MASCI: Allogeneic SCT Of Pts With SCID And Other Primary Immunodeficiency Disorders

Sponsor
Baylor College of Medicine (Other)
Overall Status
Terminated
CT.gov ID
NCT00579137
Collaborator
Center for Cell and Gene Therapy, Baylor College of Medicine (Other)
3
Enrollment
1
Location
1
Arm
24
Duration (Months)
0.1
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This study is to discover whether children with severe combined immunodeficiency disease (SCID) or other primary immunodeficiency disorder (PID) for which no satisfactory treatment other than stem cell transplantation (SCT) exists can be safely and effectively transplanted from HLA mismatched (up to one haplotype) related donors or unrelated matched or mismatched (up to one antigen) donors, when leukocytolytic monoclonal antibodies (MAb) and Fludarabine are the sole conditioning agents. Three monoclonal antibodies will be used in combination. Two of them are rat IgG1 (immunoglobulin G1) antibodies directed against two contiguous epitopes on the CD45 (common leucocyte) antigen. They have been safely administered as part of the conditioning regimen for 12 patients receiving allografts (HLA matched and mismatched) at this center. They produce a transient depletion of >90% circulating leucocytes. The third MAb is Campath 1H, a humanized rat anti-CD52 MAb. Campath 1H, Alemtuzumab, has been licensed to treat B-cell chronic lymphocytic leukemia (B-CLL) and more recently has been safely given at this and other centers as part of a sub-ablative conditioning regimen to patients with malignant disease. Because these MAb produce both profound immunosuppression and significant, though transient, myelodestruction we believe they may be useful as the sole conditioning regimen in patients with SCID, in whom the use of conventional chemotherapeutic agents for conditioning may produce or aggravate unacceptable and even lethal short term toxicity. We anticipate MAb mediated subablative conditioning will permit engraftment in a high percentage of these patients with little or no immediate or long term toxicity. Campath IH persists in vivo for several days after administration and so will be present over the transplant period to deplete donor T cells as partial GvHD prophylaxis. Additional Graft versus Host Disease (GvHD) prophylaxis may be provided by administration of FK506.

Condition or DiseaseIntervention/TreatmentPhase
  • Biological: Campath -1H
  • Drug: Fludarabine
  • Biological: Anti-CD45
  • Procedure: Stem cell infusion
Phase 1/Phase 2

Detailed Description

Donor Stem Cell Processing for Mismatched Donors: Harvested peripheral blood stem cells will be enriched for CD34 cells using the CliniMACS CD34 Reagent system, according to Center for Cell and Gene Therapy (CAGT) SOPs.

Stem Cell Transplant Conditioning

Campath-1H will be given as 3 daily intravenous infusions and will be followed by Anti-CD45 which will be given as four daily intravenous infusions that will be completed two days prior to stem cell infusion. Diphenydramine will be administered i.v. q4h during the period of the course of the Campath and Anti-CD45 infusions.

Day

8 Campath 1H as per CAGT SOP Fludarabine 10 kg or less: 1 mg/kg; > 10 kg: 30 mg/m2

7 Campath 1H as per CAGT SOP Fludarabine 10 kg or less: 1 mg/kg; > 10 kg: 30 mg/m2

6 Campath 1H as per CAGT SOP Fludarabine 10 kg or less: 1 mg/kg; > 10 kg: 30 mg/m2

5 YTH 24/54 400ug/kg over 6 hr Fludarabine 10 kg or less: 1 mg/kg; > 10 kg: 30 mg/m2

4 YTH 24/54 400ug/kg over 6 hr Fludarabine 10 kg or less: 1 mg/kg; > 10 kg: 30 mg/m2

3 YTH 24/54 400ug/kg over 6 hr

2 YTH 24/54 400ug/kg over 6 hr

1 rest

0 Stem Cell Infusion

Campath 1H Infusion- Campath dose is weight based: for patients less than 15 killograms (kg) administer Campath 3 mg; for patients >15 kg to 30 kg administer Campath 5 mg; for patients > 30 kg administer Campath 10 mg. Campath will be dosed and administered as per CAGT SOP.

