Stem Cell Transplant for Scleroderma

(SSc Trial)

Recruiting at 1 trial location

Overseen By Paul Szabolcs, MD

Age: < 65

Sex: Any

Trial Phase: Phase 2

Sponsor: Paul Szabolcs

Must be taking: DMARDS

Must not be taking: Steroids

Disqualifiers: Severe cardiac, pulmonary, renal, others

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: Unknown

Duration: Up to 90 days

8 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests whether a combination of high-dose therapies, including cyclophosphamide (a chemotherapy drug), thiotepa (a chemotherapy agent), and total body irradiation (a form of radiation therapy), is safe and effective for people with systemic sclerosis, a condition that causes skin thickening and organ damage. The trial targets children, adolescents, and young adults who have not improved with at least two standard treatments and experience issues like worsening skin or lung problems, muscle inflammation, joint pain, or fingertip sores. Participants will undergo a stem cell transplant, using their own blood-forming cells to rebuild their immune system. As a Phase 2 trial, the research focuses on measuring how well the treatment works in an initial, smaller group of people.

Do I need to stop my current medications for the trial?

The trial information does not specify if you need to stop taking your current medications. However, it mentions that participants must have failed to respond to at least two disease-modifying antirheumatic drugs (DMARDS) before joining, which might imply changes to your current treatment. Please consult with the trial coordinators for specific guidance.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that using a person's own stem cells, known as autologous stem cell transplantation (ASCT), is a safe treatment option for people with systemic sclerosis (SSc). In past studies, patients who underwent this procedure found it both effective and manageable. One study examined different methods for preparing the stem cells and found that CD34-selected ASCT had a good safety record, with few serious side effects.

While side effects can occur with any medical treatment, evidence suggests that ASCT is generally safe for those with severe systemic sclerosis. The treatment uses a person's own stem cells to help repair and rebuild their immune system after a high-dose treatment that aims to eliminate the harmful immune cells causing the disease.

Overall, based on past research, ASCT appears to be a promising option for those considering participation in a trial for SSc. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about autologous stem cell transplantation for scleroderma because it offers a unique approach by using the patient's own stem cells to potentially reset the immune system. This method differs from standard treatments like immunosuppressive drugs, which mainly aim to reduce symptoms. The transplantation involves a conditioning regimen, including cyclophosphamide, thiotepa, and total body irradiation, to prepare the body for the stem cell infusion. By focusing on re-establishing a healthy immune response, this strategy may provide a more lasting solution than current options that mainly manage the disease rather than modifying its course.

What evidence suggests that this trial's treatments could be effective for scleroderma?

Research has shown that using a person's own stem cells for treatment holds promise for severe systemic sclerosis (SSc). In one study, 87.5% of participants did not experience disease progression after one year, and 81.8% maintained this result after two years. Another study found that this treatment extended survival and symptom-free periods compared to other treatments. The risk of mortality from the transplant was relatively low, with only a 6% chance over six years. This evidence suggests that the treatment can be effective for individuals with severe forms of scleroderma. ^{2 3 6 7 8}

Who Is on the Research Team?

Paul Szabolcs, MD

Principal Investigator

University of Pittsburgh

Are You a Good Fit for This Trial?

This trial is for young individuals aged 8-24 with Systemic Sclerosis diagnosed before age 19, who haven't improved after trying at least two DMARDs. They should have skin thickening or worsening lung disease and be free from HIV, hepatitis B/C, and untreated renal crisis. Participants must not be pregnant, agree to birth control if applicable, and have clearance for stem cell transplantation.

Inclusion Criteria

I am between 8 and 24 years old.

I was diagnosed with Systemic Sclerosis before I turned 20.

My lung condition has worsened in the last 18 months.

Exclusion Criteria

My kidney function is reduced, with a filtration rate under 40 mL/min.

My lung function test shows less than 35% capacity.

Your liver enzyme levels are more than four times the normal limit.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Stem Cell Mobilization

Participants undergo stem cell mobilization and conditioning before receiving CD34-selected autologous peripheral blood stem cell rescue

3-12 weeks

Treatment

Participants receive high-dose immunoablative therapy followed by transplantation of CD34+ positively selected peripheral blood stem cells

Up to 90 days

Follow-up

Participants are monitored for safety, treatment effect, and disease progression, including assessments of survival, secondary malignancies, and SSC activity

36 months

What Are the Treatments Tested in This Trial?

Interventions

• Alemtuzumab
• Anti Thymocyte Globulin
• Cyclophosphamide
• GM-CSF
• Intravenous immunoglobulin
• Mesna
• Rituximab
• Thiotepa
• Total Body Irradiation

Trial Overview

The study tests a high-dose immunoablative therapy regimen using drugs like Thiotepa and Cyclophosphamide combined with treatments such as Total Body Irradiation in patients with Systemic Sclerosis. The goal is to assess safety compared to other regimens while looking for treatment effectiveness.

