Depleted Donor Stem Cell Transplant in Children and Adults With Fanconi Anemia After Being Conditioned With a Regimen Containing JSP191

Sponsor

Rajni Agarwal (Other)

Overall Status

Recruiting

CT.gov ID

NCT04784052

Collaborator

(none)

Enrollment

Location

Arm

75.8

Anticipated Duration (Months)

0.2

Patients Per Site Per Month

Study Details

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 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.

Condition or Disease	Intervention/Treatment	Phase
Fanconi Anemia	Drug: JSP191 Device: CliniMACS Prodigy System Biological: Depleted Stem Cell Transplant Biological: Rabbit Anti-Thymoglobulin (rATG) Drug: Cyclophosphamide Drug: Fludarabine Drug: Rituximab	Phase 1/Phase 2

Study Design

Study Type:

Interventional

Anticipated Enrollment :

12 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

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

Actual Study Start Date :

Dec 7, 2021

Anticipated Primary Completion Date :

Apr 1, 2025

Anticipated Study Completion Date :

Apr 1, 2028

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Depleted Stem Cell Transplant with JSP-191 Conditioning 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.	Drug: JSP191 Participants will receive a single IV dose at start of conditioning Device: CliniMACS Prodigy System The device used to remove the αβ+T cells from donor stem cell transplant before being given to the recipient Biological: Depleted Stem Cell Transplant TCRαβ+ T-cell/CD19+ B-cell depleted hematopoietic cells will be administered by IV after completion of conditioning regimen. Biological: Rabbit Anti-Thymoglobulin (rATG) 3 consecutive daily doses of rATG will be given by IV during conditioning Drug: Cyclophosphamide 4 consecutive daily doses of cyclophosphamid will be given by IV during conditioning Other Names: Cytoxan Drug: Fludarabine 4 consecutive daily doses of fludarabine will be given by IV during conditioning Drug: Rituximab 1 dose of rituximab will be given at the end of conditioning

Arm

Intervention/Treatment

Experimental: Depleted Stem Cell Transplant with JSP-191 Conditioning

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.

Drug: JSP191

Participants will receive a single IV dose at start of conditioning

Device: CliniMACS Prodigy System

The device used to remove the αβ+T cells from donor stem cell transplant before being given to the recipient

Biological: Depleted Stem Cell Transplant

TCRαβ+ T-cell/CD19+ B-cell depleted hematopoietic cells will be administered by IV after completion of conditioning regimen.

Biological: Rabbit Anti-Thymoglobulin (rATG)

3 consecutive daily doses of rATG will be given by IV during conditioning

Drug: Cyclophosphamide

4 consecutive daily doses of cyclophosphamid will be given by IV during conditioning

Other Names:

Cytoxan

Drug: Fludarabine

4 consecutive daily doses of fludarabine will be given by IV during conditioning

Drug: Rituximab

1 dose of rituximab will be given at the end of conditioning

Outcome Measures

Primary Outcome Measures

Number of participants without grade 3 and 4 treatment-emergent adverse events (TEAEs) (infusion related reactions) following administration of JSP191 [From start of conditioning regimen administration until cell infusion (up to 30 days)]
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 [Up to 2 years post-cell infusion]
Number of participants able to achieve donor engraftment [Assessed at Day +42 post-cell infusion]
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 [Assessed at Day +100 post-cell infusion]

Secondary Outcome Measures

Serum concentration of JSP191 [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]
Assessed as serum concentrations in the peripheral blood from administration until time of cell infusion
Serum concentration of rATG [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]
Assessed as serum concentrations in the peripheral blood from administration until time of cell infusion
Serum concentration of fludarabine [Prior to start of fludarabine infusion, and 15 minutes, 1 hour, 3 hours, and 6 hours after the fludarabine infusion]
Assessed as serum concentrations in the peripheral blood from administration until time of cell infusion
Participants who do not develop mucositis [Start of conditioning regimen until +12 weeks post-cell infusion (up to 15 weeks)]
Mucositis incidence will be scored using the CTC criteria
Participants who do not develop veno-occlusive disease (VOD) [Start of conditioning regimen until +12 weeks post-cell infusion (up to 15 weeks)]
VOD incidence will be scored using the Modified Seattle criteria
Number of participants who achieve hematopoietic recovery [Up to 107 weeks (after start of conditioning regimen through Week +104 post-cell infusion)]
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 [Weeks +1 through +104 post-cell infusion]
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 [Weeks +1 through +104 post-cell infusion]
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) [Day +100 post-cell infusion]
Number of participants who develop chronic graft-vs-host disease (GvHD) [Day +100 through Week +104 post-cell infusion]
Number of participants who achieve disease-free survival [Up to 104 weeks (from time of cell infusion through Week +104)]
Disease-free defined by improved DEB-induced chromosomal breakage analysis in peripheral blood lymphocyte cultures

Eligibility Criteria

Criteria

Ages Eligible for Study:

2 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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