Mafia: Antibody Conditioning Regimen For Allogeneic Donor Stem Cell Transplantation Of Patients With Fanconi Anemia
Study Details
Study Description
Brief Summary
The purpose of this study is to discover whether children and adults with Fanconi anemia (FA) can be safely and effectively transplanted with Human Leukocyte Antigen (HLA) mismatched (up to one haplotype), HLA-matched sibling, or unrelated donor stem cells, when leukocytolytic monoclonal antibodies are the sole conditioning agents (patients receiving an HLA mismatched transplant will receive Fludarabine as part of the conditioning regimen). Three monoclonal antibodies (MAb) will be used in combination. Two of them, YTH 24 and YTH 54 are rat 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. This MAb has been widely used 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 Fanconi anemia, in whom the use of conventional chemotherapeutic agents for conditioning produces a high rate of short and long 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 graft versus host disease (GvHD) prophylaxis. Additional GvHD prophylaxis will be provided by administration of the medication FK506.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 1/Phase 2 |
Detailed Description
If clinically feasible (no aplasia, no active malignancy), the recipients marrow will be harvested and cryopreserved as a back up for use if non-engraftment/rejection is followed by failure to undergo autologous reconstitution.
For HLA Mismatched donors, harvested peripheral blood stem cells will be enriched for CD34 cells using the Clinimacs CD34 Reagent system.
Fludarabine will be given as 5 daily intravenous infusions. 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 intravenously every 4 hours during the period of the course of each infusion.
Day -8 Campath 1H as per CAGT SOP Fludarabine 30 mg/m2 -7 Campath 1H as per CAGT SOP Fludarabine 30 mg/m2 -6 Campath 1H as per CAGT SOP Fludarabine 30 mg/m2 -5 YTH 24/54 400ug/kg over 6 hr Fludarabine 30 mg/m2 -4 YTH 24/54 400ug/kg over 6 hr Fludarabine 30 mg/m2 -3 YTH 24/54 400ug/kg over 6 hr -2 YTH 24/54 400ug/kg over 6 hr -1 -0 Stem Cell Infusion
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 10e4 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 10e4 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.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Single Arm Study: Stem Cell Transplant CAMPATH-1H Anti-CD45 Fludarabine Stem Cell Infusion |
Biological: CAMPATH-1H
Given intravenous on days -8, -7, and -6
Other Names:
Biological: Anti-CD45
Given intravenous on days -5, -4, -3 and -2
dose is 400 micrograms/kg
Drug: Fludarabine
Given intravenous on days -8, -7, -6, -5 and -4
Dose is 30 mg/m2
Procedure: Stem cell infusion
Stem cells are infused on day 0
|
Outcome Measures
Primary Outcome Measures
- Number of Patients With Donor Engraftment [100 Days]
Number of patients with engraftment of at least 65% of donor cells 100 days after transplantation
Secondary Outcome Measures
- Number of Patients With Graft Failure [100 days]
Graft failure is defined as engraftment of less than 65% of donor cells 100 days after transplantation.
- Patients With Treated Related Death [100 days]
Number of patients with treated related death
- Days to Absolute Neutrophil Count (ANC) of 500/mm3 [30 Days]
Number of days to Absolute neutrophil count (ANC) of 500/mm3
- Days to Platelet Count of 20,000/mm3 Without Transfusions [30 Days]
Number of days to Platelet count of 20,000 / mm3 without transfusions
- Patients With Grade II - IV Acute Graft Versus Host Disease (GVHD) [100 days]
Number of patients with grade II - IV acute Graft versus Host Disease (GVHD)
- Number of Patients Alive at 1 Year Post Transplant [1 year]
Number of patients alive at 1 year post allogeneic stem cell transplant
- Patients With Limited Chronic GVHD From Day 100 to 365 [365 days]
Number of patients with limited chronic GVHD from day 100 to 365
- Patients With Extensive Chronic GVHD From Day 100 to 365 [365 days]
Number of patients with extensive chronic GVHD from day 100 to 365.
- Patients With Grade III - IV Acute GVHD [100 days]
Number of patients with Grade III-IV acute GVHD
Eligibility Criteria
Criteria
Inclusion Criteria:
Diagnosis of Fanconi Anemia or other suspected DNA breakage/chromosomal instability syndromes, such as dyskeratosis congenita or Nijmegen breakage syndrome of all ages are eligible.