Anti-CD45- Infusion Anti-CD45 infusion will be administered according to CAGT SOPs. 3 ml of heparinized blood will be drawn 48 hr post Anti-CD45 to evaluate for free Anti-CD45 levels in the plasma. This estimation will be used to determine whether treatment with irradiated leukocytes is required before the bone marrow is infused.

GVHD Prophylaxis- GVHD prophylaxis will be achieved through positive selection for CD34 resulting in > 3 log T cell depletion. Previous reports have indicated that there is a low frequency of severe (Grade II/IV) GVHD after haploidentical transplants if recipients receive stem cell populations containing <5 x 10 CD3 positive T cells. We hope to achieve such levels with our CD34 enrichment protocol. However, pharmacologic prophylaxis will be added if the CD34 selected product contains more than 5 x 10 CD3+ve T cells/kg recipient weight. In addition, Campath 1H persists in the recipient circulation through the immediate transplant period and will contribute anti-GVHD activity, in vivo. Patients who develop acute or chronic GVHD will be managed according to CAGT SOPs.

Study Design

Study Type:
Interventional
Actual Enrollment :
3 participants
Allocation:
N/A
Intervention Model:
Single Group Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
CD45 and Alemtuzumab Monoclonal Antibody Conditioning Regimen For Allogeneic Donor Stem Cell Transplantation Of Patients With Severe Combined Immunodeficiency Disease (SCID) And Other Primary Immunodeficiency Disorders
Study Start Date :
Oct 1, 2007
Actual Primary Completion Date :
Oct 1, 2009
Actual Study Completion Date :
Oct 1, 2009

Arms and Interventions

ArmIntervention/Treatment
Experimental: Participants With SCID or Primary Immunodeficiency Disorder

all patient will receive an allogeneic transplant with the following conditioning regimen Campath -1H, Fludarabine, Anti-CD45

Biological: Campath -1H
Given intravenous on Days -8,-7, and -6 Campath dose is weight based: for patients less than 15 kg the dose is 3 mg; for patients >15 kg to 30 kg the dose 5 mg; for patients > 30 kg the dose is 10 mg
Other Names:
  • Alemtuzumab
  • Drug: Fludarabine
    Given intravenous on Days -8,-7,-6,-5, and -4 Dose is 30 mg/m2
    Other Names:
  • Fludara
  • Biological: Anti-CD45
    Given intravenous over 6 hours on Days -5,-4,-3, and -2 Dose is 400 microgram/kg

    Procedure: Stem cell infusion
    stem cells are infused on day 0

    Outcome Measures

    Primary Outcome Measures

    1. Number of Patients With Donor Engraftment [100 Days]

    Secondary Outcome Measures

    1. Patients Alive at 1 Year [1 Year]

    2. Number of Patients With Grade III or IV Toxicity [100 days]

    3. Number of Patients With Grade III to IV Acute GVHD [100 days]

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    N/A and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:
    • Patients with a diagnosis of: Severe combined immunodeficiency disease

    This includes patients whose SCID is characterized by gene specific mutations as well as patients with clinically severe combined immunodeficiency without a defined genetic cause in which the diagnosis will be determined by a combination of clinical course with lymphocyte quantification and function assays.

    OR

    Severe primary immunodeficiency disorder, including undefined T cell deficiency disorder, Wiskott-Aldrich syndrome, and other severe immunodeficiencies for which satisfactory conventional therapy does not exist.

    • Availability of an HLA mismatched (up to one haplotype) family member or an HLA matched or mismatched (up to one antigen) unrelated donor.

    • Creatinine < 2.5 x normal for age.

