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Stem Cell Transplant (SCT) for Dyskeratosis Congenita or SAA

Primary Purpose

Dyskeratosis Congenita, Aplastic Anemia

Status
Completed
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Campath 1H
Cyclophosphamide
Fludarabine
Total Body Irradiation
Stem Cell Transplantation
antithymocyte globulin
Methylprednisolone
Sponsored by
Masonic Cancer Center, University of Minnesota
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Dyskeratosis Congenita focused on measuring Dyskeratosis Congenita, Hematopoietic Stem Cell Transplantation, Severe Aplastic Anemia

Eligibility Criteria

undefined - 70 Years (Child, Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Patients with dyskeratosis congenita (DC) or severe aplastic anemia (SAA) 0-70 years of age with an acceptable hematopoietic stem cell (HSC) donor

    • HSC source

      • Human leukocyte antigen (HLA) identical or 1 antigen mismatched sibling or other relative eligible to donate bone marrow (BM), umbilical cord blood (UCB) or mobilized peripheral blood (PB) at cell doses that meet current institutional standards.
      • HLA identical or up to a 1 antigen mismatched unrelated donor.
      • Two units of unrelated umbilical cord blood (UCB) that are (a) up to 2 HLA antigens mismatched to the patient (b) up to 2 HLA antigens mismatched to each other, (c) minimum cell dose of ≥ 3.5 x 10^7 nucleated cells/kg and optimal cell dose ≥ 5 x 10^7 nucleated cells/kg.
      • If two units are not available: single unrelated UCB unit selected according to Minnesota Bone Marrow Transplant (BMT) program guidelines

    • Disease Characteristics for DC (both of the following):

      • Evidence of BM failure:

        • Requirement for red blood cell and/or platelet transfusions,
        • Requirement for granulocyte colony-stimulating factor (G-CSF) or granulocyte-macrophage colony-stimulating factor (GM-CSF) or erythropoietin, or
        • Refractory cytopenias defined as two out of three: platelets <40,000/microliter (uL) or transfusion dependent, Absolute neutrophil count <500/uL without hematopoietic growth factor support, Hemoglobin <9g/uL or transfusion dependent

      • Diagnosis of DC:

        • A triad of mucocutaneous features: oral leukoplakia, nail dystrophy, abnormal reticular skin hyperpigmentation.
        • Or one of the following: Short telomeres (under a research study), Dyskerin mutation, Telomerase RNA (TERC) mutation

    • Disease Characteristics for SAA (both of the following):

      • Evidence of BM failure:

        • Refractory cytopenia defined by bone marrow cellularity <25-50% (with < 30% residual hematopoietic cells)

      • Diagnosis of SAA:

        • Refractory cytopenias defined as two out of three: Platelets <20,000/uL or transfusion dependent, Absolute neutrophil count <500/uL without hematopoietic growth factor support, Absolute reticulocyte count <20,000/uL
    • Patients with early myelodysplastic features.
    • Patients with or without clonal cytogenetic abnormalities.

Patient Exclusion Criteria:

  • Patients with one or more of the following:

    • Decompensated congestive heart failure; left ventricular ejection fraction <35%
    • Acute hepatitis or evidence of moderate or severe portal fibrosis or cirrhosis on biopsy
    • Carbon Monoxide Diffusing Capacity (DLCO) <30% predicted, and oxygen requirement
    • Glomerular filtration rate (GFR) <30% predicted
    • Pregnant or lactating female
    • Active serious infection whereby patient has been on intravenous antibiotics for at least one week prior to study entry. Any patient with AIDS or HIV seropositivity. If recent mold infection e.g. Aspergillus - must have >30 days of appropriate treatment before HSC transplantation and infection must be controlled and cleared by the Infectious Disease consultant.
    • Cannot receive total body irradiation (TBI) due to prior radiation therapy
    • Diagnosis of Fanconi anemia based on diepoxybutane (DEB).
    • DC patients with advanced myelodysplastic syndrome (MDS) or acute myeloid leukemia with >30 blasts.
    • History of non hematopoietic malignancy within 2 years except resected basal cell carcinoma or treated carcinoma in situ.

Sites / Locations

  • Masonic Cancer Center, University of Minnesota

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Experimental

Arm Label

Patients with DC

Patients with SAA

Arm Description

Patients with dyskeratosis congenita (DC). Patients are treated with alemtuzumab (Campath 1H), Cyclophosphamide, Fludarabine, total body irradiation and stem cell transplantation.

