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

Trial Summary

What is the purpose of this trial?

This is a Phase I, single arm, open label, single center pilot study to assess a reduced-intensity conditioning regimen, bone marrow transplantation with high dose cyclophosphamide (PTCy) in recipients with refractory systemic sclerosis. This study expects to enroll 15 donor/recipient pairs for a total of 30 participants. The primary objective of this study is to assess the safety of using a reduced intensity condition (RIC) preparative regimen bone marrow transplant (BMT) with post-transplant cyclophosphamide for graft vs host disease (GVHD) prophylaxis as treatment for patients with scleroderma. Safety events are grade III-IV GVHD and treatment related mortality within 1 year. Eligibility includes patients \>18 years who are eligible for transplantation according to the BMT Policy Manual, meet the 2013 ACR/EULAR Criteria for Systemic Sclerosis and display active diffuse cutaneous disease. The trial also includes analyses of the effects of BMT on skeletal and cardiac muscle using systemic scleroderma serum biomarkers of CK, aldolase, and troponin as well as periodic monitoring of circulating scleroderma auto-antibody titers, autoreactive T cells, and flow cytometric signatures over the one-year study period to correlate with response.

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 data supports the idea that RIC alloBMT + Cyclophosphamide for Scleroderma is an effective treatment?

The available research shows that the SCOT trial found significant benefits of stem cell transplant compared to Cyclophosphamide alone for patients with scleroderma. This suggests that while Cyclophosphamide is used, the combination with stem cell transplant may offer better outcomes. Additionally, a study using Cyclophosphamide with another drug showed effectiveness in treating lung inflammation in scleroderma patients, indicating its potential usefulness in combination therapies. ^{1 2 3 4 5}

What safety data exists for RIC alloBMT + Cyclophosphamide in treating Scleroderma?

The safety data for cyclophosphamide in treating scleroderma includes concerns about cardiotoxicity, as seen in a case where a patient developed congestive heart failure during treatment. A study on high-dose cyclophosphamide without stem cell rescue aimed to assess its safety and tolerability. In a systematic review and meta-analysis, autologous hematopoietic stem cell transplantation (AHSCT) with cyclophosphamide as a control showed reduced all-cause mortality but higher treatment-related mortality compared to standard therapy. Overall, cyclophosphamide is associated with potential cardiac risks, and its safety profile varies depending on the treatment regimen and patient condition. ^{1 4 6 7 8}

Is the drug Cyclophosphamide a promising treatment for scleroderma?

Cyclophosphamide has been studied as a treatment for scleroderma, but research shows that a different treatment, stem cell transplant, has more benefits for patients with this condition. ^{1 2 3 5 9}

Research Team

Cole Sterling, MD

Principal Investigator

Johns Hopkins University

Eligibility Criteria

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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]

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]

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]

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]

References

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

High-dose cyclophosphamide without stem cell rescue in scleroderma. [2023]

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

Lymphocyte subset abnormalities in early severe scleroderma favor a Th2 phenotype and are not altered by prior immunosuppressive therapy. [2023]

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

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

4. Canada 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. [2016]

5. England pubmed.ncbi.nlm.nih.gov

Machine learning predicts stem cell transplant response in severe scleroderma. [2021]

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. England 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. [2023]

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

Autologous Hematopoietic Stem Cell Transplantation for Systemic Sclerosis: A Systematic Review and Meta-Analysis. [2019]

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

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