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}

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 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

Find a Clinic Near You

Research Locations Nearby Select from list below to view details:

University of Pittsburgh Medical Center Pittsburgh, PA

Children's Hospital of Pittsburgh of UPMC Pittsburgh, PA

Who Is Running the Clinical Trial?

Paul Szabolcs Lead Sponsor

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] To determine whether consolidation therapy with high-dose melphalan, etoposide, and total-body irradiation (TBI) with autologous stem-cell support would improve the prognosis for patients with newly diagnosed metastatic Ewing's sarcoma (ES).

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

Analysis of stem cell collections in adult patients with Ewing sarcoma. [2022] Ewing sarcoma is one of the most frequent soft-tissue tumors in pediatric patients. The current treatment protocols recommend stem cell apheresis (SCA) after completion of the second course of induction therapy with vincristine, ifosfamide, doxorubicine, and etoposide (VIDE). The feasibility of SCA and graft compositions in adult patients with Ewing sarcoma have not been previously analyzed.

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] High-dose chemotherapy with autologous peripheral blood stem cell transplantation was administered to 10 patients with refractory bone and soft tissue sarcoma (2 patients with primitive neuroectodermal tumor, 4 patients with Ewing's sarcoma, 3 patients with synovial sarcoma and one patient with osteosarcoma). Busulfan 4 mg/kg x 4, melphalan 140 mg/m2 and thiotepa 200 mg/m2 x 3 were used in the high-dose chemotherapy. Complications related to the treatment were limited to one patient who developed hepatic veno-occlusive disease, no serious complications were seen in the other patients. Four patients died of their disease, one patient was alive with the disease and 5 patients were alive with no evidence of disease. The prognosis for non-resectable primitive neuroectodermal tumor and Ewing's sarcoma is said to be very poor. However, there are some patients in whom the disease is kept in remission by high-dose chemotherapy with autologous peripheral blood stem cell transplantation, so this therapy may be a possible substitute for radical operation. With spindle cell sarcomas, the efficacy of this treatment was temporary, so it will be necessary to investigate frequent high-dose chemotherapy and to change the high-dose chemotherapy regimen.

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

Ewing's sarcoma: a trial of adjuvant chemotherapy and sequential half-body irradiation. [2019] The results of a pilot study using adjuvant chemotherapy and sequential half-body irradiation (HBI) for nonmetastatic Ewing's sarcoma are presented. Seventeen patients received Cyclophosphamide, Vincristine, and Adriamycin (8 cycles), followed by sequential radiation treatment of the upper (500 cGy) and lower (600 cGy) half body. Survival at 3 years was 49%. These results are contrasted with those for 18 concurrently treated patients who received standard adjuvant therapy. Overall 5-year survival and relapse-free survival for these 35 consecutive patients was 61 and 53%. The pilot protocol was given on an out-patient basis with limited and acceptable acute toxicology. Further study is necessary to determine the value of the pilot protocol.

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] Patients with Ewing's sarcoma who present with a central axis or proximal extremity primary and/or with metastatic disease have a poor prognosis despite aggressive combination chemotherapy and local irradiation. In this high risk group of patients, total body irradiation (TBI) has been proposed as a systemic adjuvant. To aid in the design of a clinical TBI protocol, we have studied the in vitro radiation response of two established cell lines of Ewing's sarcoma and human bone marrow CFUc. The Ewing's lines showed a larger Do (1.26 Gy, 2.04 Gy) and n (6.0, 3.2) compared to the bone marrow CFUc (Do = 0.86 Gy, n = 1.2). No repair of potentially lethal radiation damage (PLDR) was found after 4.5 Gy in plateau phase Ewing's sarcoma cells. A theoretical split dose survival curve for both the Ewing's sarcoma lines and human bone marrow CFUc using this TBI schedule shows a significantly lower surviving fraction (10(-4)-10(-5] for the bone marrow CFUc. Based on these in vitro results, two 4.0 Gy fractions separated by 24 hours is proposed as the TBI regimen. Because of the potentially irreversible damage to bone marrow, autologous bone marrow transplantation following the TBI is felt to be necessary. The details of this clinical protocol in high risk Ewing's sarcoma patients are outlined.

