CD34+ (Malignant) Stem Cell Selection for Patients Receiving Allogenic Stem Cell Transplant

• ClinicalTrials.gov Identifier: NCT02061800
• Recruitment Status: Recruiting
• First Posted: February 13, 2014
• Last Update Posted: June 18, 2020
• Sponsor: Diane George
• Information provided by (Responsible Party): Diane George, Columbia University

Tracking Information

• First Submitted Date: February 11, 2014
• First Posted Date: February 13, 2014
• Last Update Posted Date: June 18, 2020
• Actual Study Start Date: June 3, 2013
• Estimated Primary Completion Date: December 2021 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: July 13, 2017)

Incidence of acute GVHD [ Time Frame: Up to 2 years post-transplant ]

Acute GVHD will be assessed and graded with standard NCI grading criteria.Evaluated daily while hospitalized, then weekly (1-60 days post-transplant), as clinically indicated (60-365 days post transplant), then 1 year, 1.5 years, 2 years and yearly (366+ days post-transplant)

Original Primary Outcome Measures (submitted: February 11, 2014)

• Incidence of acute GVHD [ Time Frame: Up to 2 years post-transplant ]
  Acute GVHD will be assessed and graded with standard NCI grading criteria.Evaluated daily while hospitalized, then weekly (1-60 days post-transplant), as clinically indicated (60-365 days post transplant), then 1 year, 1.5 years, 2 years and yearly (366+ days post-transplant)
• Incidence of chronic GVHD [ Time Frame: Up to 2 years post-transplant ]
  Chronic GVHD will be assessed and graded with standard NCI grading criteria. Evaluated daily while hospitalized, then weekly (1-60 days post-transplant), as clinically indicated (60-365 days post transplant), then 1 year, 1.5 years, 2 years and yearly (366+ days post-transplant)
• Severity of acute GVHD [ Time Frame: Up to 2 years post-transplant ]
  Actue GVHD will be assessed and graded with standard NCI grading criteria. Evaluated daily while hospitalized, then weekly (1-60 days post-transplant), as clinically indicated (60-365 days post transplant), then 1 year, 1.5 years, 2 years and yearly (366+ days post-transplant)
• Severity of chronic GVHD [ Time Frame: Up to 2 years post-transplant ]
  Chronic GVHD will be assessed and graded with standard NCI grading criteria. Evaluated daily while hospitalized, then weekly (1-60 days post-transplant), as clinically indicated (60-365 days post transplant), then 1 year, 1.5 years, 2 years and yearly (366+ days post-transplant).
• Incidence of primary graft failure [ Time Frame: 42 (or more) days post-transplant ]
  Primary graft rejection is defined as the presence of < 20% donor cells assessed by bone marrow or peripheral blood chimerism assays on day 42 post-transplant. Infusion of a second stem cell product on or prior to day 42 post-transplant will be considered primary graft rejection.
• Incidence of secondary graft failure [ Time Frame: 42 (or more) days post-transplant ]
  The presence of < 20% donor derived hematopoietic cells in peripheral blood or bone marrow after day 42 post-transplant in a patient with prior evidence of > 20% donor cells will be considered late graft rejection. Also, infusion of a second stem cell product beyond day 42 post initial transplant will be considered late graft rejection.

Current Secondary Outcome Measures (submitted: July 13, 2017)

