Stem Cell Transplant for Scleroderma

(SSc Trial)

Recruiting in Palo Alto (17 mi)

+1 other location

Overseen by Paul Szabolcs, MD

Age: < 65

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 2

Recruiting

Sponsor: Paul Szabolcs

Must be taking: DMARDS

Must not be taking: Steroids

Disqualifiers: Severe cardiac, pulmonary, renal, others

No Placebo Group

Prior Safety Data

Breakthrough Therapy

Trial Summary

What is the purpose of this trial?

The purpose of this study is to determine whether a regimen of high-dose immunoablative therapy will demonstrate safety that is consistent or improved with other published regimens in SSc patients, while maintaining a treatment effect.

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.

What data supports the effectiveness of the treatment for Scleroderma?

The research does not directly address the effectiveness of the treatment for Scleroderma, but it does mention the use of high-dose chemotherapy and stem cell transplantation in other conditions like Ewing's sarcoma, where some patients achieved remission. This suggests potential benefits of similar approaches in other diseases, though further specific research for Scleroderma is needed. ^{1 2 3 4 5}

Is stem cell transplant using thiotepa safe for humans?

Thiotepa, used in stem cell transplants, can cause myelosuppression (a decrease in bone marrow activity) and skin toxicity, but these side effects are generally manageable with preventive care. In studies, thiotepa did not increase transplant-related mortality and was used to reduce heart-related side effects from other drugs like cyclophosphamide. ^{6 7 8 9 10}

How does the stem cell transplant treatment for scleroderma differ from other treatments?

This treatment is unique because it combines stem cell transplantation with a conditioning regimen that includes cyclophosphamide, thiotepa, and total body irradiation, which aims to reset the immune system and reduce disease progression. It offers an alternative to traditional immunosuppression and has shown significant benefits in stabilizing the disease compared to cyclophosphamide alone. ^{6 11 12 13 14}

Research Team

Paul Szabolcs, MD

Principal Investigator

University of Pittsburgh

Eligibility Criteria

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.

Trial Timeline

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

Treatment Details

Interventions

• Alemtuzumab (Monoclonal Antibodies)
• Anti Thymocyte Globulin (Immunotherapy)
• Cyclophosphamide (Chemotherapy)
• GM-CSF (Immunotherapy)
• Intravenous immunoglobulin (Immunotherapy)
• Mesna (Chemotherapy)
• Rituximab (Monoclonal Antibodies)
• Thiotepa (Chemotherapy)
• Total Body Irradiation (Radiation)

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.

Participant Groups

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 Canada, Japan for the following indications:

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+

Findings from Research

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]

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 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 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]

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]

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]

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 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 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]

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]

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]

References

1. United States 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. [2020]

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

Analysis of stem cell collections in adult patients with Ewing sarcoma. [2022]

3. Japan pubmed.ncbi.nlm.nih.gov

[High-dose chemotherapy with autologous peripheral blood stem cell transplantation (PBSCT) for refractory bone and soft tissue sarcomas]. [2013]

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

Ewing's sarcoma: a trial of adjuvant chemotherapy and sequential half-body irradiation. [2019]

5. United States 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). [2019]

6. Japan pubmed.ncbi.nlm.nih.gov

Successful autologous peripheral blood stem cell transplantation using thiotepa in a patient with systemic sclerosis and cardiac involvement. [2019]

7. United States 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. [2021]

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

Phase I/pharmacokinetic reevaluation of thioTEPA. [2013]

9. England 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. [2023]

10. England pubmed.ncbi.nlm.nih.gov

Thiotepa-induced cutaneous toxicity in pediatric patients: Case report and implementation of preventive care guidelines. [2019]

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

Matching Protocol and Practice: The Challenge of Meeting Lung and Kidney Total Body Irradiation Constraints for Scleroderma. [2023]

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

Myeloablative Autologous Stem-Cell Transplantation for Severe Scleroderma. [2022]

13. England pubmed.ncbi.nlm.nih.gov

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

14. England 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. [2019]