Diagnosis of Fanconi anemia confirmed by studies of peripheral blood or bone marrow sensitivity to mitomycin C or DEB or clinical evidence of other DNA breakage/chromosomal instability syndrome as determined by genetic testing or clinical diagnosis by a geneticist
Severe aplasia anemia as evidenced by a hypocellular bone marrow and at least 1 of the 3 criteria below: ANC < 500/mm3 Hemoglobin < 10 gm/dl with reticulocyte count < 1% Platelet count < 50,000/mm3
Availability of an HLA matched or mismatched (up to one haplotype) family member who has been documented not to have Fanconi anemia or of an unrelated HLA matched stem cell donor. Fully matched is defined at 6/6 match by high resolution DR based DNA typing.
Life expectancy greater than 6 weeks limited by diseases other than FA
Creatinine 2X normal for age or less
Karnofsky score 70% or more
Exclusion Criteria:
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.
Patients with severe personality disorder or mental illness.
Patients with documented HIV positivity.
Pregnant
NOTE: Patients who would be excluded from the protocol strictly for laboratory abnormalities can be included at the investigator's discretion after approval by the CCGT Protocol Review Committee and the FDA Reviewer.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Methodist Hospital | Houston | Texas | United States | 77030 |
| 2 | Texas Children's Hospital | Houston | Texas | United States | 77030 |
Sponsors and Collaborators
- Baylor College of Medicine
- The Methodist Hospital Research Institute
- Center for Cell and Gene Therapy, Baylor College of Medicine
Investigators
- Principal Investigator: Malcolm Brenner, M.B., Ph.D.,, Baylor College of Medicine
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- H-9938
- NCT00058565
Study Results
Participant Flow
| Recruitment Details | |
|---|---|
| Pre-assignment Detail |
| Arm/Group Title | Allo Stem Cell Transplant |
|---|---|
| Arm/Group Description | Allogeneic Stem Cell Transplant |
| Period Title: Overall Study | |
| STARTED | 5 |
| COMPLETED | 5 |
| NOT COMPLETED | 0 |
Baseline Characteristics
| Arm/Group Title | Group1 |
|---|---|
| Arm/Group Description | only one group |
| Overall Participants | 5 |
| Age, Customized (participants) [Number] | |
| <=5 years |
1
20%
|
| Between 5 and 9 years |
2
40%
|
| Between 10 and 15 years |
2
40%
|
| Sex: Female, Male (Count of Participants) | |
| Female |
1
20%
|
| Male |
4
80%
|
Outcome Measures
| Title | Number of Patients With Donor Engraftment |
|---|---|
| Description | Number of patients with engraftment of at least 65% of donor cells 100 days after transplantation |
| Time Frame | 100 Days |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | Allogeneic Stem Cell Transplant |
|---|---|
| Arm/Group Description | Single Group: Allogeneic Stem Cell Transplant |
| Measure Participants | 5 |
| Number [participants] |
2
40%
|
| Title | Number of Patients With Graft Failure |
|---|---|
| Description | Graft failure is defined as engraftment of less than 65% of donor cells 100 days after transplantation. |
| Time Frame | 100 days |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | Allogeneic Stem Cell Transplant |
|---|---|
| Arm/Group Description | Single Group - Allogeneic Stem Cell Transplant |
| Measure Participants | 5 |
| Number [participants] |
3
60%
|
| Title | Patients With Treated Related Death |
|---|---|
| Description | Number of patients with treated related death |
| Time Frame | 100 days |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | Allo Stem Cell Transplant |
|---|---|
| Arm/Group Description | Allogeneic Stem Cell Transplant |
| Measure Participants | 5 |
| Number [participants] |
0
0%
|
| Title | Days to Absolute Neutrophil Count (ANC) of 500/mm3 |
|---|---|
| Description | Number of days to Absolute neutrophil count (ANC) of 500/mm3 |
| Time Frame | 30 Days |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | Allogeneic Stem Cell Transplant |
|---|---|
