Back to resultsDepleted Donor Stem Cell Transplant in Children and Adults With Fanconi Anemia After Being Conditioned With a Regimen Containing JSP191 Antibody
Primary Purpose
Fanconi Anemia
Status
Recruiting
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
JSP191
CliniMACS Prodigy System
Depleted Stem Cell Transplant
Rabbit Anti-Thymoglobulin (rATG)
Cyclophosphamide
Fludarabine
Rituximab
Sponsored by
About this trial
This is an interventional treatment trial for Fanconi Anemia focused on measuring Cell Transplants, Grafts, Stem Cells
Eligibility Criteria
Inclusion Criteria:
All patients must have:
- Fanconi Anemia diagnosis as demonstrated by abnormal chromosome breakage studies with increased sensitivity to mitomycin-C (MMC) or diepoxybutane (DEB) and at least one mutation in a known Fanconi-associated gene
- Bone marrow failure (defined by reduction in at least one cell line on two separate occasions at least one month apart (e.g., platelet count of <100,000 per cubic millimeter, hemoglobin <9 gm/dl and/or absolute neutrophil count (ANC) of <1000/mm)
- Age of ≥2 years
- Consenting ≥5/10 HLA-matched related or unrelated donor available for apheresis
Organ function defined as:
- Serum Creatinine <2.0 mg/dL and corrected creatinine clearance/cystatin cL >60 mL/min/1.73m^2 without dialysis
- Forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), and diffusing capacity of the lung for carbon monoxide (DLCO) corrected for hemoglobin and volume, >50% predicted by pulmonary function tests (PFTs)
- For patients unable to cooperate for PFTs, criteria are no evidence of dyspnea at rest, no exercise intolerance, and no requirement for supplemental oxygen with spO2 >93%
- Shortening fraction of ≥29% or ejection fraction of ≥45% by echocardiogram
- Serum total bilirubin of <4 x ULN
- Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) < 5 x ULN
- Prothrombin time international normalized ratio (PT INR) and partial thromboplastin time (PTT) <1.5 x ULN
- Life expectancy of at least 2 years
- Patients of childbearing potential must be willing to use an effective contraceptive method for the duration of the peri-transplant conditioning through hematopoietic recovery
- Patients and/or parents or legal guardians must be able to provide written informed consent and authorize use and disclosure of personal health information in accordance with Health Insurance Portability and Accountability Act
Exclusion Criteria:
- Patients with available and consenting 10/10 HLA-identical sibling donor for apheresis
- Patients with any acute or uncontrolled infections at the time of enrollment, including bacterial, fungal or viral
- Patients who are seropositive for HIV-I/II or HTLV-I/II.
- Patients receiving any other investigational agents or other biological, chemotherapy, or radiation therapy within 14 days of enrollment
- Patients with any active malignancies, myelodysplastic syndrome or other concerns for high-risk bone marrow disease
- Patients who received androgens in last 3 months
- Pregnant or lactating women
- Women who are nursing and do not wish to discontinue breastfeeding
- Lansky/Karnofsky performance score <50%.
- Any other medical condition or history that, in the opinion of the Principal Investigator, could pose a significant safety risk to the participant or jeopardize the integrity of the study
- Patients who, in the opinion of the Principal Investigator, may not be able to comply with the safety monitoring requirements of the study
Sites / Locations
- Stanford UniversityRecruiting
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
Depleted Stem Cell Transplant with JSP-191 Conditioning
Arm Description
Participants will receive an infusion of donor stem cells which have been depleted of αβ+T cells using the CliniMACS System device. Before the stem cell transplant, they will receive a reduced-intensity preparative regimen containing JSP191 in combination with rATG, cyclophosphamide, fludarabine and rituximab.
