Vedolizumab Post-Stem Cell Transplant for Crohn's Disease

Overseen By Aaron Etra, MD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Aaron Etra

Must not be taking: Cyclophosphamide, Thymoglobulin

Disqualifiers: Pregnancy, Age <18, HIV, others

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

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 1

50 Participants Needed

Trial Summary

What is the purpose of this trial?

Crohn's Disease (CD) is an inflammatory bowel disease. It can lead to significant complications and discomfort in the stomach and intestines. Crohn's disease is a debilitating, incurable disease of immune cells; it affects almost 1 million people in the United States. CD is characterized by inflammation of the stomach and intestine as well as organs outside of the intestines such as the skin, eyes, and joints. Current therapies to treat CD aim to suppress the patient's immune cells but these therapies become ineffective for the majority of patients and lead to complications including the requirement for surgical bowel resection, impaired quality of life, and lifelong disability. Hematopoietic stem cell transplantation (HCT) is a procedure used to treat a number of medical conditions including Crohn's disease. To improve success of HCT in CD doctors considered combining transplant with other drugs to improve the chances of achieving remission and also maintaining the remission. The Investigators' plan in this study is to incorporate the drug Vedolizumab after transplant to test if this drug will improve remission and make patients healthier. Patients may qualify to take part in this research study because Crohn's disease is active, because surgery is not a treatment option and because there is evidence that the disease has failed to respond to treatments for Crohn's disease including the following: * corticosteroids * azathioprine, 6-mercaptopurine, methotrexate * Anti-TNFα (infliximab, adalimumab, certolizumab, golimumab) * Anti-integrin agents (natalizumab, Vedolizumab) If patients meet entry criteria will undergo a baseline endoscopy, colonoscopy and MR or CT enterography. If documentation of active mucosal disease patients will then be tapered off of current medications and undergo stem cell mobilization. Mobilization will involve low dose chemotherapy, growth factors and require 1-2 week hospitalization. Patients will then undergo stem cell transplant which will involve high dose chemotherapy and require a 2-4 week hospitalization. After restoration of the immune system patients will be placed on vedolizumab per standard dosing (0,2,6 then 8 every weeks) for a total of 8 doses. Patients will have monthly study visits and a repeat colonoscopy and MR/CT scan at 6 months.

Will I have to stop taking my current medications?

Yes, participants will need to taper off their current medications before undergoing stem cell mobilization as part of the trial process.

What data supports the effectiveness of the treatment Vedolizumab Post-Stem Cell Transplant for Crohn's Disease?

Rabbit antithymocyte globulin (ATG) is used in stem cell transplants to reduce the risk of graft-versus-host disease, which is a complication where the transplanted cells attack the recipient's body. This suggests that ATG can help improve outcomes in transplant procedures, which may be relevant to its use in Crohn's Disease treatment post-transplant. ^{1 2 3 4 5}

Is rabbit antithymocyte globulin (ATG) safe for use in humans?

Rabbit antithymocyte globulin (ATG) is generally safe for use in humans, but it can cause side effects like serum sickness (a reaction to foreign proteins), cytokine release syndrome (a severe immune response), thrombocytopenia (low platelet count), and lymphopenia (low white blood cell count). However, modern antiviral medications can reduce the risk of infections like cytomegalovirus disease associated with its use. ^{1 3 4 6 7}

How is the treatment with Vedolizumab and stem cell transplant for Crohn's Disease different from other treatments?

This treatment is unique because it combines Vedolizumab, which targets gut-specific inflammation, with an autologous stem cell transplant to reset the immune system, potentially offering a novel approach for Crohn's Disease that is not typically addressed by standard therapies. ^{1 2 3 8 9}

Research Team

Aaron Etra, MD

Principal Investigator

Icahn School of Medicine at Mount Sinai

Louis Cohen, MD

Principal Investigator

Icahn School of Medicine at Mount Sinai

Eligibility Criteria

This trial is for adults with active Crohn's Disease who haven't responded to standard treatments like corticosteroids, immunosuppressants, or biologics. They should not have heart, lung issues (like needing extra oxygen), HIV, a history of bad reactions to the trial drugs, be pregnant/breastfeeding, or too sick to do daily activities.

Inclusion Criteria

I cannot have surgery due to the risk of severe digestive issues or because I chose not to.

I have been diagnosed with Crohn's disease.

My bowel disease is active, as confirmed by a specific test.

Exclusion Criteria

History of significant toxicity to any medications used in trial (cyclophosphamide, thymoglobulin, vedolizumab)

I have an infection that hasn't improved after a month of treatment.

HIV infected

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Stem Cell Mobilization

Patients undergo stem cell mobilization involving low dose chemotherapy and growth factors, requiring 1-2 week hospitalization.