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] A 19-year-old man with systemic sclerosis (SSc) was hospitalized for autologous peripheral blood stem cell transplantation (auto-PBSCT) due to progressive scleroderma and cardiac involvement despite conventional treatment. During the administration of cyclophosphamide (60 mg/kg/day for 2 days) for mobilization and collection of CD34+ selected peripheral blood stem cells, he developed congestive heart failure. Echocardiogram showed hypokinetic asynergy from the septum to posterior wall, which might indicate underlying cardiac damage. We were also concerned about the risk of high-dose cyclophosphamide-induced cardiotoxicity. Since the dose-limiting toxicity of thiotepa, an alkylating agent, is myelosuppression, and cardiac toxicity due to thiotepa is less common, we used a conditioning regimen consisting of thiotepa (10 mg/kg/day, day -5) and low-dose cyclophosphamide (50 mg/kg/day, days -3 and -2), instead of the conventional high-dose cyclophosphamide (50 mg/kg/day x 4 days/course). The post-transplant course was uneventful, and the modified Rodnan skin thickness score improved from 32 to 15. The present case report demonstrates that thiotepa can be employed as a conditioning regimen for auto-PBSCT in SSc patients with cardiac involvement in order to reduce cyclophosphamide-induced cardiotoxicity.

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] Total body irradiation (TBI)/cyclophosphamide (CY) is a standard-of-care conditioning regimen in allogeneic hematopoietic stem cell transplant (HSCT) for pediatric acute lymphoblastic leukemia (ALL). This study sought to identify whether the addition of thiotepa (TT) to TBI/CY improves HSCT outcomes for pediatric patients with ALL. A retrospective analysis was performed on 347 pediatric ALL patients who underwent HSCT between 1995 and 2015, with 242 receiving TBI/CY/TT and 105 patients receiving TBI/CY. There were no statistical differences in age, donor source, or complete remission status between the 2 groups. Comparison of the TBI/CY/TT versus TBI/CY groups demonstrated no difference in transplant-related mortality at 1 (11% versus 11%), 5 (13% versus 16%), or 10 years (16% versus 16%). There was lower relapse in the TBI/CY/TT group at 1 (14% versus 26%), 5 (24% versus 36%), 10 (26% versus 37%), and 15 years (26% versus 37%) (P= .02) but was not statistically significant on multivariate analysis. The TBI/CY/TT group showed a trend toward improved disease-free survival (DFS) at 5 (59% versus 47%), 10 (56% versus 46%), and 15 years (49% versus 40%) (P = .05) but was not statistically significant on multivariate analysis. Comparing overall survival at 5 (62% versus 53%), 10 (57% versus 50%), and 15 years (50% versus 44%) demonstrated no statistical difference between the 2 groups. The addition of thiotepa to TBI/CY demonstrated no increase in transplant-related mortality for pediatric ALL HSCT but was unable to demonstrate significant benefit in disease control. Minimal residual disease status remained the key risk factor impacting both relapse and DFS. More studies are warranted to better clarify the benefits of using thiotepa in conditioning for ALL HSCT.

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

Phase I/pharmacokinetic reevaluation of thioTEPA. [2013] Because the initial evaluation of N,N',N''-triethylenethiophosphoramide (thioTEPA) preceded the standardized approach to the Phase I trials, uncertainty surrounds the recommended dose. Since it has recently been demonstrated that an almost 100-fold increase in dose can be administered in bone marrow transplant regimens, we conducted a Phase I reevaluation of thioTEPA. ThioTEPA was administered i.v. in 50 ml 5% dextrose in water over 10 min. Twenty-seven patients were entered at doses ranging from 30 to 75 mg/m2. The major toxic effect was myelosuppression; thrombocytopenia greater than or equal to grade 3 occurred in four of seven patients, and leukopenia greater than or equal to grade 3 in two of seven patients at 75 mg/m2. Among eight patients at 65 mg/m2 only two had greater than or equal to grade 3 myelosuppression making this the recommended new phase II dose for the majority of patients. Moderate (grade 2) easily controlled nausea and vomiting was the only other major side effect. There was no alopecia or mucosal or neurological toxicity. Three partial remissions were observed among nine previously treated ovarian cancer patients. Plasma concentrations of thioTEPA and its major active metabolite triethylenephosphoramide (TEPA) were measured by gas chromatography. The half-life of thioTEPA ranged from 51.6 to 211.8 min, and its pharmacokinetics was dose dependent; total body thioTEPA clearance decreased with increasing dose. The half-life of TEPA was considerably longer than that of the parent compound (3.0 to 21.1 h); as a result, the area under the plasma concentration-time curve (AUC) of TEPA was severalfold greater than that of the parent compound. The ratio of TEPA AUC to thioTEPA AUC decreased with increasing dose, suggesting that formation of TEPA is a saturable step in elimination. The AUC and total body clearance of thioTEPA, but not of TEPA, were closely correlated with neutrophil but not platelet toxicity.