• Time to neutrophil engraftment [ Time Frame: Up to 1 year post-transplant ]
  Will be assessed multiple times while hospitalized, 1-60 days post transplant, 100 days post-transplant, 180 days post-transplant, and 1-year post transplant. Neutrophil engraftment is defined as the first of three days following the neutrophil nadir with an absolute neutrophil count above 500/mm3.
• Time to immune reconstitution [ Time Frame: Up to 2 years post-transplant ]
  Immune reconstitution studies will be conducted (For T-cell, B-cell, natural killer (NK)-cell and immunoglobulins) 60 days post-transplant, 100 days post-transplant, 150 days post-transplant, 180 days post-transplant, 270 days post-transplant, 1-year post-transplant, and 2 years post transplant.
• Incidence of infection complications including bacterial, viral, fungal and atypical mycobacterial and other infections [ Time Frame: Up to 100 days post-transplant ]
  Will be assessed weekly or more as indicated until 84 or 100 days post-transplant, then as clinically indicated.
• Time to platelet engraftment [ Time Frame: Up to 1 year post-transplant ]
  Will be assessed multiple times while hospitalized, 1-60 days post transplant, 100 days post-transplant, 180 days post-transplant, and 1-year post transplant.
• Incidence of chronic GVHD [ Time Frame: Up to 2 years post-transplant ]
  Chronic GVHD will be assessed and graded with standard NCI grading criteria.
• Severity of acute GVHD [ Time Frame: Up to 2 years post-transplant ]
  Acute GVHD will be assessed and graded with standard NCI grading criteria.
• Severity of chronic GVHD [ Time Frame: Up to 2 years post-transplant ]
  Chronic GVHD will be assessed and graded with standard NCI grading criteria. Evaluated daily while hospitalized, then weekly (1-60 days post-transplant), as clinically indicated (60-365 days post transplant), then 1 year, 1.5 years, 2
• Incidence of primary graft failure [ Time Frame: 42 (or more) days post-transplant ]
  Primary graft rejection is defined as the presence of < 20% donor cells
• Incidence of secondary graft failure [ Time Frame: 42 (or more) days post-transplant ]
  The presence of < 20% donor derived hematopoietic cells in peripheral blood

Original Secondary Outcome Measures (submitted: February 11, 2014)

• Time to neutrophil engraftment [ Time Frame: Up to 1 year post-transplant ]
  Will be assessed multiple times while hospitalized, 1-60 days post transplant, 100 days post-transplant, 180 days post-transplant, and 1 year post transplant. Neutrophil engraftment is defined as the first of three days following the neutrophil nadir with an absolute neutrophil count above 500/mm3.
• Time to immune reconstitution [ Time Frame: Up to 2 years post-transplant ]
  Immune reconstitution studies will be conducted (For T-cell, B-cell, natural killer (NK)-cell and immunoglobulins) 60 days post-transplant, 100 days post-transplant, 150 days post-transplant, 180 days post-transplant, 270 days post-transplant, 1 year post-transplant, and 2 years post transplant
• Incidence of infection complications including bacterial, viral, fungal and atypical mycobacterial and other infections [ Time Frame: Up to 100 days post-transplant ]
  Will be assessed weekly or more as indicated until 84 or 100 days post-transplant, then as clinically indicated
• Time to platelet engraftment [ Time Frame: Up to 1 year post-transplant ]
  Will be assessed multiple times while hospitalized, 1-60 days post transplant, 100 days post-transplant, 180 days post-transplant, and 1 year post transplant

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: CD34+ (Malignant) Stem Cell Selection for Patients Receiving Allogenic Stem Cell Transplant
• Official Title: CD34+ Stem Cell Selection for Patients Receiving a Matched or Partially Matched Family or Unrelated Adult Donor Allogeneic Stem Cell Transplant for Malignant Disease

Brief Summary

The purpose of this study is to learn more about the effects of (classification determinant) CD34+ stem cell selection on graft versus host disease (GVHD) in children, adolescents, and young adults. CD34+ stem cells are the cells that make all the types of blood cells in the body. GVHD is a condition that results from a reaction of transplanted donor T-lymphocytes (a kind of white blood cell) against the recipient's body and organs. Study subjects will be offered treatment involving the use of the CliniMACS® Reagent System (Miltenyi Biotec), a CD34+ selection device to remove T-cells from a peripheral blood stem cell transplant in order to decrease the risk of acute and chronic GVHD.

This study involves subjects who are diagnosed with a malignant disease, that has either failed standard therapy or is unlikely to be cured with standard non-transplant therapy, who will receive a peripheral blood stem cell transplant. A malignant disease includes the following: Chronic Myeloid Leukemia (CML) in chronic phase, accelerated phase or blast crisis; Acute Myelogenous Leukemia (AML); Myelodysplastic Syndrome (MDS); Juvenile Myelomonocytic Leukemia (JMML); Acute Lymphoblastic Leukemia (ALL); or Lymphoma (Hodgkin's and Non-Hodgkin's).