| Arm/Group Description | Single Group: Allogeneic Stem Cell Transplant |
| Measure Participants | 5 |
| Median (Full Range) [days] |
15
|
| Title | Days to Platelet Count of 20,000/mm3 Without Transfusions |
|---|---|
| Description | Number of days to Platelet count of 20,000 / mm3 without transfusions |
| Time Frame | 30 Days |
Outcome Measure Data
| Analysis Population Description |
|---|
| Participants achieved a platelet count of 20,000 / mm3 without transfusions. |
| Arm/Group Title | Allogeneic Stem Cell Transplant |
|---|---|
| Arm/Group Description | Single Group: Allogeneic Stem Cell Transplant |
| Measure Participants | 2 |
| Median (Full Range) [days] |
16
|
| Title | Patients With Grade II - IV Acute Graft Versus Host Disease (GVHD) |
|---|---|
| Description | Number of patients with grade II - IV acute Graft versus Host Disease (GVHD) |
| Time Frame | 100 days |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | Allogeneic Stem Cell Transplant |
|---|---|
| Arm/Group Description | Single Group: Allogeneic Stem Cell Transplant |
| Measure Participants | 5 |
| Number [participants] |
0
0%
|
| Title | Number of Patients Alive at 1 Year Post Transplant |
|---|---|
| Description | Number of patients alive at 1 year post allogeneic stem cell transplant |
| Time Frame | 1 year |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | Allogeneic Stem Cell Transplant |
|---|---|
| Arm/Group Description | Single group: Allogeneic Stem Cell Transplant |
| Measure Participants | 5 |
| Number [participants] |
5
100%
|
| Title | Patients With Limited Chronic GVHD From Day 100 to 365 |
|---|---|
| Description | Number of patients with limited chronic GVHD from day 100 to 365 |
| Time Frame | 365 days |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | Allogeneic Stem Cell Transplant |
|---|---|
| Arm/Group Description | Single Group: Allogeneic Stem Cell Transplant |
| Measure Participants | 5 |
| Number [participants] |
0
0%
|
| Title | Patients With Extensive Chronic GVHD From Day 100 to 365 |
|---|---|
| Description | Number of patients with extensive chronic GVHD from day 100 to 365. |
| Time Frame | 365 days |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | Allogeneic Stem Cell Transplant |
|---|---|
| Arm/Group Description | only one group |
| Measure Participants | 5 |
| Number [participants] |
0
0%
|
| Title | Patients With Grade III - IV Acute GVHD |
|---|---|
| Description | Number of patients with Grade III-IV acute GVHD |
| Time Frame | 100 days |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | Allogeneic Stem Cell Transplant |
|---|---|
| Arm/Group Description | Single Group: Allogeneic Stem Cell Transplant |
| Measure Participants | 5 |
| Number [participants] |
0
0%
|
Adverse Events
| Time Frame | 1 year | |
|---|---|---|
| Adverse Event Reporting Description | ||
| Arm/Group Title | Group1 | |
| Arm/Group Description | only one group | |
All Cause Mortality |
||
| Group1 | ||
| Affected / at Risk (%) | # Events | |
| Total | / (NaN) | |
Serious Adverse Events |
||
| Group1 | ||
| Affected / at Risk (%) | # Events | |
| Total | 1/5 (20%) | |
| Nervous system disorders | ||
| CNC hemorrhage | 1/5 (20%) | 1 |
Other (Not Including Serious) Adverse Events |
||
| Group1 | ||
| Affected / at Risk (%) | # Events | |
| Total | 5/5 (100%) | |
| Cardiac disorders | ||
| Hypertension | 3/5 (60%) | 3 |
| Gastrointestinal disorders | ||
| Anorexia | 1/5 (20%) | 1 |
| Diarrhea | 1/5 (20%) | 1 |
| General disorders | ||
| Jaw Pain | 1/5 (20%) | 1 |
| Hepatobiliary disorders | ||
| AST | 2/5 (40%) | 4 |
| Infections and infestations | ||
| Picorna virus sinusitis | 1/5 (20%) | 1 |
| Herpes simplex type I | 1/5 (20%) | 1 |
| Metabolism and nutrition disorders | ||
| Hyperkalemia | 2/5 (40%) | 5 |
Limitations/Caveats
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/Title | Malcolm Brenner, MD |
|---|---|
| Organization | BAYLOR |
| Phone | 832-824-4663 |
| mbrenner@bcm.edu |
- H-9938
- NCT00058565