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] To observe the therapeutic effect and the incidence of adverse reactions of total body irradiation plus cyclophosphamide (TBI/CY) and busulfan plus cyclophosphamide (BU/CY) in the treatment of pediatric hematopoietic stem cell transplantation.

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

Thiotepa-induced cutaneous toxicity in pediatric patients: Case report and implementation of preventive care guidelines. [2019] Thiotepa, a highly lipophilic, alkylating agent, and/or its active metabolites may be excreted in part via skin in patients receiving high-dose therapy. We present a case of cutaneous toxicity observed in a 4.5-year-old girl patient with medulloblastoma treated with a high-dose thiotepa conditioning regimen before autologous stem cell transplantation. Skin lesions, as well as their pattern and locations, were evocative of thiotepa toxidermia. After the case herein described, preventive care guidelines were implemented in our unit as from 2014. A retrospective follow-up of 26 pediatric patients receiving thiotepa prior to stem cell transplantation was performed until March 2018. In this series of patients, only one patient experienced cutaneous toxicity as reported herein. Thereafter, only mild cutaneous toxicity was observed, even with double or triple transplantation protocols with high-dose thiotepa. Clear preventive care instructions should be detailed in the Summary of Product Characteristics in order to minimize the cutaneous toxicity of thiotepa.

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] Total body irradiation (TBI), a form of immunomodulation, improves treatment outcomes for rapidly progressive scleroderma. The landmark Scleroderma: Cyclophosphamide or Transplantation (SCOT) trial used strict 200-cGy lung and kidney dose restrictions to limit the likelihood of normal tissue toxicity. The protocol as written did not specify how or where the 200-cGy limit was to be measured, opening the door to variable techniques and outcomes.

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

Myeloablative Autologous Stem-Cell Transplantation for Severe Scleroderma. [2022] Despite current therapies, diffuse cutaneous systemic sclerosis (scleroderma) often has a devastating outcome. We compared myeloablative CD34+ selected autologous hematopoietic stem-cell transplantation with immunosuppression by means of 12 monthly infusions of cyclophosphamide in patients with scleroderma.

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

Characterising the autoantibody repertoire in systemic sclerosis following myeloablative haematopoietic stem cell transplantation. [2023] Results from the SCOT (Scleroderma: Cyclophosphamide Or Transplantation) clinical trial demonstrated significant benefits of haematopoietic stem cell transplant (HSCT) versus cyclophosphamide (CTX) in patients with systemic sclerosis. The objective of this study was to test the hypothesis that transplantation stabilises the autoantibody repertoire in patients with favourable clinical outcomes.

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] Haematopoietic stem cell transplantation (HSCT) has been proposed for refractory autoimmune diseases, including systemic sclerosis (SSc). A sequential Bayesian phase I-II clinical trial was conducted in SSc patients to assess the feasibility, the tolerance and the efficacy of autologous HSCT. Peripheral blood stem cells (PBSC) were collected using cyclophosphamide (4 g/m2) and recombinant human granulocyte colony-stimulating factor (5 micro g/kg/d) and reinfused after positive CD34+ selection. Conditioning used cyclophosphamide (200 mg/kg) or melphalan (140 mg/m2) according to cardiac function. The main end-point was the failure of the procedure, defined by failure of either PBSC mobilization, CD34+ selection or intensification procedure, or by procedure-related death. Among the 12 enrolled patients, three failures occurred: one PBSC mobilization, one CD34+ selection and one CD34+ intensification. Probability of graft failure was estimated at 0.286 (95% confidence interval: 0.095-0.54). Autologous PBSC (n = 10) or bone marrow (n = 1) transplantation was actually performed in 11 patients with one procedure-related death. Median time to neutrophil (> 0.5 x 10(9)/l) and platelet (> 25 x 10(9)/l) haematopoietic reconstitution was 12 and 10 d respectively. After 18 months (range 1-26), eight out of 11 patients have shown major or partial response. Non-myeloablative conditioning, followed by a T cell-depleted autologous PBSC or bone marrow transplantation, appears feasible with low toxicity in severe SSc with short-term clinical benefits.