Outcomes
Primary Outcome Measures
Number of participants without grade 3 and 4 treatment-emergent adverse events (TEAEs) (infusion related reactions) following administration of JSP191
Recorded and graded according to the Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0
Number of participants without grade 3 and 4 treatment-emergent adverse events (TEAEs) (infusion related reactions) following infusion of TCRαβ+ T-cell/CD19+ B-cell depleted hematopoietic graft transplantation
Number of participants able to achieve donor engraftment
Participants have achieved engraftment when absolute Neutrophil Count (ANC) is above 500/mm^3 for three consecutive laboratory values obtained on different days post cell transplantation with >1% CD15 donor chimerism
Number of participants who are able to have donor engraftment persist at the same rate or better compared to alternative hematopoietic cell transplant regimens for this patient population
Secondary Outcome Measures
Serum concentration of JSP191
Assessed as serum concentrations in the peripheral blood from administration until time of cell infusion
Serum concentration of rATG
Assessed as serum concentrations in the peripheral blood from administration until time of cell infusion
Serum concentration of fludarabine
Assessed as serum concentrations in the peripheral blood from administration until time of cell infusion
Participants who do not develop mucositis
Mucositis incidence will be scored using the CTC criteria
Participants who do not develop veno-occlusive disease (VOD)
VOD incidence will be scored using the Modified Seattle criteria
Number of participants who achieve hematopoietic recovery
Hematopoietic recovery defined by hemoglobin >8g/dL and platelets >20k/dL without transfusion support achieved on 7 days post-graft transplantation documented on hematologic monitoring
Number of participants who achieve donor engraftment
Engraftment measured as peripheral blood (total, CD15+, CD3+, CD19+, CD56+, and CD34+) and bone marrow (total and CD34+) chimerism by STR analysis
Number of participants who achieve immunologic recovery
Immunologic recovery defined as >200/uL CD3+ T-cells and as assessed by percent and absolute numbers of T (CD3), B (CD19) and NK (CD56) cells by CBC differential studies and flow cytometry for lymphocyte lineages
Number of participants who develop Grade I-IV acute graft-vs-host disease (GvHD)
Number of participants who develop chronic graft-vs-host disease (GvHD)
Number of participants who achieve disease-free survival
Disease-free defined by improved DEB-induced chromosomal breakage analysis in peripheral blood lymphocyte cultures
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT04784052
Brief Title
Depleted Donor Stem Cell Transplant in Children and Adults With Fanconi Anemia After Being Conditioned With a Regimen Containing JSP191 Antibody
Official Title
TCRαβ+ T-cell/CD19+ B-cell Depleted Hematopoietic Grafts and a Reduced Intensity Preparative Conditioning Regimen Containing JSP191 to Achieve Engraftment and Blood Reconstitution in Patients With Fanconi Anemia
Study Type
Interventional
2. Study Status
Record Verification Date
February 2023
Overall Recruitment Status
Recruiting
Study Start Date
December 7, 2021 (Actual)
Primary Completion Date
April 2025 (Anticipated)
Study Completion Date
April 2028 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
Rajni Agarwal
4. Oversight
Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
The objective of this clinical trial is to develop a cell therapy for Fanconi Anemia which enables enhanced donor hematopoietic and immune reconstitution with decreased toxicity by transplanting depleted stem cells from a donor after using an experimental antibody treatment called JSP-191 as a part of conditioning. This experimental treatment will hopefully cause fewer side effects than chemotherapy (the current standard of care method).
Participants will be administered the conditioning regimen, are assessed until they receive the depleted stem cell infusion, and will be followed for up to 2 years after the cell infusion.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Fanconi Anemia
Keywords
Cell Transplants, Grafts, Stem Cells
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
12 (Anticipated)
8. Arms, Groups, and Interventions
Arm Title
Depleted Stem Cell Transplant with JSP-191 Conditioning
Arm Type
Experimental
Arm Description
Participants will receive an infusion of donor stem cells which have been depleted of αβ+T cells using the CliniMACS System device. Before the stem cell transplant, they will receive a reduced-intensity preparative regimen containing JSP191 in combination with rATG, cyclophosphamide, fludarabine and rituximab.
Intervention Type
Drug
Intervention Name(s)
JSP191
Intervention Description
Participants will receive a single IV dose at start of conditioning
Intervention Type
Device
Intervention Name(s)
CliniMACS Prodigy System
Intervention Description
The device used to remove the αβ+T cells from donor stem cell transplant before being given to the recipient
Intervention Type
Biological
Intervention Name(s)
Depleted Stem Cell Transplant
Intervention Description
TCRαβ+ T-cell/CD19+ B-cell depleted hematopoietic cells will be administered by IV after completion of conditioning regimen.
