Reduced Intensity Conditioning for Non-Malignant Disorders Undergoing UCBT, BMT or PBSCT (HSCT+RIC)

Tracking Information
First Submitted Date ICMJE	October 10, 2013
First Posted Date ICMJE	October 14, 2013
Last Update Posted Date	May 25, 2018
Actual Study Start Date ICMJE	February 4, 2014
Estimated Primary Completion Date	November 2019 (Final data collection date for primary outcome measure)
Current Primary Outcome Measures ICMJE; (submitted: October 25, 2017)	Post-transplant treatment-related mortality (TRM) [ Time Frame: 1 year post-transplant ]The number of deaths related to the research intervention at day 100, 6 months, and 1 year post-transplant.; Neurodevelopmental milestones [ Time Frame: 2 years post-transplant ]Evaluation of the pace of attaining neurodevelopmental milestones after reduced-intensity conditioning as compared to myeloablative conditioning historical controls from the target population(s).; Immune Reconstitution [ Time Frame: 2 years post-transplant ]Evaluation of the pace of immune reconstitution.; Severe opportunistic infections [ Time Frame: 2 years post-transplant ]Evaluation of the incidence of severe opportunistic infections.; GVHD occurrence [ Time Frame: 2 years post-transplant ]Description of the incidence of acute graft versus host disease (GVHD) (II-IV) and chronic extensive GVHD.
Original Primary Outcome Measures ICMJE; (submitted: October 10, 2013)	Post-transplant treatment-related mortality (TRM) [ Time Frame: 1 year post-transplant ]Assessment of post-transplant treatment-related mortality at day 100, day 180, and 1 year; Neurodevelopmental milestones [ Time Frame: 2 years post-transplant ]Evaluation of the pace of attaining neurodevelopmental milestones after reduced-intensity conditioning as compared to myeloablative conditioning historical controls from the target population; Immune Reconstitution [ Time Frame: 2 years post-transplant ]Evaluation of the pace of immune reconstitution; Severe opportunistic infections [ Time Frame: 2 years post-transplant ]Evaluation of the incidence of severe opportunistic infections; GVHD occurrence [ Time Frame: 2 years post-transplant ]Description of the incidence of acute GVHD (II-IV) and chronic extensive GVHD
Change History	Complete list of historical versions of study NCT01962415 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures ICMJE; (submitted: June 2, 2017)	Donor cell engraftment [ Time Frame: 6 months post-transplant ]Determination of the feasibility of attaining robust donor cell engraftment (>50% donor chimerism at 6 months) following reduced-intensity conditioning (RIC) regimens prior to HSCT in the target population(s).; Normal enzyme level [ Time Frame: 2 years post-transplant ]Determination of the feasibility of attaining and sustaining normal enzyme levels in the target population(s).; Neutrophil recovery [ Time Frame: 2 years post-transplant ]Determination of the pace of neutrophil recovery.; Platelet recovery [ Time Frame: 2 years post-transplant ]Determination of the pace of platelet recovery.; Grade 3-4 organ toxicity [ Time Frame: 2 years post-transplant ]The number of grade 3-4 organ adverse events.; Long-term complications [ Time Frame: 2 years post-transplant ]Evaluation of the long-term complications such as sterility, endocrinopathy, and growth failure.; Late graft failure [ Time Frame: 2 years post-transplant ]Evaluation of the incidence of late graft failure.
Original Secondary Outcome Measures ICMJE; (submitted: October 10, 2013)	Donor cell engraftment [ Time Frame: 180 days post-transplant ]Determination of the feasibility of attaining robust donor cell engraftment (>50% donor chimerism at 180 days) following reduced-intensity conditioning (RIC) regimens prior to UCBT in the target population; Normal enzyme level [ Time Frame: 2 years post-transplant ]Determination of the feasibility of attaining and sustaining normal enzyme levels in the target population; Neutrophil recovery [ Time Frame: 2 years post-transplant ]Determination of the pace of neutrophil recovery; Platelet recovery [ Time Frame: 2 years post-transplant ]Determination of the pace of platelet recovery; Grade 3-4 organ toxicity [ Time Frame: 2 years post-transplant ]Description of the incidence of grade 3-4 organ toxicity; Long-term complications [ Time Frame: 2 years post-transplant ]Evaluation of the long-term complications such as sterility, endocrinopathy, and growth failure; Late graft failure [ Time Frame: 2 years post-transplant ]Evaluation of the incidence of late graft failure
Current Other Outcome Measures ICMJE	Not Provided
Original Other Outcome Measures ICMJE	Not Provided
Descriptive Information
Brief Title ICMJE	Reduced Intensity Conditioning for Non-Malignant Disorders Undergoing UCBT, BMT or PBSCT
Official Title ICMJE	A Phase II Study of Reduced Intensity Conditioning in Pediatric Patients and Young Adults ≤40 Years of Age With Non-Malignant Disorders Undergoing Umbilical Cord Blood, Bone Marrow, or Peripheral Blood Stem Cell Transplantation
Brief Summary	The objective of this study is to evaluate the efficacy of using a reduced-intensity condition (RIC) regimen with umbilical cord blood transplant (UCBT), double cord UCBT, matched unrelated donor (MUD) bone marrow transplant (BMT) or peripheral blood stem cell transplant (PBSCT) in patients with non-malignant disorders that are amenable to treatment with hematopoietic stem cell transplant (HSCT). After transplant, subjects will be followed for late effects and for ongoing graft success.
