RIC alloBMT + Cyclophosphamide for Scleroderma

Overseen By Christopher Mecoli, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Disqualifiers: Pregnancy, HIV, Malignancy, Drug use, others

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

Approved in 4 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests the safety of a special bone marrow transplant combined with high-dose cyclophosphamide, a chemotherapy drug, for individuals with stubborn scleroderma. This disease causes skin hardening and can affect organs. Researchers aim to determine if this treatment can manage symptoms safely without causing serious side effects like graft vs host disease, where transplanted cells attack the body. Eligible participants should have moderate-to-severe scleroderma, have tried other treatments without success, and qualify for a bone marrow transplant. The study will also examine the treatment's effects on muscles and the heart by monitoring specific blood markers over a year. As a Phase 1 trial, this research seeks to understand how the treatment works in people, offering participants the chance to be among the first to receive this innovative therapy.

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

The trial protocol does not specify if you need to stop your current medications. However, since the trial is for patients who have not responded to first-line therapies, it's possible that adjustments to your current medications might be necessary. Please consult with the trial investigators for specific guidance.

What prior data suggests that this treatment is safe for scleroderma patients?

Research has shown that cyclophosphamide has been tested for safety in people with scleroderma, a condition that causes the skin to become hard and tight. Studies have specifically examined its effects on lung problems related to scleroderma.

One study found that taking cyclophosphamide for a year could improve lung function and skin symptoms. However, side effects may occur, such as infections, nausea, and lower blood cell counts, which can increase susceptibility to illness.

This trial is in an early stage, so more research is needed to confirm its safety. Cyclophosphamide has been used in other studies with people who have scleroderma, suggesting that the drug can be tolerated. Participants should discuss any concerns with the trial team. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Researchers are excited about the treatment for scleroderma in this trial because it combines reduced-intensity conditioning allogeneic bone marrow transplantation (RIC alloBMT) with high-dose cyclophosphamide, offering a potentially powerful option for severe cases. Unlike standard treatments that mainly focus on managing symptoms with medications like methotrexate or mycophenolate mofetil, this approach aims to reset the immune system. The use of high-dose cyclophosphamide following bone marrow transplantation is designed to enhance graft tolerance and reduce the immune system's attack on the body, which is particularly promising for patients with severe scleroderma. This approach could offer long-term relief and potentially alter the disease course in ways current treatments cannot.

What evidence suggests that this treatment might be an effective treatment for scleroderma?

Research has shown that a type of bone marrow transplant from a donor, known as allogeneic bone marrow transplant (alloBMT), might help achieve long-term remission in people with systemic sclerosis (SSc). In this trial, participants will receive a reduced-intensity conditioning alloBMT regimen that includes the drug cyclophosphamide. Studies have found that a gentler treatment plan with cyclophosphamide can effectively manage this condition. Previous research demonstrated that this method can be safe while offering potential benefits for patients with widespread SSc. The main risks include graft vs host disease (GVHD) and infections, but the treatment shows promise in improving symptoms and outcomes for those with difficult-to-treat SSc. ^{6 7 8 9 10}

Who Is on the Research Team?

Cole Sterling, MD

Principal Investigator

Johns Hopkins University

Are You a Good Fit for This Trial?

This trial is for adults aged 18-65 with active diffuse cutaneous systemic sclerosis who haven't improved with first-line therapy. They must meet the 2013 ACR/EULAR criteria, have a Karnofsky performance score over 70%, and proper organ function. Pregnant individuals, those with certain infections or uncontrolled diseases like diabetes, recent major surgery or live vaccines are excluded.

Inclusion Criteria

I am a male and follow the required contraceptive measures.

Donors meeting specific criteria

I have widespread skin disease with noticeable symptoms.

Exclusion Criteria

I have not received a live vaccine in the last 4 weeks.

You have had hepatitis C and it was not successfully treated.