Patients with severe aplastic anemia (SAA). Patients are treated with alemtuzumab (Campath 1H), Cyclophosphamide, Fludarabine, antithymocyte globulin, total body irradiation and stem cell transplantation.

Outcomes

Primary Outcome Measures

Neutrophil Engraftment
Defined as an absolute neutrophil count (ANC) >5 x 10^8/L (first of three consecutive laboratory measurements on different days) with at least 10% donor cells by day 100. Demonstrate sustained engraftment after a fludarabine based preparative regimen in patients with dyskeratosis congenita followed by hematopoietic cell transplantation.

Secondary Outcome Measures

Incidence of Regimen Related Mortality at 100 Days
all deaths without previous relapse or progression
Incidence of Chronic GVHD
Chronic Graft-Versus-Host Disease is a severe long-term complication created by infusion of donor cells into a foreign host.
Incidence of Chronic GVHD
Chronic Graft-Versus-Host Disease is a severe long-term complication created by infusion of donor cells into a foreign host.
Incidence of Late Secondary Malignancies
Defined as patients who have a secondary malignancy (cancer) occurring.
Incidence of Grade 2-4 Acute Graft Versus Host Disease (GVHD)
Acute Graft-Versus-Host Disease is a severe short-term complication created by infusion of donor cells into a foreign host.
Incidence of Grade 3-4 Acute Graft Versus Host Disease (GVHD)
Acute Graft-Versus-Host Disease is a severe short-term complication created by infusion of donor cells into a foreign host.
Overall Survival
Overall survival is defined as time from date of transplant to date of death or censored at the date of last documented contact for patients still alive.
Overall Survival
Overall survival is defined as time from date of transplant to date of death or censored at the date of last documented contact for patients still alive.
Incidence of Pulmonary Complications
Defined as patients who exhibit a pulmonary (lung) adverse event.

Full Information

First Posted
March 30, 2007
Last Updated
December 3, 2017
Sponsor
Masonic Cancer Center, University of Minnesota
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1. Study Identification

Unique Protocol Identification Number
NCT00455312
Brief Title
Stem Cell Transplant (SCT) for Dyskeratosis Congenita or SAA
Official Title
Hematopoietic Stem Cell Transplant For Patients With Dyskeratosis Congenita and Severe Aplastic Anemia
Study Type
Interventional

2. Study Status

Record Verification Date
December 2017
Overall Recruitment Status
Completed
Study Start Date
August 2007 (undefined)
Primary Completion Date
March 2015 (Actual)
Study Completion Date
June 2016 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Masonic Cancer Center, University of Minnesota

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
Transplantation with stem cells is a standard therapy in many centers around the world. Previous experience with stem cell transplantation therapy for leukemias, lymphomas, other cancers, aplastic anemia and other non-malignant diseases, has led to prolonged disease-free survival or cure for some patients. However, the high doses of pre-transplant radiation and chemotherapy drugs used, and the type of drugs used, often cause many side effects that are intolerable for some patients. Slow recovery of blood counts is a frequent complication of high dose pre-transplant regimens, resulting in a longer period of risk for bleeding and infection plus a longer time in the hospital. Recent studies have shown that using lower doses of radiation and chemotherapy (ones that do not completely kill all of the patient's bone marrow cells) before blood or bone marrow transplant, may be a better treatment for high risk patients, such as those with Dyskeratosis Congenita (DC) or Severe Aplastic Anemia(SAA). These low dose transplants may result in shorter periods of low blood counts, and blood counts that do not go as low as with traditional pre-transplant radiation and chemotherapy. Furthermore, in patients with Dyskeratosis Congenita or SAA, the stem cell transplant will replace the blood forming cells with healthy cells. It has recently been shown that healthy marrow can take and grow after transplantation which uses doses of chemotherapy and radiation that are much lower than that given to patients with leukemia. While high doses of chemotherapy and radiation may be necessary to get rid of leukemia, this may not be important to patients with Dyskeratosis Congenita or SAA. The purpose of this research is to see if this lower dose chemotherapy and radiation regimen followed by transplant is a safe and effective treatment for patients with Dyskeratosis Congenita or SAA.
Detailed Description
This is an open label, single arm, phase II clinical trial designed to evaluate the safety and efficacy of the treatment regimen. Efficacy will be measured by long-term engraftment of the transplanted cells.The primary endpoint of neutrophil engraftment is defined as an absolute neutrophil count (ANC) >5 x 108/L (first of three consecutive laboratory measurements on different days) with at least 10% donor cells by day 100. We will evaluate the proportion of success (P) and its 95% confidence interval (CI) for the entire group. The null hypothesis of 90% engraftment will be rejected if 4 or more patients fail to engraft out of 15 evaluable patients. The secondary endpoints of regimen related mortality, acute and chronic graft-versus-host disease (GVHD) and secondary malignancies will be estimated by cumulative incidence treating non-event deaths as a competing risk. Survival will be estimated by Kaplan-Meier methods. Immune reconstitution will be summarized with descriptive statistics. SAA and DC arms will be analyzed separately.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Dyskeratosis Congenita, Aplastic Anemia
Keywords
Dyskeratosis Congenita, Hematopoietic Stem Cell Transplantation, Severe Aplastic Anemia