    • Life expectancy greater than 6 weeks

    • Lansky/Karnofsky greater than or equal to 70%

    Exclusion Criteria:
    • Patients with an HLA matched related donor

    • Patients with symptomatic cardiac disease, or evidence of significant cardiac disease by echocardiogram (i.e., shortening fraction less than 25%)

    • Patients with known allergy to rat serum products

    • Patients with a severe infection that on evaluation by the Principal Investigator precludes ablative chemotherapy or successful transplantation

    • HIV positive

    • Pregnant

    Contacts and Locations

    Locations

    SiteCityStateCountryPostal Code
    1Texas Children's HospitalHoustonTexasUnited States77030

    Sponsors and Collaborators

    • Baylor College of Medicine
    • Center for Cell and Gene Therapy, Baylor College of Medicine

    Investigators

    • Principal Investigator: Robert Krance, MD, Baylor College of Medicine
    • Study Chair: Malcolm Brenner, MD, Baylor College of Medicine

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    Robert Krance, Professor Pediatrics Hematology Oncology Center for Cell and Gene Therapy, Baylor College of Medicine
    ClinicalTrials.gov Identifier:
    NCT00579137
    Other Study ID Numbers:
    • 21123-MASCI
    • NCT00609258
    First Posted:
    Dec 21, 2007
    Last Update Posted:
    Jul 2, 2013
    Last Verified:
    Jun 1, 2013

    Study Results

    Participant Flow

    Recruitment Details
    Pre-assignment Detail
    Arm/Group TitleParticipants With SCID or Primary Immunodeficiency Disorder
    Arm/Group DescriptionParticipants received an allogeneic stem cell transplant with the following conditioning: Day 8 Campath 1H as per CAGT SOP, Fludarabine 10 kg or less: 1 mg/kg; > 10 kg: 30 mg/m2 D7 Campath 1H as per CAGT SOP, Fludarabine 10 kg or less: 1 mg/kg; > 10 kg: 30 mg/m2 D6 Campath 1H as per CAGT SOP, Fludarabine 10 kg or less: 1 mg/kg; > 10 kg: 30 mg/m2 D5 Anti-CD45 MAb 400ug/kg over 6 hr, Fludarabine 10 kg or less: 1 mg/kg; > 10 kg: 30 mg/m2 D4 Anti-CD45 MAb 400ug/kg over 6 hr, Fludarabine 10 kg or less: 1 mg/kg; > 10 kg: 30 mg/m2 D3 Anti-CD45 MAb 400ug/kg over 6 hr D2 Anti-CD45 MAb 400ug/kg over 6 hr D1 rest D0 Stem Cell Infusion Campath dose is weight based: for patients less than 15 kg administer Campath 3 mg; for patients >15 kg to 30 kg administer Campath 5 mg; for patients > 30 kg administer Campath 10 mg. Campath will be dosed and administered as per CAGT SOP. Anti-CD45 infusion will be administered according to CAGT SOPs.
    Period Title: Overall Study
    STARTED3
    COMPLETED3
    NOT COMPLETED0

    Baseline Characteristics

    Arm/Group TitleSingle Group
    Arm/Group Descriptiononly one group
    Overall Participants3
    Age, Customized (participants) [Number]
    <=1 years
    3
    100%
    Sex: Female, Male (Count of Participants)
    Female
    0
    0%
    Male
    3
    100%

    Outcome Measures

    1. Primary Outcome
    TitleNumber of Patients With Donor Engraftment
    Description
    Time Frame100 Days

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group TitleSingle Group
    Arm/Group Descriptiononly one group
    Measure Participants3
    Number [participants]
    1
    33.3%
    2. Secondary Outcome
    TitlePatients Alive at 1 Year
    Description
    Time Frame1 Year

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group TitleSingle Group
    Arm/Group Descriptiononly one group
    Measure Participants3
    Number [participants]
    3
    100%
    3. Secondary Outcome
    TitleNumber of Patients With Grade III or IV Toxicity
    Description
    Time Frame100 days

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group TitleSingle Group
    Arm/Group Descriptiononly one group
    Measure Participants3
    Number [participants]
    0
    0%
    4. Secondary Outcome
    TitleNumber of Patients With Grade III to IV Acute GVHD
    Description
    Time Frame100 days

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group TitleSingle Group
    Arm/Group Descriptiononly one group
    Measure Participants3
    Number [participants]
    0
    0%