1-2 weeks

Hospitalization

Stem Cell Transplant

Patients undergo stem cell transplant involving high dose chemotherapy, requiring a 2-4 week hospitalization.

2-4 weeks

Hospitalization

Vedolizumab Maintenance

Patients receive vedolizumab per standard dosing (0, 2, 6 then every 8 weeks) for a total of 8 doses.

6 months

Monthly visits

Follow-up

Participants are monitored for safety and effectiveness after treatment, including repeat colonoscopy and MR/CT scan at 6 months.

6 months

Monthly visits

Treatment Details

Interventions

• Autologous stem cell transplant
• Cyclophosphamide
• Methylprednisolone
• Thymoglobulin
• Vedolizumab

Trial Overview The study tests if combining an autologous stem cell transplant with drugs like Thymoglobulin and Cyclophosphamide followed by Vedolizumab can help achieve and maintain remission in Crohn's Disease. It involves hospital stays for chemotherapy and monitoring after the transplant.

Participant Groups

Group I: Experimental Experimental Treatment 5 Interventions

Hematopoietic Stem Cell Transplant followed by maintenance Vedolizumab

Autologous stem cell transplant is already approved in European Union, United States for the following indications:

Approved in European Union as Autologous Hematopoietic Stem Cell Transplantation for:

• Severe Crohn's disease
• Perianal fistulas

Approved in United States as Autologous Hematopoietic Stem Cell Transplantation for:

• Clinical trials only; not FDA-approved for Crohn's disease

Who Is Running the Clinical Trial?

Aaron Etra

Lead Sponsor

Trials

1

Recruited

50+

Icahn School of Medicine at Mount Sinai

Lead Sponsor

Trials

933

Recruited

579,000+

Findings from Research

Rabbit-derived antithymocyte globulin (ATG) can induce a strong immune response in patients, leading to the production of antibodies against specific rabbit glycoprotein epitopes, which may compromise its effectiveness in treating conditions like type 1 diabetes.

The study found that patients developed significant levels of antibodies against these rabbit-specific epitopes after ATG treatment, suggesting that using IgGs without these xenoantigens could enhance the safety and efficacy of ATG therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Anti-Gal and Anti-Neu5Gc Responses in Nonimmunosuppressed Patients After Treatment With Rabbit Antithymocyte Polyclonal IgGs. Salama, A., Evanno, G., Lim, N., et al.[2022]

In a systematic review of 26 studies involving 3601 patients, lower doses of rabbit thymoglobulin (rATG) at ≤4.5 mg/kg were linked to reduced rates of acute rejection and infections, while maintaining similar rates of graft function and patient survival compared to higher doses.

Doses of rATG between 3-4.5 mg/kg showed the best outcomes, suggesting that using lower doses can be just as effective while minimizing potential side effects in kidney transplant recipients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Association between cumulative rATG induction doses and kidney graft outcomes and adverse effects in kidney transplant patients: a systematic review and meta-analysis. Mohammadi, K., Khajeh, B., Dashti-Khavidaki, S., et al.[2022]

In a study of 352 patients undergoing HLA-mismatched allogeneic hematopoietic stem cell transplantation, low to medium doses of rabbit anti-thymocyte globulin (ATG) (2.5 to 7.5 mg/kg) were associated with higher 5-year overall survival rates compared to other doses.

Patients receiving low to medium doses of ATG also experienced lower rates of extensive chronic graft-versus-host disease (ecGVHD), suggesting that these doses improve patient outcomes without increasing relapse rates.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical impact of anti-thymocyte globulin on survival and graft-versus-host disease in patients undergoing human leukocyte antigen mismatched allogeneic stem cell transplantation. Kim, T., Choi, Y., Lee, JH., et al.[2021]

In a study of 408 patients undergoing haploidentical hematopoietic stem cell transplantation, a lower dose of 7.5 mg/kg rabbit antithymocyte globulin (ATG) significantly reduced the incidence of EBV DNAemia and CMV DNAemia compared to the higher dose of 10.0 mg/kg, without increasing the risk of graft-versus-host disease (GVHD).

The 7.5 mg/kg ATG group showed higher counts of EBV- and CMV-specific cytotoxic T cells early after transplantation, suggesting that this lower dose may enhance immune response while minimizing infections.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Two dose levels of rabbit antithymocyte globulin as graft-versus-host disease prophylaxis in haploidentical stem cell transplantation: a multicenter randomized study. Lin, R., Wang, Y., Huang, F., et al.[2020]

Thymoglobulin (TG) and ATG-Fresenius (ATG-F) rapidly bind to various receptors on dendritic cells (DCs), leading to significant immunosuppressive effects, including the induction of apoptosis in both immature and mature DCs.

These ATGs inhibit important functions of DCs, such as antigen uptake and the production of interleukin-12p70, which reduces their ability to stimulate T cells, highlighting their role as targets for immunosuppression in transplantation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antithymocyte globulins suppress dendritic cell function by multiple mechanisms. Naujokat, C., Berges, C., Fuchs, D., et al.[2016]

A systematic review of 6 phase III randomized controlled trials found that rabbit antithymocyte globulin (ATG) formulations, particularly anti-T lymphocyte globulin (ATLG), are effective in preventing graft-versus-host disease (GVHD) after allogeneic stem cell transplantation, showing significantly better outcomes compared to standard treatments.

While both ATLG and Thymoglobulin (Thymo) had similar effects on transplantation-related mortality, Thymo showed a trend towards better overall survival, suggesting that Thymo may be a preferable option for improving long-term survival outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of Different Rabbit Anti-Thymocyte Globulin Formulations in Allogeneic Stem Cell Transplantation: Systematic Literature Review and Network Meta-Analysis. Gagelmann, N., Ayuk, F., Wolschke, C., et al.[2018]

Thymoglobulin is a safe and effective treatment for preventing acute rejection in organ transplantation, with common side effects including cytokine release syndrome and thrombocytopenia, but recent studies suggest that antiviral prophylaxis can mitigate the risk of cytomegalovirus disease associated with its use.

Thymoglobulin may offer advantages over horse ATG in treating aplastic anemia and can reduce the incidence of acute and chronic graft-versus-host disease (GvHD) in patients receiving stem cell transplants, indicating its potential as a versatile immunosuppressant in various therapeutic contexts.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Thymoglobulin--new approaches to optimal outcomes. Moicean, AD., Popp, AM., Sinescu, I.[2021]

In a study involving pediatric renal transplant recipients, anti-T-cell induction therapy with polyclonal antibodies, specifically thymoglobulin (Thy), showed equal or greater suppression of T-cells compared to other agents like ATG and ALG after 10 days, indicating its potential effectiveness in improving renal allograft survival.

The study involved 30 participants aged 2 to 18 years, and the results suggest that a shorter 5-day course of Thy may be as effective as a longer 10-day course of ATG or ALG in suppressing T-cell activity, which is crucial for preventing organ rejection.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of polyclonal induction agents in pediatric renal transplantation. Brophy, PD., Thomas, SE., McBryde, KD., et al.[2021]

In a study involving 88 simultaneous pancreas/kidney (SPK) transplant recipients, the addition of an anti-CD25 monoclonal antibody to thymoglobulin induction therapy delayed the return of CD25+ T cells by 45 days compared to kidney transplant recipients receiving thymoglobulin alone.

This approach may help reduce the presence of donor-specific T effector cells at the time of transplantation, potentially improving transplant outcomes and reducing the risk of rejection.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Addition of anti-CD25 to thymoglobulin for induction therapy: delayed return of peripheral blood CD25-positive population. Sageshima, J., Ciancio, G., Gaynor, JJ., et al.[2018]

References

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

Anti-Gal and Anti-Neu5Gc Responses in Nonimmunosuppressed Patients After Treatment With Rabbit Antithymocyte Polyclonal IgGs. [2022]

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

Association between cumulative rATG induction doses and kidney graft outcomes and adverse effects in kidney transplant patients: a systematic review and meta-analysis. [2022]

3. Korea (South) pubmed.ncbi.nlm.nih.gov

Clinical impact of anti-thymocyte globulin on survival and graft-versus-host disease in patients undergoing human leukocyte antigen mismatched allogeneic stem cell transplantation. [2021]

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

Two dose levels of rabbit antithymocyte globulin as graft-versus-host disease prophylaxis in haploidentical stem cell transplantation: a multicenter randomized study. [2020]

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

Antithymocyte globulins suppress dendritic cell function by multiple mechanisms. [2016]

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

Comparison of Different Rabbit Anti-Thymocyte Globulin Formulations in Allogeneic Stem Cell Transplantation: Systematic Literature Review and Network Meta-Analysis. [2018]

7. Romania pubmed.ncbi.nlm.nih.gov

Thymoglobulin--new approaches to optimal outcomes. [2021]

8. Denmark pubmed.ncbi.nlm.nih.gov

Comparison of polyclonal induction agents in pediatric renal transplantation. [2021]

9. Denmark pubmed.ncbi.nlm.nih.gov

Addition of anti-CD25 to thymoglobulin for induction therapy: delayed return of peripheral blood CD25-positive population. [2018]