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2, Phase 3
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
36 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Patients with DC
Arm Type
Experimental
Arm Description
Patients with dyskeratosis congenita (DC). Patients are treated with alemtuzumab (Campath 1H), Cyclophosphamide, Fludarabine, total body irradiation and stem cell transplantation.
Arm Title
Patients with SAA
Arm Type
Experimental
Arm Description
Patients with severe aplastic anemia (SAA). Patients are treated with alemtuzumab (Campath 1H), Cyclophosphamide, Fludarabine, antithymocyte globulin, total body irradiation and stem cell transplantation.
Intervention Type
Drug
Intervention Name(s)
Campath 1H
Other Intervention Name(s)
Alemtuzumab
Intervention Description
10, 9, 8, 7, and 6 days before transplant subjects will be given 1 dose of campath 1H given via catheter (0.2 mg/kg over 2 hours).
Intervention Type
Drug
Intervention Name(s)
Cyclophosphamide
Other Intervention Name(s)
Cytoxan
Intervention Description
7 days before the transplant, 1 dose of cyclophosphamide is given via catheter (50mg/kg IV over 2 hours).
Intervention Type
Drug
Intervention Name(s)
Fludarabine
Other Intervention Name(s)
Fludara
Intervention Description
6, 5, 4, 3, and 2 days before the transplant, 1 dose fludarabine is given via catheter (40 mg/kg IV over 1 hour)
Intervention Type
Procedure
Intervention Name(s)
Total Body Irradiation
Other Intervention Name(s)
Radiation therapy, therapeutic radiation
Intervention Description
1 day before the transplant one dose (200 cGy) of total body irradiation is given
Intervention Type
Procedure
Intervention Name(s)
Stem Cell Transplantation
Other Intervention Name(s)
Bone Marrow Transplant
Intervention Description
Infusion of stem cells on Day 0.
Intervention Type
Drug
Intervention Name(s)
antithymocyte globulin
Other Intervention Name(s)
Atgam, Thymoglobulin, ATG
Intervention Description
ATG (rabbit) 3 mg/kg for 3 days.
Intervention Type
Drug
Intervention Name(s)
Methylprednisolone
Intervention Description
2mg/kg IV is given before each dose of antithymocyte globulin (ATG).
Primary Outcome Measure Information:
Title
Neutrophil Engraftment
Description
Defined as an absolute neutrophil count (ANC) >5 x 10^8/L (first of three consecutive laboratory measurements on different days) with at least 10% donor cells by day 100. Demonstrate sustained engraftment after a fludarabine based preparative regimen in patients with dyskeratosis congenita followed by hematopoietic cell transplantation.
Time Frame
Day 100
Secondary Outcome Measure Information:
Title
Incidence of Regimen Related Mortality at 100 Days
Description
all deaths without previous relapse or progression
Time Frame
100 days
Title
Incidence of Chronic GVHD
Description
Chronic Graft-Versus-Host Disease is a severe long-term complication created by infusion of donor cells into a foreign host.
Time Frame
6 months
Title
Incidence of Chronic GVHD
Description
Chronic Graft-Versus-Host Disease is a severe long-term complication created by infusion of donor cells into a foreign host.
Time Frame
1 year
Title
Incidence of Late Secondary Malignancies
Description
Defined as patients who have a secondary malignancy (cancer) occurring.
Time Frame
1 Year
Title
Incidence of Grade 2-4 Acute Graft Versus Host Disease (GVHD)
Description
Acute Graft-Versus-Host Disease is a severe short-term complication created by infusion of donor cells into a foreign host.
Time Frame
Day 100
Title
Incidence of Grade 3-4 Acute Graft Versus Host Disease (GVHD)
Description
Acute Graft-Versus-Host Disease is a severe short-term complication created by infusion of donor cells into a foreign host.
Time Frame
Day 100
Title
Overall Survival
Description
Overall survival is defined as time from date of transplant to date of death or censored at the date of last documented contact for patients still alive.
Time Frame
Day 100
Title
Overall Survival
Description
Overall survival is defined as time from date of transplant to date of death or censored at the date of last documented contact for patients still alive.
Time Frame
1 Year
Title
Incidence of Pulmonary Complications
Description
Defined as patients who exhibit a pulmonary (lung) adverse event.
Time Frame
6 Months

