SCT for Dyskeratosis Congenita or SAA - Full Text View

Sponsored by:	Masonic Cancer Center, University of Minnesota
Information provided by:	Masonic Cancer Center, University of Minnesota
ClinicalTrials.gov Identifier:	NCT00455312

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 or Severe Aplastic Anemia. 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 Dyskertosis 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: ATG	Phase II Phase III

Study Type:	Interventional
Study Design:	Treatment, Non-Randomized, Open Label, Active Control, Parallel Assignment, Safety/Efficacy Study
Official Title:	Hematopoietic Stem Cell Transplant For Patients With Dyskeratosis Congenita and Severe Aplastic Anemia

Resource links provided by NLM:

Genetics Home Reference related topics: L1 syndrome

MedlinePlus related topics: Anemia Bone Marrow Transplantation Cancer Leukemia, Adult Acute Leukemia, Adult Chronic Leukemia, Childhood Radiation Therapy

Drug Information available for: Cyclophosphamide Fludarabine Fludarabine monophosphate Campath Alemtuzumab

U.S. FDA Resources

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

Primary Outcome Measures:

Demonstrates sustained engraftment after fludarabine-based preparative regimen and allogenic hematopoietic stem cell transplantation in patients with DC or SAA. [ Time Frame: 1 year ] [ Designated as safety issue: No ]

Secondary Outcome Measures:

Determine the incidence of regimen related mortality at 100 days; incidence of grade 2-4 and 3-4 acute graft versus host disease (GVHD) at 100 days; [ Time Frame: 100 days ] [ Designated as safety issue: Yes ]
incidence of chronic GVHD [ Time Frame: 6 months and 1 year; overall survival at 100 days and 1 year; ] [ Designated as safety issue: No ]
immune reconstitution [ Time Frame: at 100 days, 6 months, and 1 year; ] [ Designated as safety issue: No ]
incidence of pulmonary complications and secondary malignancies [ Time Frame: at any time point ] [ Designated as safety issue: No ]

Estimated Enrollment:	34
Study Start Date:	August 2007
Estimated Study Completion Date:	March 2013
Estimated Primary Completion Date:	December 2012 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Patients with DC: Experimental Patients with dyskeratosis congenita.	Drug: Campath 1H 10, 9, 8, 7, and 6 days before transplant subjects will be given 1 dose of campath 1H given via catheter (over 2 hours). Drug: Cyclophosphamide 7 days before the transplant, 1 dose of cyclophosphamide is given via catheter (over 2 hours). Drug: Fludarabine 6, 5, 4, 3, and 2 days before the transplant, 1 dose fludarabine is given via catheter Procedure: Total Body Irradiation 1 day before the transplant one dose of total body irradiation is given Procedure: Stem Cell Transplantation 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.
Patients with SAA: Experimental Patients with severe aplastic anemia.	Drug: Cyclophosphamide 7 days before the transplant, 1 dose of cyclophosphamide is given via catheter (over 2 hours). Drug: Fludarabine 6, 5, 4, 3, and 2 days before the transplant, 1 dose fludarabine is given via catheter Procedure: Total Body Irradiation 1 day before the transplant one dose of total body irradiation is given Procedure: Stem Cell Transplantation 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. Drug: ATG ATG (rabbit) 3 mg/kg for 3 days

Arms

Assigned Interventions

Patients with DC: Experimental

Patients with dyskeratosis congenita.

Drug: Campath 1H

10, 9, 8, 7, and 6 days before transplant subjects will be given 1 dose of campath 1H given via catheter (over 2 hours).

Drug: Cyclophosphamide

7 days before the transplant, 1 dose of cyclophosphamide is given via catheter (over 2 hours).

Drug: Fludarabine

6, 5, 4, 3, and 2 days before the transplant, 1 dose fludarabine is given via catheter

Procedure: Total Body Irradiation

1 day before the transplant one dose of total body irradiation is given

Procedure: Stem Cell Transplantation

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.

Patients with SAA: Experimental

Patients with severe aplastic anemia.

Drug: Cyclophosphamide

7 days before the transplant, 1 dose of cyclophosphamide is given via catheter (over 2 hours).

Drug: Fludarabine

6, 5, 4, 3, and 2 days before the transplant, 1 dose fludarabine is given via catheter

Procedure: Total Body Irradiation

1 day before the transplant one dose of total body irradiation is given

Procedure: Stem Cell Transplantation

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.

Drug: ATG

ATG (rabbit) 3 mg/kg for 3 days

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 d100. We will evaluate the proportion of success (P) and its 95% 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 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:	1 Month to 60 Years
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

Dyskeratosis Congenita (triad of mucocutaneous features):
1. oral leukoplakia
2. nail dystrophy
3. abnormal reticular skin hyperpigmentation
4. Or one of the triad above plus one of the following:
  - Short telomeres (under a research study)
  - Dyskerin mutation
  - TERC mutation
  - TERT mutation
0 - 60 years of age
acceptable HSC donor
Evidence of BM failure:
- Requirement for red blood cell and/or platelet transfusions,
- Requirement for G-CSF or 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
DC patients with myelodysplastic syndrome (MDS).
Patients with or without clonal cytogenetic abnormalities

Disease Characteristics for SAA (both of the following)0-60 years of age with an acceptable HSC donor and disease characteristics :

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

Exclusion Criteria:

Decompensated congestive heart failure; left ventricular ejection fraction <35%
Acute hepatitis or evidence of moderate or severe portal fibrosis or cirrhosis on biopsy
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.

Contacts and Locations

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

Contacts

Contact: Jakub Tolar, M.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.

Masonic Cancer Center, University of Minnesota

More Information

No publications provided

Responsible Party:	Masonic Cancer Center, University of Minnesota ( Jakub Tolar, M.D. )
Study ID Numbers:	0612M98727, MT2006-06
Study First Received:	March 30, 2007
Last Updated:	July 6, 2009
ClinicalTrials.gov Identifier:	NCT00455312 History of Changes
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

Study placed in the following topic categories:

Antimetabolites
Immunologic Factors
Skin Diseases
Hematologic Diseases
Aplastic Anemia
Anemia
Skin Abnormalities
Fludarabine monophosphate
Cyclophosphamide
Immunosuppressive Agents
Antilymphocyte Serum
Genetic Diseases, Inborn

Dyskeratosis Congenita
Alemtuzumab
Anemia, Aplastic
Genetic Diseases, X-Linked
Antineoplastic Agents, Alkylating
Fludarabine
Antirheumatic Agents
Bone Marrow Diseases
Congenital Abnormalities
Alkylating Agents
Skin Diseases, Genetic

Additional relevant MeSH terms:

Antimetabolites
Antimetabolites, Antineoplastic
Immunologic Factors
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Physiological Effects of Drugs
Cyclophosphamide
Dyskeratosis Congenita
Alemtuzumab
Therapeutic Uses
Genetic Diseases, X-Linked
Anemia, Aplastic
Congenital Abnormalities
Skin Diseases, Genetic

Alkylating Agents
Skin Diseases
Hematologic Diseases
Skin Abnormalities
Anemia
Fludarabine monophosphate
Immunosuppressive Agents
Pharmacologic Actions
Genetic Diseases, Inborn
Myeloablative Agonists
Fludarabine
Antineoplastic Agents, Alkylating
Bone Marrow Diseases
Antirheumatic Agents

ClinicalTrials.gov processed this record on September 10, 2009