 180 post-transplant

• To describe incidence of acute Graft Versus Host Disease (GVHD) (II - IV) and chronic extensive GVHD

• To describe the incidence of grade 3-4 organ toxicity

• To evaluate long-term complications, such as sterility, endocrinopathy, and growth failure

• To evaluate the incidence of late graft failures at 2 years post-transplant

Study Design

• Study Type: Interventional
• Actual Enrollment: 22 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Pilot Study of Reduced Intensity Conditioning in Pediatric Patients <21 Years of Age With Non-Malignant Disorders Undergoing Umbilical Cord Blood Transplantation
• Study Start Date: Oct 1, 2008
• Actual Primary Completion Date: Dec 1, 2012
• Actual Study Completion Date: Apr 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Experimental: RIC Cord Blood Transplant Reduced Intensity Conditioning for Umbilical Cord Blood Transplant	Biological: Unrelated Umbilical Cord Blood Transplant; Reduced Intensity Conditioning for unrelated umbilical cord blood transplant; Drug: Reduced Intensity Conditioning; Other Names: Campath Hydroxyurea Fludarabine Melphalan Thiotepa

Outcome Measures

Primary Outcome Measures

1. Determine the Feasibility of Attaining Acceptable Rates of Donor Cell Engraftment (>25% Donor Cells at 180 Days) Following RIC Regimens in Children < 21 Years Receiving UCBT for Non-malignant Disorders. [180 days post transplant]

   Determine the feasibility of attaining acceptable rates of donor cell engraftment (>25% donor cells at 180 days) following reduced intensity conditioning regimens in children < 21 years receiving cord blood transplant for non-malignant disorders.

Secondary Outcome Measures

1. To Describe the Pace of Neutrophil Recovery [42 days post transplant]

   Neutrophil recovery was defined as the first day of an absolute neutrophil count (ANC) more than 500/uL for 3 consecutive days not secondary to granulocyte infusions

2. To Evaluate the Pace of Immune Reconstitution. [1 year post transplant]

   Immune reconstitution after RIC in UCBT was described. CD4 count is a standard measure of immune reconstitution and is described here. Additional data is available upon request.

3. To Determine the Overall Survival at day180 Post-transplant [180 days]

   To determine the overall survival at day180 post-transplant: determined by Kaplan Meier survival analysis

4. To Describe Incidence of Acute Graft Versus Host Disease (GVHD) (II - IV) [100 days post transplant]

   To describe incidence of acute Graft Versus Host Disease (GVHD) (II - IV) : measured by cumulative incidence analysis

5. To Describe the Incidence of Grade 3-4 Organ Toxicity [2 years post transplant]

6. To Evaluate Long-term Complications, Such as Sterility, Endocrinopathy, and Growth Failure [at least 2 years post transplant]

7. To Evaluate the Incidence of Late Graft Failures at 2 Years Post-transplant [2 years post transplant]

8. To Describe the Pace of Platelet Recovery [180 days post transplant]

   Platelet engraftment was defined as the first day of platelet counts more than 50,000/uL for 7 consecutive days without transfusions

Eligibility Criteria

Criteria

• Ages Eligible for Study: N/A to 21 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• 0-21 years of age with a diagnosis of a immunodeficiency, congenital marrow failure syndrome, inborn error of metabolism, or hereditary anemia

• Appropriately matched related or unrelated umbilical cord blood unit with a cell dose ≥ 3 x 10e7cells/kg

• Performance score (lansky or karnofsky) greater than or equal to 70

• Adequate organ function (Creatinine ≤ 2.0 mg/dl and creatinine clearance ≥ 50 ml/min/1.73 m2; Hepatic transaminases (ALT/AST) ≤ 4 x normal; Shortening fraction >26% or ejection fraction >40% or > 80% of normal value for age; Pulmonary function tests demonstrating CVC or FEV1/FVC of >60% of predicted for age.)

• Informed consent

• Not pregnant or breast feeding

• Minimum life expectancy of at least 6 months

• HIV negative

• No uncontrolled infections at the time of cytoreduction

• Disease specific inclusion criteria

Exclusion Criteria:

• Patients with hemoglobinopathies > 3 years of age

• UCB unit with a total nucleated cell count < 3 x 10e7/kg or > 2 antigen mismatching

• Available HLA-matched related living donor able to donate without previous UCB donation

• Allogeneic hematopoietic stem cell transplant within the previous 6 months

• Any active malignancy, MDS, or any history of malignancy

• Severe acquired aplastic anemia

• DLCO < 60% of normal value for age; requirement for supplemental oxygen

• Uncontrolled bacterial, viral or fungal infection (currently taking medication and progression of clinical symptoms)

• Pregnancy or nursing mother

• HIV/HTLV seropositive, Hep B surface antigen positive, or HCV RNA positive by PCR

• Any condition that precludes serial follow-up

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Duke University Medical Center Pediatric Blood and Marrow Transplant Program	Durham	North Carolina	United States	27705

Sponsors and Collaborators

• Duke University

Investigators

• Principal Investigator: Suhag Parikh, MD, Duke Pediatric Blood and Marrow Transplant

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Duke University
• ClinicalTrials.gov Identifier: NCT00744692
• Other Study ID Numbers: Pro00008753
• First Posted: Sep 1, 2008
• Last Update Posted: Aug 13, 2014
• Last Verified: Jul 1, 2014

• Keywords provided by Duke University: Immunodeficiencies; Congenital Marrow Failures; Hemoglobinopathies; Inborn Errors of Metabolism; SCIDS; Wiskott Aldrich; FEL; HLH; IPEX; LAD; Sickle Cell; Thalassemia; Omenn's Syndrome; Hurler's Syndrome; MLD; ALD; Sanfilippo; Krabbe; Hunter's syndrome; TaySachs; Diamond Blackfan Anemia; transplant; MPS; Gaucher
• Additional relevant MeSH terms: Thalassemia; Hemoglobinopathies; Metabolism, Inborn Errors; Lysosomal Storage Diseases; Immunologic Deficiency Syndromes; Fludarabine; Melphalan; Thiotepa; Hydroxyurea

Study Results

Participant Flow

Arm/Group Title	RIC Cord Blood Transplant
Arm/Group Description	Reduced Intensity Conditioning for Umbilical Cord Blood Transplant Unrelated Umbilical Cord Blood Transplant: Reduced Intensity Conditioning for unrelated umbilical cord blood transplant Reduced Intensity Conditioning
Period Title: Overall Study
STARTED	22
COMPLETED	22
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	RIC Cord Blood Transplant
Arm/Group Description	Reduced Intensity Conditioning for Umbilical Cord Blood Transplant Unrelated Umbilical Cord Blood Transplant: Reduced Intensity Conditioning for unrelated umbilical cord blood transplant Reduced Intensity Conditioning
Overall Participants	22
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	2.83
Age (Count of Participants)
<=18 years	22 100%
Between 18 and 65 years	0 0%
>=65 years	0 0%
Sex: Female, Male (Count of Participants)
Female	9 40.9%
Male	13 59.1%

Outcome Measures

1. Primary Outcome

Title	Determine the Feasibility of Attaining Acceptable Rates of Donor Cell Engraftment (>25% Donor Cells at 180 Days) Following RIC Regimens in Children < 21 Years Receiving UCBT for Non-malignant Disorders.
Description	Determine the feasibility of attaining acceptable rates of donor cell engraftment (>25% donor cells at 180 days) following reduced intensity conditioning regimens in children < 21 years receiving cord blood transplant for non-malignant disorders.
Time Frame	180 days post transplant

Outcome Measure Data

Analysis Population Description

Of the 22 patients enrolled, 18 patients were alive at 180 days, the time-point for primary end point

Arm/Group Title	RIC Cord Blood Transplant
Arm/Group Description	Reduced Intensity Conditioning for Umbilical Cord Blood Transplant Unrelated Umbilical Cord Blood Transplant: Reduced Intensity Conditioning for unrelated umbilical cord blood transplant Reduced Intensity Conditioning
Measure Participants	18
Number [% of participants]	88 400%

2. Secondary Outcome

Title	To Describe the Pace of Neutrophil Recovery
Description	Neutrophil recovery was defined as the first day of an absolute neutrophil count (ANC) more than 500/uL for 3 consecutive days not secondary to granulocyte infusions
Time Frame	42 days post transplant

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	RIC Cord Blood Transplant
Arm/Group Description	Reduced Intensity Conditioning for Umbilical Cord Blood Transplant Unrelated Umbilical Cord Blood Transplant: Reduced Intensity Conditioning for unrelated umbilical cord blood transplant Reduced Intensity Conditioning
Measure Participants	22
Median (Full Range) [days]	20

3. Secondary Outcome

Title	To Evaluate the Pace of Immune Reconstitution.
Description	Immune reconstitution after RIC in UCBT was described. CD4 count is a standard measure of immune reconstitution and is described here. Additional data is available upon request.
Time Frame	1 year post transplant

Outcome Measure Data

Analysis Population Description

Of the 22 patients at baseline, 5 patients died early before a year; and 2 additional patients had early graft failure. Thus 7 patients were not available for analysis of Immune reconstitution endpoint. CD4 count is reported here.

Arm/Group Title	RIC Cord Blood Transplant
Arm/Group Description	Reduced Intensity Conditioning for Umbilical Cord Blood Transplant Unrelated Umbilical Cord Blood Transplant: Reduced Intensity Conditioning for unrelated umbilical cord blood transplant Reduced Intensity Conditioning
Measure Participants	15
Median (Full Range) [cells/uL]	805

4. Secondary Outcome

Title	To Determine the Overall Survival at day180 Post-transplant
Description	To determine the overall survival at day180 post-transplant: determined by Kaplan Meier survival analysis
Time Frame	180 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	RIC Cord Blood Transplant
Arm/Group Description	Reduced Intensity Conditioning for Umbilical Cord Blood Transplant Unrelated Umbilical Cord Blood Transplant: Reduced Intensity Conditioning for unrelated umbilical cord blood transplant Reduced Intensity Conditioning
Measure Participants	22
Number (95% Confidence Interval) [percentage of participants]	81.8 371.8%

5. Secondary Outcome

Title	To Describe Incidence of Acute Graft Versus Host Disease (GVHD) (II - IV)
Description	To describe incidence of acute Graft Versus Host Disease (GVHD) (II - IV) : measured by cumulative incidence analysis
Time Frame	100 days post transplant

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	RIC Cord Blood Transplant
Arm/Group Description	Reduced Intensity Conditioning for Umbilical Cord Blood Transplant Unrelated Umbilical Cord Blood Transplant: Reduced Intensity Conditioning for unrelated umbilical cord blood transplant Reduced Intensity Conditioning
Measure Participants	22
Number (95% Confidence Interval) [percentage of participants]	22.7 103.2%

6. Secondary Outcome

Title	To Describe the Incidence of Grade 3-4 Organ Toxicity
Time Frame	2 years post transplant

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	RIC Cord Blood Transplant
Arm/Group Description	Reduced Intensity Conditioning for Umbilical Cord Blood Transplant Unrelated Umbilical Cord Blood Transplant: Reduced Intensity Conditioning for unrelated umbilical cord blood transplant Reduced Intensity Conditioning
Measure Participants	22
Number [participants]	0 0%

7. Secondary Outcome

Title	To Evaluate Long-term Complications, Such as Sterility, Endocrinopathy, and Growth Failure
Time Frame	at least 2 years post transplant

Outcome Measure Data

Analysis Population Description

Of the 22 patients at baseline, 5 patients died early before a year; and 2 additional patients had early graft failure. Thus 7 patients were not available for analysis of this 2 year late effects endpoint.

Arm/Group Title	RIC Cord Blood Transplant
Arm/Group Description	Reduced Intensity Conditioning for Umbilical Cord Blood Transplant Unrelated Umbilical Cord Blood Transplant: Reduced Intensity Conditioning for unrelated umbilical cord blood transplant Reduced Intensity Conditioning
Measure Participants	15
Number [percentage of patients]	0

8. Secondary Outcome

Title	To Evaluate the Incidence of Late Graft Failures at 2 Years Post-transplant
Time Frame	2 years post transplant

Outcome Measure Data

Analysis Population Description

Of the 22 patients at baseline, 5 patients died early before a year; and 2 additional patients had early graft failure. Thus 7 patients were not available for analysis of this 2 year late graft failure endpoint.

Arm/Group Title	RIC Cord Blood Transplant
Arm/Group Description	Reduced Intensity Conditioning for Umbilical Cord Blood Transplant Unrelated Umbilical Cord Blood Transplant: Reduced Intensity Conditioning for unrelated umbilical cord blood transplant Reduced Intensity Conditioning
Measure Participants	15
Number [participants]	0 0%

9. Secondary Outcome

Title	To Describe the Pace of Platelet Recovery
Description	Platelet engraftment was defined as the first day of platelet counts more than 50,000/uL for 7 consecutive days without transfusions
Time Frame	180 days post transplant

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	RIC Cord Blood Transplant
Arm/Group Description	Reduced Intensity Conditioning for Umbilical Cord Blood Transplant Unrelated Umbilical Cord Blood Transplant: Reduced Intensity Conditioning for unrelated umbilical cord blood transplant Reduced Intensity Conditioning
Measure Participants	22
Median (Full Range) [days]	48

Adverse Events

Adverse Event Reporting Description	Adverse events that were expected and non-serious were not collected in this study.
Arm/Group Title	RIC Cord Blood Transplant
Arm/Group Description	Reduced Intensity Conditioning for Umbilical Cord Blood Transplant Unrelated Umbilical Cord Blood Transplant: Reduced Intensity Conditioning for unrelated umbilical cord blood transplant Reduced Intensity Conditioning
All Cause Mortality
	RIC Cord Blood Transplant
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	RIC Cord Blood Transplant
	Affected / at Risk (%)	# Events
Total	18/22 (81.8%)
Blood and lymphatic system disorders
Auto Immune Hemolytic Anemia	2/22 (9.1%)
Hemolytic Transfusion Reaction	1/22 (4.5%)
Graft Failure Post Transplant	2/22 (9.1%)
Deep Vein Thrombosis	1/22 (4.5%)
Endocrine disorders
Hyperglycemia	1/22 (4.5%)
Gastrointestinal disorders
Abdominal Pain	1/22 (4.5%)
GI Distress	3/22 (13.6%)
Pnematosis	1/22 (4.5%)
General disorders
Multi System Organ Failure	2/22 (9.1%)
Graft Versus Host Disease	4/22 (18.2%)
Infections and infestations
Infection	12/22 (54.5%)
Sepsis	3/22 (13.6%)
Investigations
Fever	5/22 (22.7%)
Metabolism and nutrition disorders
Dehydration	2/22 (9.1%)
Nervous system disorders
VP Shunt Malfunction	1/22 (4.5%)
Seizure	1/22 (4.5%)
Posterior Reversible Encephalopathy Syndrome	1/22 (4.5%)
Renal and urinary disorders
Nephrotic Syndrome	1/22 (4.5%)
Respiratory, thoracic and mediastinal disorders
Respiratory Distress	2/22 (9.1%)
Respiratory Failure	1/22 (4.5%)
Skin and subcutaneous tissue disorders
Necrotic Ulcer (skin)	1/22 (4.5%)
Surgical and medical procedures
Central Line Removal	1/22 (4.5%)
Dental Rehabilitation	1/22 (4.5%)
Other (Not Including Serious) Adverse Events
	RIC Cord Blood Transplant
	Affected / at Risk (%)	# Events
Total	0/22 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.