Prisoner or subjects who are compulsorily detained

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Conditioning and Transplantation

Participants undergo reduced-intensity conditioning regimen, followed by bone marrow transplantation and post-transplant cyclophosphamide

Approximately 2 weeks

Daily visits for treatment administration

Post-transplant Monitoring

Participants receive immunosuppressive therapy and are monitored for engraftment and GVHD

Up to 1 year

Regular visits for chimerism assessment and health monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment

1 year

What Are the Treatments Tested in This Trial?

Interventions

• Cyclophosphamide

Trial Overview The study tests a reduced-intensity bone marrow transplant followed by high dose cyclophosphamide in patients with refractory systemic sclerosis to prevent graft vs host disease. It's an open-label Phase I trial enrolling 15 pairs to assess safety and monitor effects on muscle using biomarkers over one year.

How Is the Trial Designed?

Group I: RIC- alloBMT with high PTCy in SSc Experimental Treatment 1 Intervention

Days -9 Thymoglobulin 0.5 mg/kg IV Days -8,-7 Thymoglobulin 2 mg/kg IV daily Days -6, -5 Fludarabine 30 mg/M2 IV Cyclophosphamide 14.5 mg/kg IV Days -4, -3-2 Fludarabine 30 mg/M2 IV Day -1 TBI 400 cGy Day 0 Infuse unmanipulated marrow; begin antimicrobial prophylaxis. Days 3, 4 Cy 50 mg/kg IV and Mesna 40 mg/kg IV Day 5 FK-506 oral and MMF oral and G-CSF Day 30 Assess peripheral blood chimerism Day 35 Discontinue MMF Day 60 Assess peripheral blood chimerism Day 180 Discontinue FK-506 Evaluate disease Assess Chimerism in peripheral blood 1 yr. Evaluate disease by peripheral blood chimerism

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?

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Lead Sponsor

Trials

578

Recruited

33,600+

Published Research Related to This Trial

Patients with early, severe scleroderma (SSc) exhibited significant abnormalities in lymphocyte subsets compared to healthy controls, indicating a distinct immune profile associated with the disease.

Prior treatment with disease-modifying antirheumatic drugs (DMARDs) did not influence these lymphocyte abnormalities, suggesting that the immune disturbances are primarily a result of the scleroderma itself rather than the effects of previous immunosuppressive therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lymphocyte subset abnormalities in early severe scleroderma favor a Th2 phenotype and are not altered by prior immunosuppressive therapy. Shah, A., Storek, J., Woolson, 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]

In a study of six patients with active diffuse cutaneous scleroderma, high-dose cyclophosphamide (200 mg/kg) treatment resulted in significant improvements in skin scores, with reductions of up to 60% within one month, and sustained improvements in some patients for up to 24 months.

While the treatment showed promising efficacy, it also carried risks, as one patient died from an infection after treatment, highlighting the need for careful monitoring of safety during high-dose cyclophosphamide therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

High-dose cyclophosphamide without stem cell rescue in scleroderma. Tehlirian, CV., Hummers, LK., White, B., et al.[2023]

In the SCOT trial, patients with the fibroproliferative subset of scleroderma showed significant long-term benefits from hematopoietic stem cell transplant (HSCT) compared to those receiving cyclophosphamide (CYC), indicating HSCT may be a more effective treatment for this group.

Gene expression analysis revealed that HSCT led to more significant changes in immune response pathways and a higher number of differentially expressed genes compared to CYC, suggesting that HSCT may enhance immune function in these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Machine learning predicts stem cell transplant response in severe scleroderma. Franks, JM., Martyanov, V., Wang, Y., et al.[2021]

Autologous hematopoietic stem cell transplantation (AHSCT) significantly reduces all-cause mortality in patients with severe systemic sclerosis (SSc), with a risk ratio of 0.5, indicating a 50% reduction compared to standard immunosuppressive therapy.

AHSCT also improves key health measures such as skin thickness, lung capacity, and quality of life, although it carries a higher treatment-related mortality risk, with a risk ratio of 9.00, suggesting careful patient selection is necessary.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Autologous Hematopoietic Stem Cell Transplantation for Systemic Sclerosis: A Systematic Review and Meta-Analysis. Shouval, R., Furie, N., Raanani, P., 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]

Myeloablative autologous hematopoietic stem cell transplant (HSCT) significantly improves the immune response in patients with diffuse cutaneous systemic sclerosis (dcSSc) by increasing IgM antibodies and normalizing immunoglobulin heavy chain gene usage, as shown in the SCOT trial.

This treatment appears to reset the B cell repertoire to a more naïve state, which may help eliminate pathogenic B cells, providing a potential mechanism for why HSCT is more effective than cyclophosphamide (CYC) in treating dcSSc.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Myeloablative autologous haematopoietic stem cell transplantation resets the B cell repertoire to a more naïve state in patients with systemic sclerosis. Adamska, JZ., Zia, A., Bloom, MS., et al.[2023]

A treatment regimen of intravenous methylprednisolone and cyclophosphamide significantly improved skin scores and stabilized lung disease in 14 patients with scleroderma over a median follow-up of 26 months, indicating its efficacy in managing lung inflammation associated with the condition.

Despite initial stabilization, 67% of patients experienced deterioration in lung function after treatment cessation, suggesting that ongoing treatment intensity may be necessary to maintain lung function and that the rate of deterioration in DLCO could serve as a useful marker for treatment decisions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Systemic sclerosis and interstitial lung disease: a pilot study using pulse intravenous methylprednisolone and cyclophosphamide to assess the effect on high resolution computed tomography scan and lung function. Griffiths, B., Miles, S., Moss, H., et al.[2016]

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]

Citations

1. cdn.clinicaltrials.gov cdn.clinicaltrials.gov/large-docs/58/NCT05298358/Prot_SAP_001.pdf

allogeneic bone marrow transplant with post- ... Study Design: This is a Phase I, single arm, open label, single center pilot study to assess a reduced-intensity conditioning regimen, bone ...

2. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/16732546/

Allogeneic marrow transplantation in patients with ... - PubMed Allogeneic HCT may result in sustained remission of SSc. GVHD and opportunistic infections are the major risks associated with allogeneic HCT for SSc.

3. haematologica.org haematologica.org/article/view/4434

Long-term outcomes after reduced-intensity conditioning ... This study reports the outcome of 73 patients with relapsed or refractory LGL with a median follow-up of 37 months after RIC allogeneic SCT.

4. clinicaltrials.gov clinicaltrials.gov/study/NCT02049580

Reduced Intensity Conditioning (RIC) Regimen and Post- ... In this study, the investigators want to test the feasibility and efficacy of T-replete BM, infused after a RIC regimen and post-transplantation Cy, in patients ...

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10954215/

Allogeneic Stem Cell Transplantation for Systemic Sclerosis This proof-of-concept study demonstrated an acceptable safety profile of allogeneic BM-MSC for diffuse SSc, supporting the need for further clinical ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC2078679/

Effects of 1-Year Treatment with Cyclophosphamide on ... Although treatment-related benefits in pulmonary function, skin scores, and patient-centered outcomes were demonstrated after 1 year of therapy, the duration of ...

7. jrheum.org jrheum.org/content/early/2019/02/12/jrheum.180441

A Comparison of Scleroderma Lung Study I and II Abstract. Objective To compare safety and efficacy outcomes between the cyclophosphamide (CYC) arms of Scleroderma Lung Study (SLS) I and II.

8. nejm.org nejm.org/doi/full/10.1056/NEJMoa055120

Cyclophosphamide versus Placebo in Scleroderma Lung ... One year of oral cyclophosphamide in patients with symptomatic scleroderma-related interstitial lung disease had a significant but modest beneficial effect.

9. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7647679/

To use or not to use cyclophosphamide in systemic sclerosis This review summarizes the current evidences regarding the use of CYC to treat SSc, its efficacy and safety profile, and currently available or tested ...

10. clinicaltrials.gov clinicaltrials.gov/study/NCT00114530

Scleroderma: Cyclophosphamide or Transplantation The SCOT study will compare the potential benefits of stem cell transplant and high-dose monthly cyclophosphamide (Cytoxan) in the treatment of scleroderma.