Stem Cell Transplant for Scleroderma

(STAT Trial)

Recruiting at 11 trial locations

Age: Any Age

Sex: Any

Trial Phase: Phase 2

Sponsor: Fred Hutchinson Cancer Research Center

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

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 1

21 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial tests a treatment for systemic scleroderma involving stem cell collection, high-dose chemotherapy, and immune suppression, followed by returning the patient's own stem cells and using a maintenance drug to prevent disease recurrence. The treatment has shown a satisfactory risk-benefit ratio in earlier studies.

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop taking your current medications, but it mentions that participants must be willing or able to discontinue certain disease-modifying antirheumatic drugs (DMARDs) before starting the treatment.

What data supports the effectiveness of the treatment for scleroderma?

Research shows that using anti-thymocyte globulin (ATG) and mycophenolate mofetil (MMF) can be safe and effective for treating diffuse scleroderma, and stem cell transplantation has shown significant benefits over cyclophosphamide in systemic sclerosis, improving survival and lung function. ^{1 2 3 4 5}

Is stem cell transplant using anti-thymocyte globulin (ATG) generally safe for humans?

Anti-thymocyte globulin (ATG) has been used in various treatments, including stem cell transplants, and can cause adverse effects like fever, with 62.1% of patients experiencing some side effects. Severe reactions are less common, leading to treatment discontinuation in about 10.8% of cases. Additionally, ATG can induce serum sickness (a type of allergic reaction) in almost all patients without other immunosuppressive drugs. ^{6 7 8 9 10}

How is the stem cell transplant treatment for scleroderma different from other treatments?

This treatment is unique because it combines stem cell transplantation with anti-thymocyte globulin (ATG) and cyclophosphamide, which helps reset the immune system and reduce skin thickening, offering potential benefits over standard drug treatments like cyclophosphamide alone. ^{1 2 3 5 11}

Research Team

Leona Holmberg

Principal Investigator

Fred Hutch/University of Washington Cancer Consortium

Eligibility Criteria

This trial is for patients with systemic scleroderma, specifically those who have had the disease for less than two years with severe skin involvement or lung problems, and those not responding to standard treatments. It's not open to individuals with a life expectancy under five years, prior stem cell transplants, uncontrolled infections, recent cancers (except certain skin cancers), GAVE ('watermelon stomach'), smokers in the last three months, pregnant women, or those unable to consent.

Inclusion Criteria

I have systemic sclerosis with skin involvement, not in Group 5, at risk of getting worse.

My condition did not improve after 4+ months on MMF/Myfortic or cyclophosphamide.

My gastrointestinal condition is getting worse.

Exclusion Criteria

I have lung, heart, liver, or kidney problems that could affect my treatment.

I cannot or will not stop taking certain medications for my scleroderma.

I have had a stem cell transplant using my own cells.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Stem Cell Mobilization and Preparation

Patients receive filgrastim and possibly cyclophosphamide or plerixafor to mobilize stem cells for collection

1-2 weeks

Multiple visits for apheresis

HDIT Conditioning

Patients receive high-dose cyclophosphamide and anti-thymocyte globulin to prepare for transplantation

1 week

Transplantation

Patients undergo autologous peripheral blood stem cell transplantation

1 day

Maintenance Therapy

Patients receive mycophenolate mofetil to prevent worsening or reactivation of systemic sclerosis

2 years

Follow-up

Participants are monitored for safety and effectiveness after treatment

5 years

Follow-up at 1 month, weeks 12 and 26, then annually

Treatment Details

Interventions

• Anti-Thymocyte Globulin
• Cyclophosphamide
• Filgrastim
• Mycophenolate Mofetil
• Plerixafor

Trial Overview The STAT study tests whether a combination of high-dose cyclophosphamide and anti-thymocyte globulin followed by autologous hematopoietic stem cell transplantation can treat systemic scleroderma. After transplanting the patient's own stored stem cells back into their body post-chemotherapy and immunosuppression therapy, maintenance therapy with mycophenolate mofetil is used to prevent worsening of SSc.