How Is the Trial Designed?

Group I: Autologous Stem Cell Transplantation Experimental Treatment 9 Interventions

CD34-selected autologous stem cell being performed on CliniMACS depletion device. Conditioning regimen will not start sooner than 3 weeks, and ideally no more than 90 days, after cyclophosphamide dose in the mobilization regimen.

Cyclophosphamide is already approved in United States, European Union, Canada, Japan for the following indications:

Approved in United States as Cytoxan for:

• Breast cancer
• Ovarian cancer
• Multiple myeloma
• Leukemia
• Lymphoma
• Rheumatoid arthritis

Approved in European Union as Endoxan for:

• Breast cancer
• Ovarian cancer
• Multiple myeloma
• Leukemia
• Lymphoma
• Rheumatoid arthritis

Approved in Canada as Neosar for:

• Breast cancer
• Ovarian cancer
• Multiple myeloma
• Leukemia
• Lymphoma
• Rheumatoid arthritis

Approved in Japan as Endoxan for:

• Breast cancer
• Ovarian cancer
• Multiple myeloma
• Leukemia
• Lymphoma

Who Is Running the Clinical Trial?

Paul Szabolcs

Lead Sponsor

Trials

8

Recruited

230+

Published Research Related to This Trial

A phase I-II clinical trial involving 12 patients with systemic sclerosis (SSc) demonstrated that autologous hematopoietic stem cell transplantation (HSCT) is feasible and has low toxicity, with a graft failure probability of 28.6%.

After 18 months, 8 out of 11 patients showed major or partial responses, indicating that this treatment can provide significant short-term clinical benefits for severe SSc.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Autologous bone marrow transplantation in the treatment of refractory systemic sclerosis: early results from a French multicentre phase I-II study. Farge, D., Marolleau, JP., Zohar, S., et al.[2019]

In vitro studies of Ewing's sarcoma cell lines showed they are more resistant to radiation than human bone marrow cells, suggesting that total body irradiation (TBI) could be an effective systemic treatment for high-risk patients.

The proposed TBI regimen of two 4.0 Gy fractions, spaced 24 hours apart, aims to minimize damage to bone marrow, with autologous bone marrow transplantation recommended afterward to support recovery.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

In vitro radiation studies on Ewing's sarcoma cell lines and human bone marrow: application to the clinical use of total body irradiation (TBI). Kinsella, TJ., Mitchell, JB., McPherson, S., et al.[2019]

Myeloablative autologous hematopoietic stem-cell transplantation significantly improved event-free survival (79% vs. 50%) and overall survival (86% vs. 51%) compared to cyclophosphamide treatment in patients with severe scleroderma over a 54-month period.

While the transplantation method showed better long-term outcomes, it also had a treatment-related mortality rate of 3% at 54 months, indicating a higher risk of toxicity compared to cyclophosphamide, which had no treatment-related deaths.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Myeloablative Autologous Stem-Cell Transplantation for Severe Scleroderma. Sullivan, KM., Goldmuntz, EA., Keyes-Elstein, L., et al.[2022]

In a study of 32 patients with newly diagnosed metastatic Ewing's sarcoma, consolidation therapy using high-dose melphalan, etoposide, and total-body irradiation did not improve event-free survival rates, with only a 24% survival rate for those who received the therapy.

Three patients experienced severe toxicity during the high-dose phase, highlighting safety concerns, and the majority of patients ultimately relapsed and died from progressive disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

High-dose melphalan, etoposide, total-body irradiation, and autologous stem-cell reconstitution as consolidation therapy for high-risk Ewing's sarcoma does not improve prognosis. Meyers, PA., Krailo, MD., Ladanyi, M., et al.[2020]

In a study involving 10 patients with refractory bone and soft tissue sarcoma, high-dose chemotherapy followed by autologous peripheral blood stem cell transplantation showed limited complications, with only one case of hepatic veno-occlusive disease.

The treatment resulted in 5 patients being alive with no evidence of disease, suggesting that high-dose chemotherapy may be a viable alternative to radical surgery for certain sarcomas, although its efficacy was temporary for spindle cell sarcomas, indicating a need for further investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[High-dose chemotherapy with autologous peripheral blood stem cell transplantation (PBSCT) for refractory bone and soft tissue sarcomas]. Yonemoto, T., Tatezaki, S., Ishii, T., et al.[2013]

In a Phase I reevaluation of thioTEPA involving 27 patients, the recommended new dose for most patients was determined to be 65 mg/m2, as higher doses led to significant myelosuppression, particularly thrombocytopenia and leukopenia.