10. Eligibility

Sex
All
Maximum Age & Unit of Time
70 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Patients with dyskeratosis congenita (DC) or severe aplastic anemia (SAA) 0-70 years of age with an acceptable hematopoietic stem cell (HSC) donor HSC source Human leukocyte antigen (HLA) identical or 1 antigen mismatched sibling or other relative eligible to donate bone marrow (BM), umbilical cord blood (UCB) or mobilized peripheral blood (PB) at cell doses that meet current institutional standards. HLA identical or up to a 1 antigen mismatched unrelated donor. Two units of unrelated umbilical cord blood (UCB) that are (a) up to 2 HLA antigens mismatched to the patient (b) up to 2 HLA antigens mismatched to each other, (c) minimum cell dose of ≥ 3.5 x 10^7 nucleated cells/kg and optimal cell dose ≥ 5 x 10^7 nucleated cells/kg. If two units are not available: single unrelated UCB unit selected according to Minnesota Bone Marrow Transplant (BMT) program guidelines Disease Characteristics for DC (both of the following): Evidence of BM failure: Requirement for red blood cell and/or platelet transfusions, Requirement for granulocyte colony-stimulating factor (G-CSF) or granulocyte-macrophage colony-stimulating factor (GM-CSF) or erythropoietin, or Refractory cytopenias defined as two out of three: platelets <40,000/microliter (uL) or transfusion dependent, Absolute neutrophil count <500/uL without hematopoietic growth factor support, Hemoglobin <9g/uL or transfusion dependent Diagnosis of DC: A triad of mucocutaneous features: oral leukoplakia, nail dystrophy, abnormal reticular skin hyperpigmentation. Or one of the following: Short telomeres (under a research study), Dyskerin mutation, Telomerase RNA (TERC) mutation Disease Characteristics for SAA (both of the following): Evidence of BM failure: Refractory cytopenia defined by bone marrow cellularity <25-50% (with < 30% residual hematopoietic cells) Diagnosis of SAA: Refractory cytopenias defined as two out of three: Platelets <20,000/uL or transfusion dependent, Absolute neutrophil count <500/uL without hematopoietic growth factor support, Absolute reticulocyte count <20,000/uL Patients with early myelodysplastic features. Patients with or without clonal cytogenetic abnormalities. Patient Exclusion Criteria: Patients with one or more of the following: Decompensated congestive heart failure; left ventricular ejection fraction <35% Acute hepatitis or evidence of moderate or severe portal fibrosis or cirrhosis on biopsy Carbon Monoxide Diffusing Capacity (DLCO) <30% predicted, and oxygen requirement Glomerular filtration rate (GFR) <30% predicted Pregnant or lactating female Active serious infection whereby patient has been on intravenous antibiotics for at least one week prior to study entry. Any patient with AIDS or HIV seropositivity. If recent mold infection e.g. Aspergillus - must have >30 days of appropriate treatment before HSC transplantation and infection must be controlled and cleared by the Infectious Disease consultant. Cannot receive total body irradiation (TBI) due to prior radiation therapy Diagnosis of Fanconi anemia based on diepoxybutane (DEB). DC patients with advanced myelodysplastic syndrome (MDS) or acute myeloid leukemia with >30 blasts. History of non hematopoietic malignancy within 2 years except resected basal cell carcinoma or treated carcinoma in situ.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Jakub Tolar, M.D., Ph.D.
Organizational Affiliation
Masonic Cancer Center, University of Minnesota
Official's Role
Principal Investigator
Facility Information:
Facility Name
Masonic Cancer Center, University of Minnesota
City
Minneapolis
State/Province
Minnesota
ZIP/Postal Code
55455
Country
United States

12. IPD Sharing Statement

Citations:
PubMed Identifier
20383216
Citation
Dietz AC, Orchard PJ, Baker KS, Giller RH, Savage SA, Alter BP, Tolar J. Disease-specific hematopoietic cell transplantation: nonmyeloablative conditioning regimen for dyskeratosis congenita. Bone Marrow Transplant. 2011 Jan;46(1):98-104. doi: 10.1038/bmt.2010.65. Epub 2010 Apr 12.
Results Reference
derived

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Stem Cell Transplant (SCT) for Dyskeratosis Congenita or SAA

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