Participant Groups

Group I: Treatment (HDIT autologous PBSCT) Experimental Treatment 10 Interventions

STEM CELL MOBILIZATION AND PREPARATION: Patients receive filgrastim SC on mobilization days 1-4 followed by apheresis until a target dose of CD34+ cells \>= 2.5 x 10\^6/kg are collected. Patients difficult to mobilize with filgrastim alone receive cyclophosphamide IV or \*plerixafor SC on mobilization days 1-2 and filgrastim SC on mobilization days 5-7. HDIT CONDITIONING: Patients receive high-dose cyclophosphamide IV over 1-2 hours on days -5 to -2 and anti-thymocyte globulin IV on days -5, -3, -1, 1, 3, and 5. TRANSPLANTATION: Patients undergo autologous PBSCT on day 0. MAINTENANCE THERAPY: Beginning 2-3 months after transplant, patients receive mycophenolate mofetil PO BID for 2 years.

Anti-Thymocyte Globulin is already approved in European Union, United States for the following indications:

Approved in European Union as Thymoglobulin for:

• Prevention and treatment of acute rejection following organ transplantation
• Severe aplastic anemia

Approved in United States as Thymoglobulin for:

• Prevention and treatment of acute rejection following kidney transplantation
• Severe aplastic anemia

Who Is Running the Clinical Trial?

Fred Hutchinson Cancer Research Center

Lead Sponsor

Trials

444

Recruited

148,000+

Fred Hutchinson Cancer Center

Lead Sponsor

Trials

583

Recruited

1,341,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Findings from Research

In a pilot study of 13 patients with recent-onset diffuse scleroderma, treatment with anti-thymocyte globulin (ATG) followed by mycophenolate mofetil (MMF) resulted in a significant decrease in skin score from 28 to 17 over 12 months, indicating improved skin condition.

While MMF was well tolerated, some patients experienced adverse effects, including serum sickness in five patients, which was manageable with corticosteroids, suggesting that while the treatment is generally safe, monitoring for side effects is necessary.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pilot study of anti-thymocyte globulin plus mycophenolate mofetil in recent-onset diffuse scleroderma. Stratton, RJ., Wilson, H., Black, CM.[2019]

Haematopoietic stem cell transplant (HSCT) significantly alters the autoantibody repertoire in patients with systemic sclerosis, showing a more favorable outcome compared to cyclophosphamide (CTX) treatment, as evidenced by a study involving 45 participants from the SCOT trial.

Patients treated with HSCT exhibited significant changes in autoantibody levels against various antigens, suggesting that HSCT may stabilize the immune response, while CTX treatment did not show similar changes, indicating a potential mechanism for improved clinical outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Characterising the autoantibody repertoire in systemic sclerosis following myeloablative haematopoietic stem cell transplantation. Ayoglu, B., Donato, M., Furst, DE., et al.[2023]

A study comparing four batches of antithymocyte globulins (ATGs) showed that both ATG-Fresenius and Thymoglobulin had consistent binding and functional properties when interacting with human leukocytes, suggesting similar clinical efficacy across different batches.

The research utilized flow cytometric assays to analyze the reactivity of ATGs with leukocytes, indicating that variations in batch preparation are unlikely to impact their effectiveness in preventing allograft rejection and graft versus host disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Assessment of batch to batch variation in polyclonal antithymocyte globulin preparations. Popow, I., Leitner, J., Majdic, O., et al.[2014]

A systematic review of 6 phase III randomized controlled trials found that rabbit antithymocyte globulin (ATG) formulations, particularly anti-T lymphocyte globulin (ATLG), are effective in preventing graft-versus-host disease (GVHD) after allogeneic stem cell transplantation, showing significantly better outcomes compared to standard treatments.

