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

Porteus, Matthew, MD

Status and phase: Enrolling; Phase 2; Phase 1

Conditions: Fanconi Anemia

Treatments: Drug: Fludarabine; Biological: Depleted Stem Cell Transplant; Drug: Cyclophosphamide; Biological: Rabbit Anti-Thymoglobulin (rATG); Drug: JSP191; Drug: Rituximab; Device: CliniMACS Prodigy System

Study type: Interventional

Funder types: Other

Identifiers

NCT04784052

IRB-60108

Details and patient eligibility

About

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 with and without 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.

Enrollment: 18 estimated patients

Sex: All

Ages: 2+ years old

Volunteers: No Healthy Volunteers

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

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Sequential Assignment

Masking: None (Open label)

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18 participants in 2 patient groups

Depleted Stem Cell Transplant with JSP-191 Conditioning

Experimental group

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.

Treatment:

Device: CliniMACS Prodigy System

Drug: Rituximab

Drug: JSP191

Drug: Cyclophosphamide

Biological: Rabbit Anti-Thymoglobulin (rATG)

Biological: Depleted Stem Cell Transplant

Drug: Fludarabine

Depleted Stem Cell Transplant without JSP-191 Conditioning

Experimental group

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 rATG, cyclophosphamide, fludarabine and rituximab.

Treatment:

Device: CliniMACS Prodigy System

Drug: Rituximab

Drug: Cyclophosphamide

Biological: Rabbit Anti-Thymoglobulin (rATG)

Biological: Depleted Stem Cell Transplant

Drug: Fludarabine