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

Trial Summary

What is the purpose of this trial?

This early phase I trial studies the side effects and feasibility of total body irradiation using intensity modulation radiation therapy (IMRT) when given in combination with cyclophosphamide prior to stem cell transplant to treat severe systemic sclerosis. IMRT delivers total body radiation therapy more precisely and may reduce radiation exposure to sensitive normal organs. Giving chemotherapy, such as cyclophosphamide, and total body irradiation before a donor stem cell transplant helps kill cancer cells in the body and helps make room in the bone marrow for new blood-forming cells (stem cells) to grow. Giving IMRT and cyclophosphamide prior to stem cell transplant may work better in treating severe systemic sclerosis and reduce radiation doses to lung and kidneys compared to cyclophosphamide alone.

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.

What data supports the effectiveness of the treatment TBI + Cyclophosphamide and Stem Cell Transplant for Scleroderma?

Research from the SCOT trial shows that hematopoietic stem cell transplantation (HSCT) offers significant benefits over cyclophosphamide alone for patients with systemic sclerosis (scleroderma), suggesting that the combination of TBI and cyclophosphamide may improve outcomes. Additionally, total body irradiation (TBI) has been shown to improve treatment outcomes for rapidly progressive scleroderma. ^{1 2 3 4 5}

Is the combination of cyclophosphamide and total body irradiation generally safe for humans?

The combination of cyclophosphamide and total body irradiation has been associated with severe and sometimes fatal toxicities in humans, particularly when used with other drugs like cytosine arabinoside. Cardiac complications have also been reported with high-dose cyclophosphamide following total body irradiation. ^{6 7 8 9 10}

How is the TBI + Cyclophosphamide and Stem Cell Transplant treatment for scleroderma different from other treatments?

This treatment is unique because it combines total body irradiation (TBI), which helps modulate the immune system, with cyclophosphamide (a chemotherapy drug) and stem cell transplantation to improve outcomes for rapidly progressive scleroderma, using specific dose restrictions to minimize tissue damage. ^{1 6 7 11 12}

Research Team

Jeffrey Y Wong

Principal Investigator

City of Hope Medical Center

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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 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]

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 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]

References

1. 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]

2. 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]

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

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

4. England pubmed.ncbi.nlm.nih.gov

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

5. Germany pubmed.ncbi.nlm.nih.gov

Long-term effects of immunosuppressive therapy on lung function in scleroderma patients. [2019]

6. Ireland pubmed.ncbi.nlm.nih.gov

Repair capacity of mouse lung after total body irradiation alone or combined with cyclophosphamide. [2019]

7. 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]

8. England 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. [2016]

9. England 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. [2019]

10. Switzerland pubmed.ncbi.nlm.nih.gov

Dose escalation of busulfan with pentoxifylline and ciprofloxacin in patients with breast cancer undergoing autologous transplants. [2013]

11. England 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. [2015]

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

Interstitial pneumonitis following autologous bone-marrow transplantation conditioned with cyclophosphamide and total-body irradiation. [2019]