ThioTEPA showed some efficacy in treating ovarian cancer, with three partial remissions observed, and its pharmacokinetics indicated that the formation of its active metabolite, TEPA, is dose-dependent, affecting the drug's clearance and toxicity profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I/pharmacokinetic reevaluation of thioTEPA. O'Dwyer, PJ., LaCreta, F., Engstrom, PF., et al.[2013]

In a study of 347 pediatric patients with acute lymphoblastic leukemia (ALL) undergoing hematopoietic stem cell transplant (HSCT), the addition of thiotepa to the standard TBI/cyclophosphamide regimen did not increase transplant-related mortality, indicating it is a safe addition.

While the thiotepa group showed a trend towards lower relapse rates and improved disease-free survival over time, these benefits were not statistically significant, suggesting that more research is needed to determine its effectiveness in improving disease control.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Addition of Thiotepa to Total Body Irradiation and Cyclophosphamide Conditioning for Allogeneic Hematopoietic Stem Cell Transplantation in Pediatric Acute Lymphoblastic Leukemia. Chinnabhandar, V., Tran, S., Sutton, R., et al.[2021]

In a meta-analysis of 15 randomized controlled trials involving 10,160 pediatric patients, total body irradiation plus cyclophosphamide (TBI/CY) was found to be more effective than busulfan plus cyclophosphamide (BU/CY) in reducing transplant failure rates and improving long-term disease-free survival rates.

The TBI/CY regimen also demonstrated a lower incidence of adverse reactions compared to the BU/CY regimen, indicating it may be a safer option for pediatric hematopoietic stem cell transplantation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Two Different Transplant Preconditioning Regimens Combined with Irradiation and Chemotherapy in the Treatment of Childhood Leukemia: Systematic Review and Meta-Analysis. Wang, X., Mu, D., Geng, A., et al.[2023]

A case of cutaneous toxicity was observed in a 4.5-year-old girl with medulloblastoma treated with high-dose thiotepa, leading to the identification of thiotepa toxidermia as a potential side effect.

After implementing preventive care guidelines in 2014, only one additional case of cutaneous toxicity was reported among 26 pediatric patients treated with thiotepa, suggesting that these guidelines effectively reduced the incidence of skin-related side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Thiotepa-induced cutaneous toxicity in pediatric patients: Case report and implementation of preventive care guidelines. Van Schandevyl, G., Bauters, T.[2019]

Total body irradiation (TBI) for treating rapidly progressive scleroderma often results in lung and kidney doses that exceed the safety limits set by the SCOT trial, with average lung doses reaching 629 cGy, which is triple the mandated 200 cGy.

The study highlights significant variability and inaccuracy in measuring lung and kidney doses during TBI, suggesting that the current protocol needs clearer guidelines to ensure safety and efficacy in treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Matching Protocol and Practice: The Challenge of Meeting Lung and Kidney Total Body Irradiation Constraints for Scleroderma. Chiang, BH., Wallner, K., Ermoian, R., et al.[2023]

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 19-year-old man with systemic sclerosis experienced congestive heart failure during high-dose cyclophosphamide treatment, prompting a change in his conditioning regimen for stem cell transplantation.

Using thiotepa instead of high-dose cyclophosphamide helped reduce the risk of cardiotoxicity, leading to a successful post-transplant recovery and significant improvement in skin thickness associated with scleroderma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Successful autologous peripheral blood stem cell transplantation using thiotepa in a patient with systemic sclerosis and cardiac involvement. Komatsuda, A., Kawabata, Y., Horiuchi, T., et al.[2019]

Stem cell apheresis (SCA) is feasible and effective in mobilizing stem cells from adult patients with Ewing sarcoma, with a median yield of 10.6 CD34+ cells/kg body weight in 89% of patients studied.

The study indicates that it is safe to delay stem cell collection until after later cycles of VIDE chemotherapy, suggesting flexibility in treatment protocols for Ewing sarcoma patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Analysis of stem cell collections in adult patients with Ewing sarcoma. Franke, GN., Pfannes, R., Heyn, S., et al.[2022]

In a pilot study of 17 patients with nonmetastatic Ewing's sarcoma, the combination of adjuvant chemotherapy and sequential half-body irradiation resulted in a 3-year survival rate of 49%.

When compared to 18 patients receiving standard adjuvant therapy, the overall 5-year survival rate was higher at 61%, suggesting that the pilot protocol may offer comparable efficacy with manageable side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ewing's sarcoma: a trial of adjuvant chemotherapy and sequential half-body irradiation. Berry, MP., Jenkin, RD., Harwood, AR., et al.[2019]

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