While both ATLG and Thymoglobulin (Thymo) had similar effects on transplantation-related mortality, Thymo showed a trend towards better overall survival, suggesting that Thymo may be a preferable option for improving long-term survival outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of Different Rabbit Anti-Thymocyte Globulin Formulations in Allogeneic Stem Cell Transplantation: Systematic Literature Review and Network Meta-Analysis. Gagelmann, N., Ayuk, F., Wolschke, C., et al.[2018]

Rabbit-derived antithymocyte globulin (ATG) can induce a strong immune response in patients, leading to the production of antibodies against specific rabbit glycoprotein epitopes, which may compromise its effectiveness in treating conditions like type 1 diabetes.

The study found that patients developed significant levels of antibodies against these rabbit-specific epitopes after ATG treatment, suggesting that using IgGs without these xenoantigens could enhance the safety and efficacy of ATG therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Anti-Gal and Anti-Neu5Gc Responses in Nonimmunosuppressed Patients After Treatment With Rabbit Antithymocyte Polyclonal IgGs. Salama, A., Evanno, G., Lim, N., et al.[2022]

In a study of 29 patients receiving anti-thymocyte globulin (ATG) and anti-lymphocyte globulin (ALG) for aplastic anemia, 62.1% experienced adverse effects, with fever being the most common.

ATG, which is rabbit-derived, was associated with more frequent adverse effects compared to ALG, and shorter intervals between treatment cycles increased the risk of these reactions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Adverse effects of anti-thymocyte globulin/anti-lymphocyte globulin therapy]. Kobayashi, R., Kaneda, M., Watanabe, N., et al.[2006]

In a study of six patients with steroid-resistant T-cell-mediated rejection after kidney transplantation, anti-thymocyte globulin (ATG) treatment led to a significant increase in T-cell repopulation from 24% to 75%, primarily driven by effector memory CD8+ T cells.

The administration of ATG also resulted in an increase in regulatory T cells, suggesting a potential mechanism for modulating immune responses, while other immune cell types like B cells and natural killer cells showed no significant changes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Analysis of Immune Cell Repopulation After Anti-thymocyte Globulin Administration for Steroid-Resistant T-cell-mediated Rejection. Sim, JH., Han, SS., Lee, DS., et al.[2020]

References

1. England pubmed.ncbi.nlm.nih.gov

Pilot study of anti-thymocyte globulin plus mycophenolate mofetil in recent-onset diffuse scleroderma. [2019]

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

Anti-thymocyte globulin exposure in patients with diffuse cutaneous systemic sclerosis undergoing autologous haematopoietic stem cell transplantation. [2023]

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

Characterising the autoantibody repertoire in systemic sclerosis following myeloablative haematopoietic stem cell transplantation. [2023]

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

Pilot study of antithymocyte globulin in systemic sclerosis. [2019]

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

Assessment of batch to batch variation in polyclonal antithymocyte globulin preparations. [2014]

6. Germany pubmed.ncbi.nlm.nih.gov

Low-dose anti-thymocyte globulin reduce severe acute and chronic graft-versus-host disease after allogeneic stem cell transplantation. [2018]

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

Rabbit antithymocyte globulin. A 10-year experience in cardiac transplantation. [2019]

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

Comparison of Different Rabbit Anti-Thymocyte Globulin Formulations in Allogeneic Stem Cell Transplantation: Systematic Literature Review and Network Meta-Analysis. [2018]

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

Anti-Gal and Anti-Neu5Gc Responses in Nonimmunosuppressed Patients After Treatment With Rabbit Antithymocyte Polyclonal IgGs. [2022]

10. Japan pubmed.ncbi.nlm.nih.gov

[Adverse effects of anti-thymocyte globulin/anti-lymphocyte globulin therapy]. [2006]

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

Analysis of Immune Cell Repopulation After Anti-thymocyte Globulin Administration for Steroid-Resistant T-cell-mediated Rejection. [2020]