TBI + Cyclophosphamide and Stem Cell Transplant for Scleroderma

Age: 18+

Sex: Any

Trial Phase: Phase < 1

Sponsor: City of Hope Medical Center

Disqualifiers: Uncontrolled illness, Active infection, Pregnancy, others

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

Compensation: Varies

Number of Visits: 30

15 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new combination treatment for individuals with severe systemic sclerosis, a condition where the skin and connective tissues become overly tight and thick. Researchers are testing whether a precise form of total body radiation, Intensity-Modulated Radiation Therapy (IMRT), combined with the chemotherapy drug cyclophosphamide before a stem cell transplant, can better prepare the body and protect sensitive organs like the lungs and kidneys. Suitable candidates for this trial include those with severe systemic sclerosis who have been evaluated for this specific treatment approach and have adequate organ function. As an Early Phase 1 trial, this research aims to understand how the treatment works in people, offering participants the opportunity to be among the first to receive this innovative approach.

Do I have to stop taking my current medications for the trial?

The trial protocol does not specify whether you need to stop taking your current medications. It's best to discuss this with the study team or your doctor.

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

Research has shown that intensity-modulated radiation therapy (IMRT) is generally well-tolerated. In a small initial study, adult patients who underwent stem cell transplants managed it well, experiencing early side effects that were manageable.

Cyclophosphamide, a chemotherapy drug, has undergone more extensive study. One study found that some patients experienced serious side effects, though these were often not directly linked to the treatment. Another study reported a modest but beneficial effect on lung problems related to scleroderma.

While both treatments carry some risks, current evidence suggests they are generally tolerated in similar situations. As this trial is in the early stages, the researchers will continue to gather safety information. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for scleroderma?

Researchers are excited about this treatment for scleroderma because it combines total-body irradiation using intensity-modulated radiation therapy (IMRT) with cyclophosphamide and a stem cell transplant. Unlike standard treatments, which often focus on managing symptoms with drugs like methotrexate or mycophenolate mofetil, this approach aims to reset the immune system more comprehensively. The use of IMRT allows for precise targeting of radiation, minimizing damage to healthy tissues. Additionally, the inclusion of a stem cell transplant offers the potential to rebuild a healthier immune system, potentially altering the course of the disease more effectively.

What evidence suggests that this trial's treatments could be effective for severe systemic sclerosis?

Research has shown that cyclophosphamide can help treat severe systemic sclerosis, particularly when it affects the lungs. One study found it improved lung function, although some side effects occurred. In this trial, participants will receive a combination of treatments, including cyclophosphamide and total-body irradiation using intensity-modulated radiation therapy (IMRT). IMRT can more precisely target the body and may reduce radiation exposure to sensitive organs like the lungs and kidneys. This combination aims to create space for healthy stem cells to grow, potentially improving outcomes for patients with severe forms of the disease. Early findings suggest this approach might be more effective than using cyclophosphamide alone. ^{2 3 4 6 7}

Who Is on the Research Team?

Jeffrey Y Wong

Principal Investigator

City of Hope Medical Center

Are You a Good Fit for This Trial?

This trial is for severe systemic sclerosis patients with good organ function and performance status, who can undergo total body irradiation (TBI) as part of a stem cell transplant. Participants must use birth control and be able to consent. Excluded are those with uncontrolled illnesses, prior radiation therapy without PI approval, or pregnant women due to potential harm.

Inclusion Criteria

Your organs must work well enough for the hematologist to approve you for the treatment.

Patients must be suitable for TBI conditioning regimens as part of transplant per radiation the referring hematologist

You are able to perform daily activities without much difficulty.

Exclusion Criteria

Patients should not have any uncontrolled illness including ongoing or active infection

Prior history of radiation therapy must be presented to study principal investigator (PI) for eligibility determination

Subjects, who in the opinion of the investigator, may not be able to comply with the safety monitoring requirements of the study

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Radiation

Participants undergo total body irradiation using IMRT twice daily on days -5 and -4

2 days

Daily visits for radiation therapy

Chemotherapy

Participants receive cyclophosphamide on days -3 and -2

2 days

Daily visits for chemotherapy administration

Transplantation

Participants undergo hematopoietic stem cell transplantation on day 0

1 day

Inpatient procedure

Follow-up

Participants are monitored for safety and effectiveness after treatment

100 days

Follow-up visits on days 30 and 100

What Are the Treatments Tested in This Trial?