    Adverse Events

    Time Frame
    Adverse Event Reporting Description
    Arm/Group TitleSingle Group
    Arm/Group Descriptiononly one group
    All Cause Mortality
    Single Group
    Affected / at Risk (%)# Events
    Total/ (NaN)
    Serious Adverse Events
    Single Group
    Affected / at Risk (%)# Events
    Total0/3 (0%)
    Other (Not Including Serious) Adverse Events
    Single Group
    Affected / at Risk (%)# Events
    Total3/3 (100%)
    Blood and lymphatic system disorders
    Hemoglobin1/3 (33.3%) 5
    Leukocytes (total WBC)1/3 (33.3%) 17
    Lymphopenia1/3 (33.3%) 23
    Neutrophils/granulocytes (ANC/AGC)1/3 (33.3%) 10
    PTT (Partial Thromboplastin Time)1/3 (33.3%) 1
    Platelets1/3 (33.3%) 1
    Gastrointestinal disorders
    Constipation1/3 (33.3%) 3
    Diarrhea1/3 (33.3%) 5
    Mucositis/stomatitis (clinical exam) - Oral cavity1/3 (33.3%) 1
    Nausea1/3 (33.3%) 3
    Vomiting1/3 (33.3%) 5
    General disorders
    Fever (in the absence of neutropenia, where neutropenia is defined as ANC <1.0 x 10e9/L)1/3 (33.3%) 1
    Pain - Abdomen NOS1/3 (33.3%) 1
    Hepatobiliary disorders
    Hepatobiliary/Pancreas - Other: Liver GvHD1/3 (33.3%) 1
    Immune system disorders
    Allergic reaction/hypersensitivity (including drug fever)1/3 (33.3%) 1
    Infections and infestations
    Infection (documented clinically or microbiologically) with Grade 3 or 4 neutrophils (ANC <1.0 x 10e1/3 (33.3%) 2
    Infection with normal ANC or Grade 1 or 2 neutrophils - Catheter-related1/3 (33.3%) 1
    Metabolism and nutrition disorders
    AST, SGOT(serum glutamic oxaloacetic transaminase)1/3 (33.3%) 5
    Albumin, serum-low (hypoalbuminemia)1/3 (33.3%) 5
    Calcium, serum-low (hypocalcemia)1/3 (33.3%) 2
    Glucose, serum-low (hypoglycemia)1/3 (33.3%) 1
    Phosphate, serum-low (hypophosphatemia)1/3 (33.3%) 4
    Potassium, serum-high (hyperkalemia)1/3 (33.3%) 7
    Sodium, serum-low (hyponatremia)2/3 (66.7%) 2
    Triglyceride, serum-high (hypertriglyceridemia)1/3 (33.3%) 1
    ALT, SGPT (serum glutamic pyruvic transaminase)1/3 (33.3%) 5
    Respiratory, thoracic and mediastinal disorders
    Bronchospasm, wheezing1/3 (33.3%) 1
    Cough1/3 (33.3%) 3
    Dyspnea (shortness of breath)1/3 (33.3%) 2
    Pulmonary/Upper Respiratory - Other: Nasal congestion1/3 (33.3%) 1
    Skin and subcutaneous tissue disorders
    Dermatology/Skin - Other: Livedo reticularis1/3 (33.3%) 2
    Dry skin1/3 (33.3%) 1
    Rash/desquamation1/3 (33.3%) 3

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

    All Principal Investigators ARE employed by the organization sponsoring the study.

    There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

    Results Point of Contact

    Name/TitleRobert Krance, MD
    OrganizationBaylor
    Phone832-824-4661
    Emailrkrance@bcm.edu
    Responsible Party:
    Robert Krance, Professor Pediatrics Hematology Oncology Center for Cell and Gene Therapy, Baylor College of Medicine
    ClinicalTrials.gov Identifier:
    NCT00579137
    Other Study ID Numbers:
    • 21123-MASCI
    • NCT00609258
    First Posted:
    Dec 21, 2007
    Last Update Posted:
    Jul 2, 2013
    Last Verified:
    Jun 1, 2013