Trial document




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  DRKS00000330

Trial Description

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Title

Phase I/II Pilotstudy: Feasability, safety and efficacy of transplantation of retrovirus-transduced hematopoetic stem cells for the treatment of Wiskott-Aldrich-Syndrome

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Trial Acronym

WAS-GT

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URL of the Trial

[---]*

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Brief Summary in Lay Language

The Wiskott-Aldrich-Syndrome (WAS) is an inherited disorder of the immune system characterized by recurrent infections, bleeding tendency, eczema and patients are likely to develope malignant lymphomas (cancer of the lymph nodes). WAS is a uniformly lethal disease, the only curative treatment option consists in the transplantation of allogeneic hematopoietic stem cells. However, this approach is associated with severe side effects.
WAS is caused by mutations in the gene encoding the Wiskott-Aldrich-Syndrom-Protein, which is present in all hematopoetic cells. A defective version of this gene leads to loss/impairment of function of the white blood cells and blood platelets. Although therapy of WAS has improved substantially in the last years, most of the patients with WAS die of complications of the immune deficiency as young adults. The only long lasting therapy is the blood stem cell transplantation, which has however some severe side effects.
The aims of this protocol are to assess feasibility, safety and efficacy of a hematopoietic stem cell gene therapy approach.
Blood stem cells from WAS patients will be isolated and genetically modified using a retroviral vector which contains a correct version of the WAS gene. A mild preparatory chemotherapy consisting of Busulfan will be given to patients to enhance engraftment of genetically modified cells. The patient will receive a transfusion of the genetically modified blood stem cells. After 10 to 14 days the genetically correct cells are expected to have engrafted.

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Brief Summary in Scientific Language

The Wiskott-Aldrich-Syndrome (WAS) is a primary immunodeficiency disorder characterized by recurrent infections, thrombocytopenia, eczema and propensity to malignant lymphomas. WAS is a uniformly lethal disease, the only curative treatment option consists in the transplantation of allogeneic hematopoietic stem cells. However, this approach is associated with severe side effects.
The aims of this protocol are to assess feasibility, safety and efficacy of a hematopoietic stem cell gene therapy approach. CD 34+ cells from WAS patients will be isolated or cleaned after G-CSF mediated mobilisation and after cytokin-stimulation transduced with GALV-pseudotyped retroviral vectors. The retroviral vector encodes for a modfied version of the WASP-gene. A mild preparatory regimen of Busulfan will be given to patients to enhance engraftment of the genetically modified cells. Thereafter the modified autologous hematopoietic stem cells will be transfused.

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Organizational Data

  •   DRKS00000330
  •   2010/09/30
  •   2005/04/05
  •   yes
  •   Approved
  •   2783, Ethikkommission der Medizinischen Hochschule Hannover
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Secondary IDs

  •   DeReG-Nr: 77  (Deutsches Register für somatische Gentransferstudien)
  •   4022911 
  •   1271/01 
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Health Condition or Problem studied

  •   D82.0 -  Wiskott-Aldrich syndrome
  •   [---]* -  [---]*
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Interventions/Observational Groups

  •   transfusion of gene-corrected hematopoietic stem/progenitor cells
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Characteristics

  •   Interventional
  •   [---]*
  •   Single arm study
  •   Open (masking not used)
  •   [---]*
  •   Uncontrolled/Single arm
  •   Other
  •   Single (group)
  •   I-II
  •   [---]*
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Primary Outcome

1. Feasibility of ex vivo gene marking of autologous hematopoietic cells which contribute to short- and long-term hematopoiesis after partially myeloablative conditioning
2. Safety of retroviral gene transfer into hematopoietic stem cells, in particular with regards to the absence of replication-competent retroviral particles and analysis of insertional mutagenesis after transfusion of genetically modified stem cells
3. Efficacy of WASP reconstitution in the hematopoietic system, as demonstrated by reconstitution of immunologic effector cell function, normalization of blood paramaters and decrease of infectious complications

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Secondary Outcome

Determination of frequency and functionality of the gene therapy vector encoding WASP by molecular insertion site analysis and demonstration of genetic correction using cell biological assays in peripheral blood and bone marrow leukocytes
2. Determination of the engraftment potential and efficacy of differentiation into multiple hematopoietic cell lineages
3. Determination of persistence of molecular cell clones in diverse cell lineages of the hematopoietic system
4. Monitoring of hematopoiesis with an emphasis on the potential contribution of genetically marked and reconstituted cells to the development of myelodysplastic syndrome or malignant transformation
5. Determination of the expression level of WASP in hematopoietic cells and correction of cellular phenotype

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Countries of Recruitment

  •   Germany
  •   United States
  •   Australia
  •   Russian Federation
  •   Hungary
  •   Syrian Arab Republic
  •   Lebanon
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Locations of Recruitment

  • [---]*
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Recruitment

  •   2006/10/13
  •   Actual
  •   15
  •   Monocenter trial
  •   National
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Inclusion Criteria

  •   Male
  •   12   Months
  •   no maximum age
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Additional Inclusion Criteria

1. Classic Wiskott-Aldrich-Syndrome verified by molecular analysis of the WASP-gene. Patients with residual protein expression can be enroled, if they experienced at least one episode of life-threatening complications (severe infection or bleeding)
2. Age > 12 months
3. No signs of a malignant disease (exclusion of lymphoma by ultrasonic abdomen examination, chest x-ray, bone marrow cytological analysis)
4. informed consent or informed assent by patients or legal representative
5. Sufficient number of vital CD34+ cells (>1 x 10e5 CD34+ cells/kg bodyweight) isolated from bone marrow or mobilised apherese preparation

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Exclusion Criteria

1.WASP mutations in the context of congenital neutropenia (GBD-mutations) or congenital thrombocytopenia (XLT)
2.Positive screening result for WASP proviral sequences by PCR analysis, or evidence of replication-competent retroviruses by detection of GALV-hull protein sequences by PCR or a positive S+L- assay
3.Patients who are participating in other clinical trials with investigational drugs
4.Patients or legal representatives respectively with a medical or psychiatric condition that compromises the ability to participate in the study or to give informed consent

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Addresses

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    • Direktor der Kinderklinik und Kinderpoliklinik im Dr. von Haunerschen Kinderspital
    • Mr.  Prof. Dr. med.  Christoph  Klein 
    • Lindwurmstr. 4
    • 80337  München
    • Germany
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    • Direktor der Kinderklinik und Kinderpoliklinik im Dr. von Haunerschen Kinderspital
    • Mr.  Prof. Dr. med.  Christoph  Klein 
    • Lindwurmstraße 4
    • 80337  München
    • Germany
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    • Direktor der Kinderklinik und Kinderpoliklinik im Dr. von Haunerschen Kinderspital
    • Mr.  Prof. Dr. med.  Christoph  Klein 
    • Lindwurmstraße 4
    • 80337  München
    • Germany
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Sources of Monetary or Material Support

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    • Deutsche Forschungsgemeinschaft e.V.
    • 53175  Bonn
    • Germany
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    • Bundesministerium für Bildung und Forschung Dienstsitz Berlin
    • Friedrichstraße 130 B
    • 10117  Berlin
    • Germany
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Status

  •   Recruiting complete, follow-up continuing
  •   [---]*
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Trial Publications, Results and other Documents

  •   Boztug et al NEJM 2010
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* This entry means the parameter is not applicable or has not been set.