• Detailed Description: Graft versus host disease (GVHD) is one of the serious complications following allogeneic stem cell transplantation. The incidence and severity of GVHD increase with the degree of HLA incompatibility between the host and donor. The most reliable way to prevent acute and chronic GVHD is to remove T cells from the graft. However, the incidence of graft failure increases with the efficiency of T cell depletion and low T cell numbers are predictive of graft failure. Immunomagnetic selection of HLA-mismatched CD34+ progenitor cells has demonstrated high levels of T cell depletion and successful engraftment in adult and pediatric patients with the malignant and nonmalignant disease.
• Study Type: Interventional
• Study Phase: Phase 1; Phase 2
• Study Design: Allocation: Non-Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Chronic Myeloid Leukemia (CML)
• Acute Myelogenous Leukemia (AML)
• Myelodysplastic Syndrome (MDS)
• Juvenile Myelomonocytic Leukemia (JMML)
• Acute Lymphoblastic Leukemia (ALL)
• Lymphoma (Hodgkin's and Non-Hodgkin's)

Intervention

• Device: CliniMACS CD34+ Reagent System
  The CliniMACS® Reagent System (Miltenyi Biotec, Germany), is a semi-automated immunomagnetic cell selection medical device that is used in vitro to select and enrich specific cell populations in a closed, sterile environment. The system is comprised of a computer controlled medical device containing a permanent magnet, a closed-system sterile tubing set containing columns coated with a ferromagnetic matrix, and a magnetic cell specific labeling reagent.
• Drug: Thiotepa
  Standard of care: Thiotepa should be diluted in normal saline (NS) (1-5 mg/ml) and infused over 2 hrs on Days -5, -4. IV fluids should be at maintenance rate (1500 ml/m2). It is recommended that total parental nutrition not being used during Thiotepa administration as amino acid infusions may interfere with Thiotepa metabolism.
  Other Name: Thioplex
• Drug: Cyclophosphamide
  Standard of care: Cyclophosphamide (Cytoxan) should be infused over one hour. The drug can be diluted in dextrose water solvent (D5W), NS, or other solutions (250cc) to a maximum concentration of 20 mg/mL.
  Other Name: Cytoxan
• Drug: Alemtuzumab
  Standard of care: Each dose of alemtuzumab is to be diluted in D5W or NS (maximum concentration: 0.3 mg/mL) for IV infusion over two hours.
  Other Name: Campath
• Drug: Tacrolimus
  Standard of care: Tacrolimus dosing will be 0.03mg/kg/24 hours as continuous IV infusion or 0.12 mg/kg/day po divided Q8-12 hr
  Other Names:

  • Prograf
  • FK506
• Drug: Melphalan
  Standard of care: Melphalan 45mg/m2 (1.5 mg/kg IV for children <1 year of age or <10 kg) diluted in 0.9% NS to a concentration of 0.1- 0.45mg/ml, given IV over 30 minutes.
  Other Name: Alkeran
• Drug: Busulfan
  Standard of care: Busulfan will be given IV in 0.9% sodium chloride or D5W to a final solution for infusion equal to 10 times the volume of diluent to Busulfex (to a concentration >0.5 mg/mL), through a central venous access device over 2 hours.
  Other Name: Busulfex
• Drug: Fludarabine
  Standard of care: Fludarabine will be given IV in 50-100 ml of D5W or 0.9% sodium chloride, over 30 minutes.
  Other Name: Fludara
• Drug: Methylprednisolone
  Standard of care: Methylprednisolone will be give IV slow infusion over 15-30 minutes.
  Other Name: Solu-Medrol

Study Arms

• Active Comparator: Full intensity with TBI
  Patients will start their pre-conditioning regimen on 8 days before scheduled transplant. Fractionated total body irradiation (TBI) will be administered twice daily on the 6th, 7th, and 8th before transplant. Patients will receive Thiotepa on the 4th and 5th day before transplant, Cyclophosphamide on the 2nd and 3rd day before transplant, and Alemtuzumab on the 1st-5th day(s) before transplant. Then the stem cell infusion will be performed (allogeneic family member or ≥ 8/10 HLA matched adult unrelated donor peripheral blood stem cell transplantation with CD34 Selection using CliniMACS CD34+ Reagent System). GVHD prophylaxis will consist of tacrolimus only. Tacrolimus administration will begin on the day after transplant, and methylprednisolone will start on day -5.
  Interventions:

