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)
• Enrollment: 3
• Location: 1
• Arm: 1
• Duration (Months): 24
• Patients Per Site Per Month: 0.1

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 Disease	Intervention/Treatment	Phase
Severe Combined Immunodeficiency Disease; Severe Primary Immunodeficiency Disorder; Undefined T Cell Deficiency Disorder; Wiskott-Aldrick Syndrome	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

Arm

Intervention/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

	Site	City	State	Country	Postal Code
1	Texas Children's Hospital	Houston	Texas	United States	77030

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

• Keywords provided by Robert Krance, Professor Pediatrics Hematology Oncology Center for Cell and Gene Therapy, Baylor College of Medicine: Severe Combined Immunodeficiency Disease; Severe Primary Immunodeficiency Disorder; Undefined T cell Deficiency Disorder; Wiskott-Aldrick Syndrome; Allogeneic stem cell transplant; Fludarabine; monoclonal antibodies
• Additional relevant MeSH terms: Primary Immunodeficiency Diseases; Severe Combined Immunodeficiency; Immunologic Deficiency Syndromes; Disease; Fludarabine; Alemtuzumab

Study Results

Participant Flow

Arm/Group Title	Participants With SCID or Primary Immunodeficiency Disorder
Arm/Group Description	Participants 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
STARTED	3
COMPLETED	3
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Single Group
Arm/Group Description	only one group
Overall Participants	3
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

Title	Number of Patients With Donor Engraftment
Time Frame	100 Days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Single Group
Arm/Group Description	only one group
Measure Participants	3
Number [participants]	1 33.3%

2. Secondary Outcome

Title	Patients Alive at 1 Year
Time Frame	1 Year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Single Group
Arm/Group Description	only one group
Measure Participants	3
Number [participants]	3 100%

3. Secondary Outcome

Title	Number of Patients With Grade III or IV Toxicity
Time Frame	100 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Single Group
Arm/Group Description	only one group
Measure Participants	3
Number [participants]	0 0%

4. Secondary Outcome

Title	Number of Patients With Grade III to IV Acute GVHD
Time Frame	100 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Single Group
Arm/Group Description	only one group
Measure Participants	3
Number [participants]	0 0%

Adverse Events

Arm/Group Title	Single Group
Arm/Group Description	only one group
All Cause Mortality
	Single Group
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Single Group
	Affected / at Risk (%)	# Events
Total	0/3 (0%)
Other (Not Including Serious) Adverse Events
	Single Group
	Affected / at Risk (%)	# Events
Total	3/3 (100%)
Blood and lymphatic system disorders
Hemoglobin	1/3 (33.3%)	5
Leukocytes (total WBC)	1/3 (33.3%)	17
Lymphopenia	1/3 (33.3%)	23
Neutrophils/granulocytes (ANC/AGC)	1/3 (33.3%)	10
PTT (Partial Thromboplastin Time)	1/3 (33.3%)	1
Platelets	1/3 (33.3%)	1
Gastrointestinal disorders
Constipation	1/3 (33.3%)	3
Diarrhea	1/3 (33.3%)	5
Mucositis/stomatitis (clinical exam) - Oral cavity	1/3 (33.3%)	1
Nausea	1/3 (33.3%)	3
Vomiting	1/3 (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 NOS	1/3 (33.3%)	1
Hepatobiliary disorders
Hepatobiliary/Pancreas - Other: Liver GvHD	1/3 (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 10e	1/3 (33.3%)	2
Infection with normal ANC or Grade 1 or 2 neutrophils - Catheter-related	1/3 (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, wheezing	1/3 (33.3%)	1
Cough	1/3 (33.3%)	3
Dyspnea (shortness of breath)	1/3 (33.3%)	2
Pulmonary/Upper Respiratory - Other: Nasal congestion	1/3 (33.3%)	1
Skin and subcutaneous tissue disorders
Dermatology/Skin - Other: Livedo reticularis	1/3 (33.3%)	2
Dry skin	1/3 (33.3%)	1
Rash/desquamation	1/3 (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.