Clinical trial NCT04784052: Depleted Donor Stem Cell Transplant in Children and Adults With Fanconi Anemia After Being Conditioned With a Regimen Containing Briquilimab
Official title: TCRαβ+ T-cell/CD19+ B-cell Depleted Hematopoietic Grafts and a Reduced Intensity Preparative Conditioning Regimen Containing JSP191 (Briquilimab) to Achieve Engraftment and Blood Reconstitution in Patients With Fanconi Anemia
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
PHASE2
Conditions: Fanconi Anemia
Keywords: Cell Transplants
Grafts
Stem Cells
Lead sponsor: Stanford University
Sponsor class: OTHER
First posted: 2021-03-05
Enrollment: 12
Sex: ALL
Minimum age (years): 2
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.


Eligibility criteria: Inclusion Criteria:

All patients must have:

1. 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
2. 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)
3. Age of ≥2 years
4. Consenting ≥5/10 HLA-matched related or unrelated donor available for apheresis
5. Organ function defined as:

   1. Serum Creatinine \<2.0 mg/dL and corrected creatinine clearance/cystatin cL \>60 mL/min/1.73m\^2 without dialysis
   2. 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)
   3. 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%
   4. Shortening fraction of ≥29% or ejection fraction of ≥45% by echocardiogram
   5. Serum total bilirubin of \<4 x ULN
   6. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) \< 5 x ULN
   7. Prothrombin time international normalized ratio (PT INR) and partial thromboplastin time (PTT) \<1.5 x ULN
6. Life expectancy of at least 2 years
7. Patients of childbearing potential must be willing to use an effective contraceptive method for the duration of the peri-transplant conditioning through hematopoietic recovery
8. 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:

1. Patients with available and consenting 10/10 HLA-identical sibling donor for apheresis
2. Patients with any acute or uncontrolled infections at the time of enrollment, including bacterial, fungal or viral
3. Patients who are seropositive for HIV-I/II or HTLV-I/II.
4. Patients receiving any other investigational agents or other biological, chemotherapy, or radiation therapy within 14 days of enrollment
5. Patients with any active malignancies, myelodysplastic syndrome or other concerns for high-risk bone marrow disease
6. Patients who received androgens in last 3 months
7. Pregnant or lactating women
8. Women who are nursing and do not wish to discontinue breastfeeding
9. Lansky/Karnofsky performance score \<50%.
10. 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
11. Patients who, in the opinion of the Principal Investigator, may not be able to comply with the safety monitoring requirements of the study

Primary outcomes:
measure: Number of participants without grade 3 and 4 treatment-emergent adverse events (TEAEs) (infusion related reactions) following administration of JSP191
timeFrame: From start of conditioning regimen administration until cell infusion (up to 30 days)
measure: 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
timeFrame: Up to 2 years post-cell infusion
measure: Number of participants able to achieve donor engraftment
timeFrame: Assessed at Day +42 post-cell infusion
measure: 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
timeFrame: Assessed at Day +100 post-cell infusion
Secondary outcomes:
measure: Serum concentration of JSP191
timeFrame: 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
measure: Serum concentration of rATG
timeFrame: 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
measure: Serum concentration of fludarabine
timeFrame: Prior to start of fludarabine infusion, and 15 minutes, 1 hour, 3 hours, and 6 hours after the fludarabine infusion
measure: Participants who do not develop mucositis
timeFrame: Start of conditioning regimen until +12 weeks post-cell infusion (up to 15 weeks)
measure: Participants who do not develop veno-occlusive disease (VOD)
timeFrame: Start of conditioning regimen until +12 weeks post-cell infusion (up to 15 weeks)
measure: Number of participants who achieve hematopoietic recovery
timeFrame: Up to 107 weeks (after start of conditioning regimen through Week +104 post-cell infusion)
measure: Number of participants who achieve donor engraftment
timeFrame: Weeks +1 through +104 post-cell infusion
measure: Number of participants who achieve immunologic recovery
timeFrame: Weeks +1 through +104 post-cell infusion
measure: Number of participants who develop Grade I-IV acute graft-vs-host disease (GvHD)
timeFrame: Day +100 post-cell infusion
measure: Number of participants who develop chronic graft-vs-host disease (GvHD)
timeFrame: Day +100 through Week +104 post-cell infusion
measure: Number of participants who achieve disease-free survival
timeFrame: Up to 104 weeks (from time of cell infusion through Week +104)
Other outcomes:
Locations:
city: Stanford
country: United States
facility: Stanford University
state: California
Study officials:
affiliation: Stanford University
name: Rajni Agarwal, MD
role: PRINCIPAL_INVESTIGATOR
References: