SCT for Dyskeratosis Congenita or SAA

This study is currently recruiting participants. (see Contacts and Locations)
Verified March 2014 by Masonic Cancer Center, University of Minnesota
Sponsor:
Information provided by (Responsible Party):
Masonic Cancer Center, University of Minnesota
ClinicalTrials.gov Identifier:
NCT00455312
First received: March 30, 2007
Last updated: March 4, 2014
Last verified: March 2014
  Purpose

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.


Condition Intervention Phase
Dyskeratosis Congenita
Aplastic Anemia
Drug: Campath 1H
Drug: Cyclophosphamide
Drug: Fludarabine
Procedure: Total Body Irradiation
Procedure: Stem Cell Transplantation
Drug: antithymocyte globulin
Drug: Methylprednisolone
Phase 2
Phase 3

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Hematopoietic Stem Cell Transplant For Patients With Dyskeratosis Congenita and Severe Aplastic Anemia

Resource links provided by NLM:


Further study details as provided by Masonic Cancer Center, University of Minnesota:

Primary Outcome Measures:
  • Neutrophil Engraftment [ Time Frame: Day 100 ] [ Designated as safety issue: No ]
    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 HCT.


Secondary Outcome Measures:
  • Incidence of Regimen Related Mortality at 100 days [ Time Frame: 100 days ] [ Designated as safety issue: Yes ]
    all deaths without previous relapse or progression

  • Incidence of Chronic GVHD [ Time Frame: 6 months and 1 year ] [ Designated as safety issue: No ]
    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 [ Time Frame: 1 Year ] [ Designated as safety issue: Yes ]
    Defined as patients who have a secondary malignancy (cancer) occurring.

  • Incidence of grade 2-4 and 3-4 acute graft versus host disease (GVHD) [ Time Frame: Day 100 ] [ Designated as safety issue: Yes ]
    Acute Graft-Versus-Host Disease is a severe short-term complication created by infusion of donor cells into a foreign host.

  • Overall Survival [ Time Frame: Day 100 and 1 Year ] [ Designated as safety issue: No ]
    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 [ Time Frame: 6 Months ] [ Designated as safety issue: Yes ]
    Defined as patients who exhibit a pulmonary (lung) adverse event.


Estimated Enrollment: 34
Study Start Date: August 2007
Estimated Study Completion Date: November 2016
Estimated Primary Completion Date: December 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Patients with DC
Patients with dyskeratosis congenita (DC). Patients are treated with alemtuzumab (Campath 1H), Cyclophosphamide, Fludarabine, total body irradiation and stem cell transplantation.
Drug: Campath 1H
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).
Other Name: Alemtuzamab
Drug: Cyclophosphamide
7 days before the transplant, 1 dose of cyclophosphamide is given via catheter (50mg/kg IV over 2 hours).
Other Name: Cytoxan
Drug: Fludarabine
6, 5, 4, 3, and 2 days before the transplant, 1 dose fludarabine is given via catheter (40 mg/kg IV over 1 hour)
Other Name: Fludara
Procedure: Total Body Irradiation
1 day before the transplant one dose (200 cGy) of total body irradiation is given
Other Name: Radiation therapy, therapeutic radiation
Procedure: Stem Cell Transplantation
Infusion of stem cells on Day 0.
Other Name: Bone Marrow Transplant
Experimental: Patients with SAA
Patients with severe aplastic anemia (SAA). Patients are treated with alemtuzumab (Campath 1H), Cyclophosphamide, Fludarabine, antithymocyte globulin, total body irradiation and stem cell transplantation.
Drug: Cyclophosphamide
7 days before the transplant, 1 dose of cyclophosphamide is given via catheter (50mg/kg IV over 2 hours).
Other Name: Cytoxan
Drug: Fludarabine
6, 5, 4, 3, and 2 days before the transplant, 1 dose fludarabine is given via catheter (40 mg/kg IV over 1 hour)
Other Name: Fludara
Procedure: Total Body Irradiation
1 day before the transplant one dose (200 cGy) of total body irradiation is given
Other Name: Radiation therapy, therapeutic radiation
Procedure: Stem Cell Transplantation
Infusion of stem cells on Day 0.
Other Name: Bone Marrow Transplant
Drug: antithymocyte globulin
ATG (rabbit) 3 mg/kg for 3 days.
Other Names:
  • Atgam
  • Thymoglobulin
  • ATG
Drug: Methylprednisolone
2mg/kg IV is given before each dose of ATG.

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.

  Eligibility

Ages Eligible for Study:   up to 70 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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

      • 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/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, 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 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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00455312

Contacts
Contact: Jakub Tolar, M.D., Ph.D. 612-626-1926 tolar003@umn.edu
Contact: Timothy Krepski 612-273-2800 tkrepsk1@fairview.org

Locations
United States, Minnesota
Masonic Cancer Center, University of Minnesota Recruiting
Minneapolis, Minnesota, United States, 55455
Sponsors and Collaborators
Masonic Cancer Center, University of Minnesota
Investigators
Principal Investigator: Jakub Tolar, M.D., Ph.D. Masonic Cancer Center, University of Minnesota
  More Information

No publications provided by Masonic Cancer Center, University of Minnesota

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Masonic Cancer Center, University of Minnesota
ClinicalTrials.gov Identifier: NCT00455312     History of Changes
Other Study ID Numbers: MT2006-06, 0612M98727
Study First Received: March 30, 2007
Last Updated: March 4, 2014
Health Authority: United States: Institutional Review Board

Keywords provided by Masonic Cancer Center, University of Minnesota:
Dyskeratosis Congenita
Hematopoietic Stem Cell Transplantation
Severe Aplastic Anemia

Additional relevant MeSH terms:
Anemia
Anemia, Aplastic
Dyskeratosis Congenita
Hematologic Diseases
Bone Marrow Diseases
Skin Abnormalities
Congenital Abnormalities
Genetic Diseases, X-Linked
Genetic Diseases, Inborn
Skin Diseases, Genetic
Skin Diseases
Antilymphocyte Serum
Cyclophosphamide
Fludarabine monophosphate
Campath 1G
Fludarabine
Alemtuzumab
Methylprednisolone Hemisuccinate
Prednisolone
Methylprednisolone acetate
Prednisolone acetate
Methylprednisolone
Prednisolone hemisuccinate
Prednisolone phosphate
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Pharmacologic Actions
Antirheumatic Agents
Therapeutic Uses

ClinicalTrials.gov processed this record on July 28, 2014