  • Device: CliniMACS CD34+ Reagent System
  • Drug: Thiotepa
  • Drug: Cyclophosphamide
  • Drug: Alemtuzumab
  • Drug: Tacrolimus
  • Drug: Methylprednisolone
• Experimental: Full intensity without TBI
  Patients will start their pre-conditioning regimen 9 days before their scheduled transplant. Patients will receive busulfan twice daily on the 5th-8th day before transplant, and Melphalan on the 2nd-4th days before transplant and Alemtuzumab on the 1st-5th day before transplant. Subjects will then undergo with their stem cell infusion (allogeneic family member or ≥ 8/10 HLA matched adult unrelated donor peripheral blood stem cell transplantation with CD34 Selection using CliniMACS CD34+ Reagent System) and GVHD prophylaxis will consist of tacrolimus only. Tacrolimus administration will begin on the day after their transplant, and methylprednisolone will start on day -5.
  Interventions:

  • Device: CliniMACS CD34+ Reagent System
  • Drug: Alemtuzumab
  • Drug: Tacrolimus
  • Drug: Melphalan
  • Drug: Busulfan
  • Drug: Methylprednisolone
• Experimental: Reduced intensity
  Patients will begin tacrolimus 8 days pre-transplant, and then will receive alemtuzumab on the 3rd-7th day pre-transplant; busulfan twice daily on the 5th-8th day pre-transplant; and fludarabine on the 2nd-7th day pre-transplant. Methylprednisolone will start on day -7.The stem cell infusion will be performed (with CD34 Selection using CliniMACS CD34+ Reagent System). GVHD prophylaxis will consist of tacrolimus or sirolimus. For patients with a history of hepatic toxicity and/or high-risk for veno-occlusive disease or other liver toxicity post stem cell transplant, melphalan at 70 mg/m2 will be substituted for Busulfan, followed by fludarabine on the 2nd-7th day before transplant and alemtuzumab on the 3rd-7th day before transplant.
  Interventions:

  • Device: CliniMACS CD34+ Reagent System
  • Drug: Alemtuzumab
  • Drug: Tacrolimus
  • Drug: Busulfan
  • Drug: Fludarabine
  • Drug: Methylprednisolone

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: June 17, 2020): 15
• Original Estimated Enrollment (submitted: February 11, 2014): 25
• Estimated Study Completion Date: December 2028
• Estimated Primary Completion Date: December 2021 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria: General Eligibility (All Patients)

• Must be < 22 years of age
• Diagnosed with a malignant disease
• Must be fully informed about their illness and the investigational nature of the study protocol (including foreseeable risks and possible side effects), and must sign an informed consent
• For unrelated donor: A human leukocyte antigen (HLA) 8/10, 9/10 or 10/10 matched unrelated adult donor (MUD) will be required for study entry
• For related donor: A 5/10, 6/10, 7/10, 8/10, 9/10 or 10/10 matched (or partially matched) family donor will be required for study entry
• Adequate renal function
• Adequate liver function
• Adequate cardiac function
• Adequate pulmonary function

Exclusion Criteria:

• Patients with documented uncontrolled infection at the time of study entry are not eligible
• Females who are pregnant or breast feeding at the time of study entry are not eligible

Sex/Gender

• Sexes Eligible for Study: All

• Ages: up to 22 Years (Child, Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Jody Campbell, MPA; jc5422@cumc.columbia.edu

Contact: Desmarie Sherwood; ds3851@cumc.columbia.edu

• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT02061800
• Other Study ID Numbers: AAAK8060
• 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

IPD Sharing Statement

• Plan to Share IPD: Undecided

• Current Responsible Party: Diane George, Columbia University
• Original Responsible Party: Diane George, MD, Columbia University, Assistant Professor of Pediatrics, Department of Pediatrics Onc/BMT/Hem
• Current Study Sponsor: Diane George
• Original Study Sponsor: Diane George, MD
• Collaborators: Not Provided

Investigators

• Principal Investigator: Diane George, MD; Columbia University

• PRS Account: Columbia University
• Verification Date: June 2020