Intervention Type
Biological
Intervention Name(s)
Rabbit Anti-Thymoglobulin (rATG)
Intervention Description
3 consecutive daily doses of rATG will be given by IV during conditioning
Intervention Type
Drug
Intervention Name(s)
Cyclophosphamide
Other Intervention Name(s)
Cytoxan
Intervention Description
4 consecutive daily doses of cyclophosphamid will be given by IV during conditioning
Intervention Type
Drug
Intervention Name(s)
Fludarabine
Intervention Description
4 consecutive daily doses of fludarabine will be given by IV during conditioning
Intervention Type
Drug
Intervention Name(s)
Rituximab
Intervention Description
1 dose of rituximab will be given at the end of conditioning
Primary Outcome Measure Information:
Title
Number of participants without grade 3 and 4 treatment-emergent adverse events (TEAEs) (infusion related reactions) following administration of JSP191
Description
Recorded and graded according to the Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0
Time Frame
From start of conditioning regimen administration until cell infusion (up to 30 days)
Title
Number of participants without grade 3 and 4 treatment-emergent adverse events (TEAEs) (infusion related reactions) following infusion of TCRαβ+ T-cell/CD19+ B-cell depleted hematopoietic graft transplantation
Time Frame
Up to 2 years post-cell infusion
Title
Number of participants able to achieve donor engraftment
Description
Participants have achieved engraftment when absolute Neutrophil Count (ANC) is above 500/mm^3 for three consecutive laboratory values obtained on different days post cell transplantation with >1% CD15 donor chimerism
Time Frame
Assessed at Day +42 post-cell infusion
Title
Number of participants who are able to have donor engraftment persist at the same rate or better compared to alternative hematopoietic cell transplant regimens for this patient population
Time Frame
Assessed at Day +100 post-cell infusion
Secondary Outcome Measure Information:
Title
Serum concentration of JSP191
Description
Assessed as serum concentrations in the peripheral blood from administration until time of cell infusion
Time Frame
Prior to start of conditioning regimen, and 5 minutes, 4 hours, +2, +3, +4, +6, +8, +10 days after start of conditioning regimen, and day of cell infusion
Title
Serum concentration of rATG
Description
Assessed as serum concentrations in the peripheral blood from administration until time of cell infusion
Time Frame
Prior to start of rATG infusion; 15 minutes after first, second, and third rATG infusion; day of cell infusion; and week +1, week +2 and week +12 post cell infusion
Title
Serum concentration of fludarabine
Description
Assessed as serum concentrations in the peripheral blood from administration until time of cell infusion
Time Frame
Prior to start of fludarabine infusion, and 15 minutes, 1 hour, 3 hours, and 6 hours after the fludarabine infusion
Title
Participants who do not develop mucositis
Description
Mucositis incidence will be scored using the CTC criteria
Time Frame
Start of conditioning regimen until +12 weeks post-cell infusion (up to 15 weeks)
Title
Participants who do not develop veno-occlusive disease (VOD)
Description
VOD incidence will be scored using the Modified Seattle criteria
Time Frame
Start of conditioning regimen until +12 weeks post-cell infusion (up to 15 weeks)
Title
Number of participants who achieve hematopoietic recovery
Description
Hematopoietic recovery defined by hemoglobin >8g/dL and platelets >20k/dL without transfusion support achieved on 7 days post-graft transplantation documented on hematologic monitoring
Time Frame
Up to 107 weeks (after start of conditioning regimen through Week +104 post-cell infusion)
Title
Number of participants who achieve donor engraftment
Description
Engraftment measured as peripheral blood (total, CD15+, CD3+, CD19+, CD56+, and CD34+) and bone marrow (total and CD34+) chimerism by STR analysis
Time Frame
Weeks +1 through +104 post-cell infusion
Title
Number of participants who achieve immunologic recovery
Description
Immunologic recovery defined as >200/uL CD3+ T-cells and as assessed by percent and absolute numbers of T (CD3), B (CD19) and NK (CD56) cells by CBC differential studies and flow cytometry for lymphocyte lineages