Detailed Description	For some non-malignant diseases (NMD; i.e., thalassemia, sickle cell disease, most immune deficiencies) a hematopoietic stem cell transplant may be curative by healthy donor stem cell engraftment alone. HSCT in patients with NMD differs from that in malignant disorders for two important reasons: 1) these patients are typically naïve to chemotherapy and immunosuppression. This may potentially lead to difficulties with engraftment. And 2) RIC with subsequent bone marrow chimerism may be beneficial even in mixed chimerism and result in decreased transplant-related mortality (TRM). Nevertheless, any previous organ damage, as a result of the underlying disease, may remain present after the HSCT. For other diseases (metabolic disorders, some immunodeficiencies, etc.), a transplant is not curative. For these diseases, the main intent of the transplant is to slow down, or stop, the progress of the disease. In select few cases/diseases, the presence of healthy bone marrow derived cells may even prevent progression and prevent neurological decline. In this research study, instead of using the standard myeloablative conditioning, the study doctor is using RIC, in which significantly lower doses of chemotherapy will be used. The lower doses may not eradicate every stem cell in the patient's bone marrow, however, in the presented combination, the intention is to eliminate already formed immune cells and provide maximum growth advantage to healthy donor stem cells. This paves the way to successful engraftment of donor stem cells. Engrafting donor stem cells can outcompete, and donor lymphocytes could suppress, the patients' surviving stem cells. With RIC, the side effects on the brain, heart, lung, liver, and other organ functions are less severe and late toxic effects should also be reduced. The purpose of this study is to collect data from the patients undergoing reduced-intensity conditioning before HSCT, and compare it to the standard myeloablative conditioning. It is expected there will be therapeutic benefits, paired with better survival rate, less organ toxicity and improved quality of life, following the RIC compared to the myeloablative regimen.
Study Type ICMJE	Interventional
Study Phase	Phase 2
Study Design ICMJE	Allocation: Non-Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
Condition ICMJE	Primary Immunodeficiency (PID); Congenital Bone Marrow Failure Syndromes; Inherited Metabolic Disorders (IMD); Hereditary Anemias; Inflammatory Conditions
Intervention ICMJE	Drug: Hydroxyurea Oral administration at 30 mg/kg/day. Other Names: hydroxycarbamide Hydrea Droxia; Drug: Alemtuzumab Intravenous (IV) administration. The first dose for each arm will be a test dose (0.2 mg/kg max 5 mg). The treatment doses of alemtuzumab will be based on the patients' assigned stratum as determined by their age, lymphocyte count and presence of infection. Stratum 1: 1 mg/kg (max dose of 30 mg); Stratum 2: 0.5 mg/kg (max dose of 30 mg); Stratum 3: No treatment dose, test dose only. Other Name: Campath; Drug: Fludarabine IV administration at 30 mg/m2/day or 1 mg/kg/dose, whichever is lower. Other Name: Fludara; Drug: Melphalan IV administration at 70 mg/m2/dose. Other Names: Melphalan hydrochloride Alkeran; Drug: Thiotepa IV administration at 200 mg/m2/dose
Study Arms	Experimental: UCBT:transfusion dependent anemias or increased rejection risk Day -21 to -19: Alemtuzumab + Hydroxyurea; Day -18 to -10: Hydroxyurea; Day -9 to -5: Fludarabine + Hydroxyurea; Day -4 to -3: Melphalan; Day -2: Thiotepa; Day -1: Rest; Day 0: Transplant Interventions: Drug: Hydroxyurea Drug: Alemtuzumab Drug: Fludarabine Drug: Melphalan Drug: Thiotepa; Experimental: BMT, PBSCT and not transfusion dependent UCBT Start of conditioning to Day -15: Hydroxyurea; Day -14 to -13: Alemtuzumab + Hydroxyurea; Day -12 to -10: Hydroxyurea; Day -9 to -5: Fludarabine + Hydroxyurea; Day -4 to -3: Melphalan; Day -2: Thiotepa; Day -1: Rest; Day 0: Transplant Interventions: Drug: Hydroxyurea Drug: Alemtuzumab Drug: Fludarabine Drug: Melphalan Drug: Thiotepa
Publications *	Not Provided
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
Recruitment Information
Recruitment Status ICMJE	Recruiting
Estimated Enrollment ICMJE; (submitted: May 23, 2018)	100
Original Estimated Enrollment ICMJE; (submitted: October 10, 2013)	30
Estimated Study Completion Date	November 2020
Estimated Primary Completion Date	November 2019 (Final data collection date for primary outcome measure)
