Stem Cell Transplant + JSP191 for Fanconi Anemia

Recruiting in Palo Alto (17 mi)

Overseen by Rajni Agarwal, MD

Age: Any Age

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1 & 2

Recruiting

Sponsor: Porteus, Matthew, MD

Must not be taking: Investigational agents

Disqualifiers: HIV, Active infections, Malignancies, others

No Placebo Group

Breakthrough Therapy

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}

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.

Trial 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 (Stem Cell Transplant)
• JSP191 (Monoclonal Antibodies)

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.

Find a Clinic Near You

Research Locations Nearby Select from list below to view details:

Stanford University Stanford, CA

Who Is Running the Clinical Trial?

Porteus, Matthew, MD Lead Sponsor

Maria Grazia Roncarolo Lead Sponsor

Rajni Agarwal Lead Sponsor

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] We report on the outcome of 24 patients with Fanconi anemia (FA) lacking an HLA matched related or unrelated donor, given an HLA-haploidentical T-cell receptor αβ (TCRαβ+) and CD19+ cell-depleted hematopoietic stem cell transplantation (HSCT) in the context of a prospective, single-center phase 2 trial. Sustained primary engraftment was achieved in 22 (91.6%) of 24 patients, with median time to neutrophil recovery of 12 days (range, 9-15 days) and platelet recovery of 10 days (range, 7-14 days). Cumulative incidences of grade 1 to 2 acute graft-versus-host disease (GVHD) and chronic GVHD were 17.4% (95% confidence interval [CI], 5.5%-35.5%) and 5.5% (95% CI, 0.8%-33.4%), respectively. The conditioning regimen, which included fludarabine, low-dose cyclophosphamide and, in most patients, single-dose irradiation was well tolerated; no fatal transplant-related toxicity was observed. With a median follow-up of 5.2 years (range, 0.3-8.7 years), the overall and event-free survival probabilities were 100% and 86.3% (95% CI, 62.8%-95.4%), respectively (2 graft failures and 1 case of poor graft function were considered as events). The 2 patients who experienced primary graft failure underwent a subsequent successful HSCT from the other parent. This is the first report of FA patients given TCRαβ+/CD19+-depleted haplo-HSCT in the context of a prospective trial, and the largest series of T-cell-depleted haplo-HSCT in FA reported to date. This trial was registered at www.clinicaltrials.gov as #NCT01810120.

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

Successful haploidentical bone marrow transplantation in Fanconi anemia. [2004] A 10-year-old girl with Fanconi anemia and severe aplastic anemia underwent a haploidentical BMT from her mother due to lack of a matched family donor. T cell depletion was done by positive selection of CD34 cells with immunomagnetic beads. Due to graft rejection a second haploidentical BMT from the father was successfully undertaken. No immunosuppression was given after the transplant. Immunological reconstitution took approximately 6 months, with no GVHD or severe infections. Such a transplant, containing a large purified CD34 cell fraction with a minimal number of added T cells, should be considered as the treatment of choice for patients with Fanconi anemia if no HLA matched donor is available.

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] Rejection after allogeneic bone marrow transplantation for Fanconi anemia (FA) is a complication with a high risk of mortality. We describe a patient who, following a second episode of rejection after a second allogeneic stem cell transplantation, was successfully treated with antilymphocyte globulin, followed by donor lymphocyte infusion. At three and a half years after donor lymphocyte infusion, she is alive with a Karnofsky score of 90%. Her molecular chimerism is of donor origin. Thus, donor lymphocyte infusion can be considered as a therapy option for rejection after allogeneic bone marrow transplantation for FA.

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

Generation and flow cytometric quality control of clinical-scale TCRαβ/CD19-depleted grafts. [2017] Label="BACKGROUND">The depletion of TCR&#945;&#946;+ T cells and CD19+ B cells is a graft purification method for haploidentical stem cell transplantation (HSCT) retaining stem cells, NK cells and TCR&#947;&#948;+ T cells. To avoid treatment-related occurrence of severe GvHD a precise quantification of residual TCR&#945;&#946;+ T cells in the graft is of essential importance.

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

TcRαβ-depleted haploidentical transplantation results in adult acute leukemia patients. [2017] The use of αβ+ T-cell-depleted grafts is a novel approach to prevent graft failure, graft-versus-host disease (GVHD), and non-relapse mortality (NRM) in patients undergoing haploidentical hematopoietic stem cell transplantation.

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] We evaluated the depletion of TCR-alpha/beta cells from the graft of children with high-risk AML, who received transplantation from unrelated (n=20) and haploidentical donors (n=13). The preparative regimen included treosulfan, melphalan, fludarabine and anti-thymocyte globulin. Grafts were PBSC engineered by TCR-alpha/beta and CD19 depletion. The graft contained a median of 9 × 10(6)/kg of CD34+ and 20 × 10(3)/kg of αβ-T cells. Post-transplant immune suppression included tacrolimus till day +30 and Mtx in 21 patients, tacrolimus in 5, Mtx in 2 and no prophylaxis in 5 patients. Sixteen patients received native or TCR-alpha/beta-depleted donor lymphocytes at a median of 47 (40-204) days. Median follow-up is 1.76 years. Primary engraftment was achieved in 33 patients (100%). Cumulative incidence of acute GvHD (aGvHD) grade 2-3 was 39 (26-60)%, half of them had skin-only aGvHD. Cumulative incidence of chronic GvHD was 30(18-50)%. Transplant-related mortality is 10(4-26)%. Event-free survival (EFS) is 60(43-76)% and overall survival (OS) is 67(50-84)% at 2 years. In a subgroup of patients, who received transplantation in CR, EFS is 66(48-84)% and OS-72(53-90)% at 2 years. Our data suggest that TCR-alpha/beta and CD19 depletion is a robust method of graft manipulation, which can be used to engineer grafts for children with AML.

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] Transplant results for Fanconi anemia with alternative-donor bone marrow transplantation currently entail a high incidence of graft failure and graft-versus-host disease (GVHD). The authors sought to improve outcome in this disease category with alternative donors with a 5-6/6 antigen match by transplantation of highly purified peripheral blood progenitor cells (PBPC) using the Isolex 300i v2.5 device as a means of T-cell depletion to lessen the risk of GVHD.

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] Allogeneic hematopoietic cell transplantation (HCT) is the only curative option for bone marrow failure or hematopoietic malignant diseases for Fanconi anemia (FA) patients. Although results have improved over the last decades, reaching more than 90% survival when a human leukocyte antigen (HLA)-identical donor is available, alternative HCT donors are still less reported. We compared HCT outcomes using HLA-mismatched unrelated donors (MMUD; n = 123) or haplo-identical donors (HDs), either using only in vivo T cell depletion (n = 33) or T cells depleted in vivo with some type of graft manipulation ex vivo (n = 59) performed for FA between 2000 and 2018. Overall survival (OS) by 24 months was 62% (53-71%) for MMUD, versus 80% (66-95%) for HDs with only in vivo T cell depletion and 60% (47-73%) for HDs with in vivo and ex vivo T cell depletion (p = .22). Event-free survival (EFS) was better for HD-transplanted FA patients with only in vivo T cell depletion 86% (73-99%) than for those transplanted from a MMUD 58% (48-68%) or those with graft manipulation 56% (42-69%) (p = .046). Grade II-IV acute graft-versus-host disease (GVHD) was 41% (MMUD) versus 40% (HDs with no graft manipulation) versus 17% (HDs with T cell depleted graft), (p = .005). No differences were found for the other transplant related outcomes. These data suggest that HDs might be considered as an alternative option for FA patients with better EFS using unmanipulated grafts.