Interventions

• Cyclophosphamide
• Intensity-Modulated Radiation Therapy
• Total-Body Irradiation

Trial Overview The study tests the combination of intensity-modulated radiation therapy (IMRT) and cyclophosphamide before a stem cell transplant in treating severe systemic sclerosis. IMRT aims to precisely target the body while sparing normal organs from excessive radiation exposure.

How Is the Trial Designed?

Group I: Treatment (TBI using IMRT, cyclophosphamide, HSCT) Experimental Treatment 4 Interventions

Patients undergo TBI using IMRT BID on days -5 and -4 in the absence of disease progression or disease progression. Patients then receive cyclophosphamide on days -3 and -2 and undergo HSCT on day 0 in the absence of disease progression or unacceptable toxicity.

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?

City of Hope Medical Center

Lead Sponsor

Trials

614

Recruited

1,924,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

In a study of 30 adult patients undergoing haematopoietic stem cell transplantation, conditioning with fractionated total body irradiation and high-dose cyclophosphamide showed no evidence of cardiotoxicity, as indicated by stable cardiac troponin T levels and echocardiographic parameters over a median follow-up of 5 months.

The findings suggest that TBI/CY is safe for patients without pre-existing cardiac dysfunction, indicating that any cardiotoxic effects of cyclophosphamide may arise from interactions with other chemotherapy drugs rather than from cyclophosphamide alone.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Monitoring of cardiac function by serum cardiac troponin T levels, ventricular repolarisation indices, and echocardiography after conditioning with fractionated total body irradiation and high-dose cyclophosphamide. Auner, HW., Tinchon, C., Brezinschek, RI., et al.[2019]

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]

In a phase I study involving 9 patients with advanced hematological malignancies, the combination of cytosine arabinoside (Ara-C) and cyclophosphamide (CY) with total body irradiation (TBI) resulted in severe toxicity, with multiple patients experiencing fatal outcomes at higher doses.

The study concluded that the concurrent administration of Ara-C and CY may not be suitable for phase I trials due to the high risk of severe, dose-independent toxicity, highlighting the need for caution in developing such treatment regimens.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Simultaneous infusion of high-dose cytosine arabinoside with cyclophosphamide followed by total body irradiation and marrow infusion for the treatment of patients with advanced hematological malignancy. Petersen, FB., Appelbaum, FR., Buckner, CD., et al.[2016]

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]

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]

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 75 adult patients undergoing hematopoietic stem cell transplantation (HSCT) with myeloablative conditioning, the timing of total body irradiation (TBI) before HSCT did not significantly affect overall survival or progression-free survival rates.

Regardless of the interval between TBI and HSCT (ranging from 2 to 10 days), there were no significant differences in relapse rates, non-relapse mortality, or the incidence of acute and chronic graft-versus-host disease, suggesting that the timing of TBI may not be critical for patient outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of the duration between total body irradiation and stem cell infusion on the outcome of allogeneic transplantation with myeloablative conditioning. Akahoshi, Y., Kako, S., Nakano, H., et al.[2015]

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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8892929/

Is there still a role for cyclophosphamide in the treatment ... Forty-two percent of the included patients in the SLS II study had dcSSc. Both cyclophosphamide and MMF proven to be equally effective in SSc-ILD after 24 ...

2. atsjournals.org atsjournals.org/doi/10.1513/AnnalsATS.202301-053OC

Cyclophosphamide in Patients with Systemic Sclerosis– ... A review of the published evidence shows that cyclophosphamide is effective in SSc-ILD compared with placebo, with an increased risk of side effects.

3. 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.

4. sciencedirect.com sciencedirect.com/science/article/abs/pii/S1568997223001738

Is cyclophosphamide still the gold standard in early severe ... Cyclophosphamide (CYC) has been a gold standard of treatment for severe progressive Systemic Sclerosis (SSc), especially in patients with concomitant ...

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

A Comparison of Scleroderma Lung Study I and II Conclusion Treatment with 1 year of oral CYC led to similar improvements in lung function in both SLS I and II, although the effects were not ...

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

Effects of 1-Year Treatment with Cyclophosphamide on ... Also during the second year, 27 serious adverse events (SAEs: four probably and four possibly treatment related) occurred in the CYC group and 22 SAEs (five ...

7. 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.