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

• ClinicalTrials.gov Identifier: NCT01962415
• Recruitment Status: Recruiting
• First Posted: October 14, 2013
• Last Update Posted: June 4, 2020
• Sponsor: Paul Szabolcs
• Information provided by (Responsible Party): Paul Szabolcs, University of Pittsburgh

Tracking Information

• First Submitted Date: October 10, 2013
• First Posted Date: October 14, 2013
• Last Update Posted Date: June 4, 2020
• Actual Study Start Date: February 4, 2014
• Estimated Primary Completion Date: November 2021 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: June 2, 2020)

• 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: 1 year 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: 1 year post-transplant ]
  Evaluation of the pace of immune reconstitution.
• Severe opportunistic infections [ Time Frame: 1 year post-transplant ]
  Evaluation of the incidence of severe opportunistic infections.
• GVHD occurrence [ Time Frame: 1 year post-transplant ]
  Description of the incidence of acute graft versus host disease (GVHD) (II-IV) and chronic extensive GVHD.

Original Primary Outcome Measures (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

Current Secondary Outcome Measures (submitted: June 2, 2020)

• 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: 1 year post-transplant ]
  Determination of the feasibility of attaining and sustaining normal enzyme levels in the target population(s).
• Neutrophil recovery [ Time Frame: 1 year post-transplant ]
  Determination of the pace of neutrophil recovery.
• Platelet recovery [ Time Frame: 1 year post-transplant ]
  Determination of the pace of platelet recovery.
• Grade 3-4 organ toxicity [ Time Frame: 1 year post-transplant ]
  The number of grade 3-4 organ adverse events.
• Long-term complications [ Time Frame: 1 year post-transplant ]
  Evaluation of the long-term complications such as sterility, endocrinopathy, and growth failure.
• Late graft failure [ Time Frame: 1 year post-transplant ]
  Evaluation of the incidence of late graft failure.

Original Secondary Outcome Measures (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 Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Reduced Intensity Conditioning for Non-Malignant Disorders Undergoing UCBT, BMT or PBSCT
• Official Title: A Phase II Study of Reduced Intensity Conditioning in Pediatric Patients and Young Adults ≤55 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: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Non-Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Primary Immunodeficiency (PID)
• Congenital Bone Marrow Failure Syndromes
• Inherited Metabolic Disorders (IMD)
• Hereditary Anemias
• Inflammatory Conditions

Intervention

• 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 *: Vander Lugt MT, Chen X, Escolar ML, Carella BA, Barnum JL, Windreich RM, Hill MJ, Poe M, Marsh RA, Stanczak H, Stenger EO, Szabolcs P. Reduced-intensity single-unit unrelated cord blood transplant with optional immune boost for nonmalignant disorders. Blood Adv. 2020 Jul 14;4(13):3041-3052. doi: 10.1182/bloodadvances.2020001940.

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: May 23, 2018): 100
• Original Estimated Enrollment (submitted: October 10, 2013): 30
• Estimated Study Completion Date: November 2022
• Estimated Primary Completion Date: November 2021 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion:

1. 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.

2. Adequate organ function as measured by:

   1. Creatinine ≤ 2.0 mg/dL and creatinine clearance ≥ 50 mL/min/1.73 m2.
   2. Hepatic transaminases (ALT/AST) ≤ 4 x upper limit of normal (ULN).
   3. Adequate cardiac function by echocardiogram or radionuclide scan (shortening fraction > 26% or ejection fraction > 40% or > 80% of normal value for age).
   4. 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.
3. Written informed consent and/or assent according to FDA guidelines.
4. Negative pregnancy test if pubertal and/or menstruating.
5. HIV negative.

6. A non-malignant disorder amenable to treatment by stem cell transplantation, including but not limited to:

   1. 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

   2. Congenital bone marrow failure syndromes including but not limited to:

      • Dyskeratosis Congenita (DC)
      • Congenital Amegakaryocytic Thrombocytopenia (CAMT)
      • Osteopetrosis

   3. Inherited Metabolic Disorders (IMD) including but not limited to:

      • Mucopolysaccharidoses

        • Hurler syndrome (MPS I)
        • Hunter syndrome (MPS II)

      • Leukodystrophies

        • Krabbe Disease, also known as globoid cell leukodystrophy
        • Metachromatic leukodystrophy (MLD)
        • X-linked adrenoleukodystrophy (ALD)
        • Hereditary diffuse leukoencephalopathy with spheroids (HDLS)

      • Other inherited metabolic disorders

        • alpha mannosidosis
        • Gaucher Disease
      • Other inheritable metabolic diseases where hematopoietic stem cell transplantation may be beneficial.

   4. 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

   5. Inflammatory Conditions

      • Crohn's Disease/Inflammatory Bowel Disease

Exclusion:

1. Allogeneic hematopoietic stem cell transplant within the previous 6 months.
2. Any active malignancy or MDS.
3. Severe acquired aplastic anemia.
4. Uncontrolled bacterial, viral or fungal infection (currently taking medication and with progression of clinical symptoms).
5. Pregnancy or nursing mother.
6. Poorly controlled pulmonary hypertension.
7. Any condition that precludes serial follow-up.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 2 Months to 55 Years (Child, Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Paul Szabolcs, MD; 412-692-5427; paul.szabolcs@chp.edu

Contact: Shawna McIntyre, RN; 412-692-5552; mcintyresm@upmc.edu

• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT01962415
• Other Study ID Numbers: 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: Paul Szabolcs
• Collaborators: Not Provided

Investigators

• Principal Investigator: Paul Szabolcs, MD; University of Pittsburgh

• PRS Account: University of Pittsburgh
• Verification Date: June 2020