Eligibility Criteria ICMJE	Inclusion: A 4/6, 5/6 or 6/6 HLA matched related or unrelated UCB unit available that will deliver a pre-cryopreservation total nucleated cell dose of ≥ 3 x 10e7 cells/kg, or double unit grafts, each cord blood unit delivering at least 2 x 10e7 cells/kg OR an 8 of 8 or 7 of 8 HLA allele level matched unrelated donor bone marrow or peripheral blood progenitor graft.; Adequate organ function as measured by: Creatinine ≤ 2.0 mg/dL and creatinine clearance ≥ 50 mL/min/1.73 m2. Hepatic transaminases (ALT/AST) ≤ 4 x upper limit of normal (ULN). Adequate cardiac function by echocardiogram or radionuclide scan (shortening fraction > 26% or ejection fraction > 40% or > 80% of normal value for age). Pulmonary evaluation testing demonstrating CVC or FEV1/FVC of ≥ 50% of predicted for age and/or resting pulse oximeter ≥ 92% on room air or clearance by the pediatric or adult pulmonologist. For adult patients DLCO (corrected for hemoglobin) should be ≥ 50% of predicted if the DLCO can be obtained.; Written informed consent and/or assent according to FDA guidelines.; Negative pregnancy test if pubertal and/or menstruating.; HIV negative.; A non-malignant disorder amenable to treatment by stem cell transplantation, including but not limited to: Primary Immunodeficiency syndromes including but not limited to: Severe Combined Immune Deficiency (SCID) with NK cell activity Omenn Syndrome Bare Lymphocyte Syndrome (BLS) Combined Immune Deficiency (CID) syndromes Combined Variable Immune Deficiency (CVID) syndrome Wiskott-Aldrich Syndrome Leukocyte adhesion deficiency Chronic granulomatous disease (CGD) X-linked Hyper IgM (XHIM) syndrome IPEX syndrome Chediak - Higashi Syndrome Autoimmune Lymphoproliferative Syndrome (ALPS) Hemophagocytic Lymphohistiocytosis (HLH) syndromes Lymphocyte Signaling defects Other primary immune defects where hematopoietic stem cell transplantation may be beneficial Congenital bone marrow failure syndromes including but not limited to: Dyskeratosis Congenita (DC) Congenital Amegakaryocytic Thrombocytopenia (CAMT) Osteopetrosis Inherited Metabolic Disorders (IMD) including but not limited to: Mucopolysaccharidoses Hurler syndrome (MPS I) Hunter syndrome (MPS II) Sanfilippo syndrome (MPS II) Leukodystrophies Krabbe Disease, also known as globoid cell leukodystrophy Metachromatic leukodystrophy (MLD) X-linked adrenoleukodystrophy (ALD) Other inherited metabolic disorders alpha mannosidosis Gaucher Disease Other inheritable metabolic diseases where hematopoietic stem cell transplantation may be beneficial. Hereditary anemias Thalassemia major Sickle cell disease (SCD) - patients with sickle disease must have one or more of the following: Overt or silent stroke Pain crises ≥ 2 episodes per year for past year One or more episodes of acute chest syndrome Osteonecrosis involving ≥ 1 joints Priapism Diamond Blackfan Anemia (DBA) Other congenital transfusion dependent anemias Inflammatory Conditions Crohn's Disease/Inflammatory Bowel Disease Exclusion: Allogeneic hematopoietic stem cell transplant within the previous 6 months.; Any active malignancy or MDS.; Severe acquired aplastic anemia.; Uncontrolled bacterial, viral or fungal infection (currently taking medication and with progression of clinical symptoms).; Pregnancy or nursing mother.; Poorly controlled pulmonary hypertension.; Any condition that precludes serial follow-up.
Sex/Gender	Sexes Eligible for Study: All
Ages	2 Months to 40 Years (Child, Adult)
Accepts Healthy Volunteers	No
Contacts ICMJE	Contact: Paul Szabolcs, MD 412-692-5427 paul.szabolcs@chp.edu Contact: Jason Rowan, RN 412-692-6195 jason.rowan@chp.edu
Listed Location Countries ICMJE	United States
Removed Location Countries
Administrative Information
NCT Number ICMJE	NCT01962415
Other Study ID Numbers ICMJE	PRO13100018
Has Data Monitoring Committee	Yes
U.S. FDA-regulated Product	Studies a U.S. FDA-regulated Drug Product: Yes Studies a U.S. FDA-regulated Device Product: No Product Manufactured in and Exported from the U.S.: No
IPD Sharing Statement	Plan to Share IPD: No
Responsible Party	Paul Szabolcs, University of Pittsburgh
Study Sponsor ICMJE	Paul Szabolcs
Collaborators ICMJE	Not Provided
Investigators ICMJE	Principal Investigator: Paul Szabolcs, MD University of Pittsburgh
PRS Account	University of Pittsburgh
Verification Date	May 2018
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP