Stem Cell Transplant + JSP191 for Fanconi Anemia

Age: Any Age

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Porteus, Matthew, MD

Must not be taking: Investigational agents

Disqualifiers: HIV, Active infections, Malignancies, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: Unknown

12 Participants Needed

Trial Summary

What is the purpose of this trial?

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.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot participate if you have taken investigational agents, chemotherapy, or radiation therapy within 14 days before enrolling. Also, you cannot have used androgens in the last 3 months.

What data supports the effectiveness of this treatment for Fanconi Anemia?

Research shows that using TCRαβ+/CD19+-depleted stem cell transplants in patients with Fanconi Anemia resulted in a high success rate, with 91.6% achieving sustained engraftment and a 100% overall survival rate over a median follow-up of 5.2 years. This suggests that the treatment is effective in achieving long-term survival and engraftment in these patients. ^{1 2 3 4 5}

Is the Stem Cell Transplant + JSP191 treatment generally safe for humans?

The treatment involving TCRαβ+/CD19+-depleted stem cell transplantation has shown to be generally safe in humans, with low rates of severe complications like graft-versus-host disease (GVHD) and no fatal transplant-related toxicity observed in a study with Fanconi anemia patients. Another study in children with acute myeloid leukemia also reported manageable safety outcomes, with a 10% transplant-related mortality rate and a 39% incidence of moderate acute GVHD. ^{1 2 3 6 7}

How is the treatment Stem Cell Transplant + JSP191 for Fanconi Anemia different from other treatments?

This treatment is unique because it uses a specific type of stem cell transplant that is depleted of certain immune cells (TCRαβ+ T-cells and CD19+ B-cells) to reduce the risk of complications like graft-versus-host disease (GVHD), making it a safer option for patients without a fully matched donor. ^{1 2 3 7 8}

Research Team

Rajni Agarwal, MD

Principal Investigator

Stanford University

Eligibility Criteria

This trial is for children and adults with Fanconi Anemia, confirmed by specific tests and genetic mutations. Participants must be over 2 years old, have certain organ function levels (kidney, lung, heart), not be pregnant or breastfeeding, willing to use contraception if of childbearing potential, and have a life expectancy of at least 2 years. They should not have active cancers or uncontrolled infections.

Inclusion Criteria

My blood tests show low counts in at least one type of blood cell on two different tests a month apart.

Organ function criteria: 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), 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

I have a donor who matches at least half of my HLA markers for a cell donation.

Exclusion Criteria

I do not have any active cancers, myelodysplastic syndrome, or high-risk bone marrow diseases.

I need considerable assistance and medical care.

I haven't had any experimental treatments or other cancer therapies in the last 14 days.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Conditioning

Participants receive a reduced-intensity preparative regimen containing JSP191 in combination with rATG, cyclophosphamide, fludarabine, and rituximab before the stem cell transplant

Up to 30 days

Stem Cell Infusion

Participants receive an infusion of donor stem cells depleted of αβ+T cells

1 day

Follow-up

Participants are monitored for safety and effectiveness after treatment, including hematopoietic and immunologic recovery

104 weeks

Treatment Details

Interventions

• Depleted Stem Cell Transplant
• JSP191

Trial Overview The trial is testing a new cell therapy using depleted stem cells from donors after conditioning with JSP191 antibody treatment. This aims to rebuild the patient's blood and immune systems with less toxicity than chemotherapy. Patients will undergo this regimen before receiving the stem cell infusion and will be monitored for up to two years.

Participant Groups

Group I: Depleted Stem Cell Transplant with JSP-191 Conditioning Experimental Treatment 7 Interventions

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.

Who Is Running the Clinical Trial?

Porteus, Matthew, MD

Lead Sponsor

Trials

2

Recruited

30+

Maria Grazia Roncarolo

Lead Sponsor

Trials

1

Recruited

10+

Rajni Agarwal

Lead Sponsor

Trials

2

Recruited

20+

Findings from Research

In a phase 2 trial involving 24 patients with Fanconi anemia, 91.6% achieved sustained primary engraftment after receiving T-cell receptor αβ (TCRαβ+) and CD19+ cell-depleted hematopoietic stem cell transplantation, with quick recovery times for neutrophils and platelets.

The treatment was well tolerated with no fatal transplant-related toxicities, and after a median follow-up of 5.2 years, the overall survival rate was 100%, indicating high efficacy and safety of this transplantation method.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

HLA-haploidentical TCRαβ+/CD19+-depleted stem cell transplantation in children and young adults with Fanconi anemia. Strocchio, L., Pagliara, D., Algeri, M., et al.[2022]

A 10-year-old girl with Fanconi anemia successfully received a haploidentical bone marrow transplant (BMT) from her father after an initial transplant from her mother failed due to graft rejection, highlighting the potential for using family donors when matched donors are unavailable.

The transplant involved T cell depletion and did not require post-transplant immunosuppression, leading to a successful immunological reconstitution within 6 months without complications like graft-versus-host disease (GVHD) or severe infections, suggesting this method could be a preferred treatment for Fanconi anemia in similar cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Successful haploidentical bone marrow transplantation in Fanconi anemia. Elhasid, R., Ben Arush, MW., Katz, T., et al.[2004]

A patient with Fanconi anemia successfully overcame severe rejection after a second allogeneic stem cell transplantation using antilymphocyte globulin followed by donor lymphocyte infusion, demonstrating a potential treatment strategy for this complication.

Three and a half years post-treatment, the patient is alive with a high Karnofsky score of 90% and has maintained donor-origin molecular chimerism, indicating effective engraftment and health.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rejection of the second allogeneic graft in a child with Fanconi anemia reversed by antilymphocyte globulin and donor lymphocyte infusion. Abdelkefi, A., Ben Othman, T., Ladeb, S., et al.[2016]

A new 10-color quality control panel was developed to accurately quantify residual TCRαβ+ T cells and CD19+ B cells in stem cell grafts, which is crucial for preventing severe graft-versus-host disease (GvHD) after haploidentical stem cell transplantation (HSCT).

The immunomagnetic purification method achieved significant depletion of TCRαβ and CD19 cells, with recovery rates of 82.1% for stem cells, 67.1% for NK cells, and 72.7% for TCRγδ+ T cells, potentially improving transplantation outcomes by ensuring a safer graft composition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Generation and flow cytometric quality control of clinical-scale TCRαβ/CD19-depleted grafts. Bremm, M., Cappel, C., Erben, S., et al.[2017]

In a study of 34 patients with acute leukemia receiving αβ T-cell-depleted grafts from haploidentical donors, the approach showed promising results with low rates of severe graft-versus-host disease (GVHD) at 5.9% and a 1-year overall survival rate of 54%.

The study demonstrated that neutrophil and platelet engraftment occurred relatively quickly, on days 12 and 11 respectively, suggesting that this method may lead to faster recovery compared to other graft types.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

TcRαβ-depleted haploidentical transplantation results in adult acute leukemia patients. Kaynar, L., Demir, K., Turak, EE., et al.[2017]

In a study involving 33 children with high-risk acute myeloid leukemia (AML) who received TCR-alpha/beta and CD19-depleted grafts, primary engraftment was achieved in all patients, indicating the effectiveness of this graft manipulation method.

The cumulative incidence of acute graft-versus-host disease (aGvHD) was 39%, with a 10% transplant-related mortality rate, while the overall survival rate at 2 years was 67%, suggesting that this approach is both safe and effective for improving outcomes in pediatric AML patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

TCR-alpha/beta and CD19 depletion and treosulfan-based conditioning regimen in unrelated and haploidentical transplantation in children with acute myeloid leukemia. Maschan, M., Shelikhova, L., Ilushina, M., et al.[2022]

Transplanting highly purified peripheral blood progenitor cells (PBPC) from alternative donors in 8 patients with Fanconi anemia resulted in a low incidence of graft-versus-host disease (GVHD), with only 2 cases of grade I acute GVHD and no chronic GVHD observed.

Despite some challenges, including two cases of secondary graft failure and three patient deaths, the overall survival rate at a median follow-up of 12 months was 58%, indicating that this method may improve transplant outcomes for patients with Fanconi anemia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Low risk of graft-versus-host disease with transplantation of CD34 selected peripheral blood progenitor cells from alternative donors for Fanconi anemia. Boyer, MW., Gross, TG., Loechelt, B., et al.[2019]

Haplo-identical donors (HDs) provide better event-free survival (EFS) for Fanconi anemia patients undergoing hematopoietic cell transplantation (HCT) compared to HLA-mismatched unrelated donors (MMUD), especially when using unmanipulated grafts, with EFS rates of 86% versus 58%.

The study found that acute graft-versus-host disease (GVHD) rates were significantly lower in patients receiving T cell-depleted grafts from HDs (17%) compared to those from MMUD (41%) and unmanipulated HDs (40%), suggesting that T cell depletion may enhance safety in HCT.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Haplo-identical or mismatched unrelated donor hematopoietic cell transplantation for Fanconi anemia: Results from the Severe Aplastic Anemia Working Party of the EBMT. Zubicaray, J., Pagliara, D., Sevilla, J., et al.[2021]

References

1. United States pubmed.ncbi.nlm.nih.gov

HLA-haploidentical TCRαβ+/CD19+-depleted stem cell transplantation in children and young adults with Fanconi anemia. [2022]

2. England pubmed.ncbi.nlm.nih.gov

Successful haploidentical bone marrow transplantation in Fanconi anemia. [2004]

3. England pubmed.ncbi.nlm.nih.gov

Rejection of the second allogeneic graft in a child with Fanconi anemia reversed by antilymphocyte globulin and donor lymphocyte infusion. [2016]

4. United States pubmed.ncbi.nlm.nih.gov

Generation and flow cytometric quality control of clinical-scale TCRαβ/CD19-depleted grafts. [2017]

5. England pubmed.ncbi.nlm.nih.gov

TcRαβ-depleted haploidentical transplantation results in adult acute leukemia patients. [2017]

6. England pubmed.ncbi.nlm.nih.gov

TCR-alpha/beta and CD19 depletion and treosulfan-based conditioning regimen in unrelated and haploidentical transplantation in children with acute myeloid leukemia. [2022]

7. United States pubmed.ncbi.nlm.nih.gov

Low risk of graft-versus-host disease with transplantation of CD34 selected peripheral blood progenitor cells from alternative donors for Fanconi anemia. [2019]

8. United States pubmed.ncbi.nlm.nih.gov

Haplo-identical or mismatched unrelated donor hematopoietic cell transplantation for Fanconi anemia: Results from the Severe Aplastic Anemia Working Party of the EBMT. [2021]