Time Frame
Weeks +1 through +104 post-cell infusion
Title
Number of participants who develop Grade I-IV acute graft-vs-host disease (GvHD)
Time Frame
Day +100 post-cell infusion
Title
Number of participants who develop chronic graft-vs-host disease (GvHD)
Time Frame
Day +100 through Week +104 post-cell infusion
Title
Number of participants who achieve disease-free survival
Description
Disease-free defined by improved DEB-induced chromosomal breakage analysis in peripheral blood lymphocyte cultures
Time Frame
Up to 104 weeks (from time of cell infusion through Week +104)
10. Eligibility
Sex
All
Minimum Age & Unit of Time
2 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
All patients must have:
Fanconi Anemia diagnosis as demonstrated by abnormal chromosome breakage studies with increased sensitivity to mitomycin-C (MMC) or diepoxybutane (DEB) and at least one mutation in a known Fanconi-associated gene
Bone marrow failure (defined by reduction in at least one cell line on two separate occasions at least one month apart (e.g., platelet count of <100,000 per cubic millimeter, hemoglobin <9 gm/dl and/or absolute neutrophil count (ANC) of <1000/mm)
Age of ≥2 years
Consenting ≥5/10 HLA-matched related or unrelated donor available for apheresis
Organ function defined as:
Serum Creatinine <2.0 mg/dL and corrected creatinine clearance/cystatin cL >60 mL/min/1.73m^2 without dialysis
Forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), and diffusing capacity of the lung for carbon monoxide (DLCO) corrected for hemoglobin and volume, >50% predicted by pulmonary function tests (PFTs)
For patients unable to cooperate for PFTs, criteria are no evidence of dyspnea at rest, no exercise intolerance, and no requirement for supplemental oxygen with spO2 >93%
Shortening fraction of ≥29% or ejection fraction of ≥45% by echocardiogram
Serum total bilirubin of <4 x ULN
Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) < 5 x ULN
Prothrombin time international normalized ratio (PT INR) and partial thromboplastin time (PTT) <1.5 x ULN
Life expectancy of at least 2 years
Patients of childbearing potential must be willing to use an effective contraceptive method for the duration of the peri-transplant conditioning through hematopoietic recovery
Patients and/or parents or legal guardians must be able to provide written informed consent and authorize use and disclosure of personal health information in accordance with Health Insurance Portability and Accountability Act
Exclusion Criteria:
Patients with available and consenting 10/10 HLA-identical sibling donor for apheresis
Patients with any acute or uncontrolled infections at the time of enrollment, including bacterial, fungal or viral
Patients who are seropositive for HIV-I/II or HTLV-I/II.
Patients receiving any other investigational agents or other biological, chemotherapy, or radiation therapy within 14 days of enrollment
Patients with any active malignancies, myelodysplastic syndrome or other concerns for high-risk bone marrow disease
Patients who received androgens in last 3 months
Pregnant or lactating women
Women who are nursing and do not wish to discontinue breastfeeding
Lansky/Karnofsky performance score <50%.
Any other medical condition or history that, in the opinion of the Principal Investigator, could pose a significant safety risk to the participant or jeopardize the integrity of the study
Patients who, in the opinion of the Principal Investigator, may not be able to comply with the safety monitoring requirements of the study
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Rajni Agarwal, MD
Organizational Affiliation
Stanford University
Official's Role
Principal Investigator
Facility Information:
Facility Name
Stanford University
City
Stanford
State/Province
California
ZIP/Postal Code
94305
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Rajni Agarwal, MD
Phone
650-725-9250
Email
scgt_clinical_trials_office@lists.stanford.edu
12. IPD Sharing Statement
Plan to Share IPD
No
Learn more about this trial
Depleted Donor Stem Cell Transplant in Children and Adults With Fanconi Anemia After Being Conditioned With a Regimen Containing JSP191 Antibody
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