Vedolizumab Post-Stem Cell Transplant for Crohn's Disease

Recruiting in Palo Alto (17 mi)

Overseen by Aaron Etra, MD

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 2

Recruiting

Sponsor: Aaron Etra

Must not be taking: Cyclophosphamide, Thymoglobulin

Disqualifiers: Pregnancy, Age <18, HIV, others

No Placebo Group

Prior Safety Data

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.

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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.

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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.

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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

Trial 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

Participant Groups

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.

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

Find a Clinic Near You

Research Locations Nearby Select from list below to view details:

Icahn School of Medicine at Mount Sinai New York, NY

Who Is Running the Clinical Trial?

Aaron Etra Lead Sponsor

Icahn School of Medicine at Mount Sinai Lead Sponsor

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] Polyclonal antihuman thymocyte rabbit IgGs (antithymocyte globulin [ATG]) are popular immunosuppressive drugs used to prevent or treat organ or bone-marrow allograft rejection, graft versus host disease, and autoimmune diseases. However, animal-derived glycoproteins are also strongly immunogenic and rabbit ATG induces serum sickness disease in almost all patients without additional immunosuppressive drugs, as seen in the Study of Thymoglobulin to arrest Type 1 Diabetes (START) trial of ATG therapy in new-onset type 1 diabetes.

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] This systematic review and meta-analysis were performed to explore the association between rabbit thymoglobulin (rATG) doses and transplant-related efficacy and safety outcomes.

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] Rabbit anti-thymocyte globulin (ATG) is usually incorporated in hematopoietic stem cell transplantation (HSCT) to reduce the incidence of graft-versus-host disease (GVHD). This study aimed to find optimal ATG doses in patients undergoing human leukocyte antigen (HLA)-mismatched allogeneic HSCT.

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] The optimal dose of rabbit antithymocyte globulin (ATG, ImtixSangstat) minimizing infections without increasing graft-versus-host disease (GVHD) is unknown in T cell-replete, G-CSF-primed haploidentical hematopoietic stem cell transplantation (haplo-HSCT).

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

Antithymocyte globulins suppress dendritic cell function by multiple mechanisms. [2016] The polyclonal rabbit antithymocyte and anti-T-cell immunoglobulins (ATGs) Thymoglobulin (TG) and ATG-Fresenius S (ATG-F) have been widely used for the prevention and therapy of allograft rejection and graft versus host disease in transplantation. Although immunosuppressive mechanisms of ATGs on T cells are well studied, less is known about their impact on dendritic cells (DCs).

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] Since 2000, various phase III randomized controlled trials (RCTs) have investigated the efficacy of rabbit antithymocyte globulin (ATG) in patients following allogeneic stem cell transplantation (allo-SCT). Comparisons of different ATG formulations are lacking, however. Our aim was to synthesize all published efficacy evidence to enable a comparison of all available formulations of rabbit ATG in the allo-SCT setting. We performed a systematic literature review to identify all available phase III RCT evidence. We searched the Cochrane Library, MEDLINE, MEDLINE In-Process, and the website www.ClinicalTrials.gov. In addition, a trial presented at the Annual Meeting of the American Society of Hematology 2016 was added to include the most recent evidence. We identified a total of 6 RCTs, including 2 formulations: anti-T lymphocyte globulin (ATLG; Grafalon, Neovii Biotech, Lexington, MA) and polyclonal globulin immunized with human thymocytes (Thymoglobulin [Thymo]; Genzyme-Sanofi, Cambridge, MA). The evidence was synthesized using a conventional network meta-analysis (NMA). The best treatment for preventing graft-versus-host disease (GVHD) was ATLG, which had a more favorable hazard ratio (HR) compared with standard treatment (chronic GVHD: HR, .42; 95% confidence interval [CI], .31 to .56; acute GVHD grade II-IV: HR, .54; 95% CI, .39 to .73; acute GVHD grade III-IV: HR, .50; 95% CI, .29 to .86), whereas both ATLG and Thymo were at least similarly effective in terms of transplantation-related mortality (TRM) (ATLG: HR, .90; 95% CI, .61 to 1.32; Thymo: HR, .90; 95% CI, .56 to 1.44). Thymo tended to be the better treatment option regarding overall survival (OS) (HR, .86; 95% CI, .59 to 1.26). Our NMA provides the first report of the relative efficacy of all available rabbit ATG formulations in patients undergoing allo-SCT. Until additional data from randomized head-to-head comparisons are available, based on the present analysis, ATLG seems to be the best option to prevent chronic and acute GVHD. Both formulations show similar efficacy in terms of TRM, whereas Thymo appears to be the better treatment option in terms of OS.

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

Thymoglobulin--new approaches to optimal outcomes. [2021] Thymoglobulin has a proven safety and efficacy profile both as treatment of acute rejection and as induction therapy in organ transplantation. The most common adverse events associated with Thymoglobulin are cytokine release syndrome, thrombocytopenia, and lymphopenia. Results of early studies showed an increased rate of cytomegalovirus disease associated with Thymoglobulin treatment, but recent studies indicate that routine administration of modern antiviral prophylaxis can reduce this risk. More research comparing Thymoglobulin with basiliximab will help individualize regimens by matching the choice of induction agent with the risk profile of each transplant recipient. The proven efficacy and safety profile of Thymoglobulin provides an excellent starting point for future investigations. Horse ATG (hATG) or Thymoglobulin + Cyclosporine are an efficacious treatment for aplastic anemia. Due to its higher potency Thymoglobulin may be superior to hATG, but further studies are required for confirmation. GvHD prophylaxis with Thymoglobulin may result in less acute and chronic GvHD, lower TRM, improved survival and quality of life in myeloablative or reduced intensity conditioning protocols in patients receiving hematopoietic stem cells from related or unrelated donors. Attributable to its polyclonal nature, Thymoglobulin provides multifaceted immunomodulation suggesting that its use should be included in the immunosuppressant therapeutic armamentarium to help reduce the incidence of organ rejection and GvHD, and for treatment of aplastic anemia.

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

Comparison of polyclonal induction agents in pediatric renal transplantation. [2021] Collective pediatric data suggest that anti-T-cell induction therapy with polyclonal antibodies improves the outcome of both short- and long-term renal allograft survival. Polyclonal agents, including thymoglobulin (Thy), a rabbit anti-thymocyte globulin; Minnesota (horse) anti-lymphoblast globulin (ALG); and ATGAM, a horse anti-thymocyte globulin (ATG), all suppress B and T cells. While no specific T-cell subset marker exists to measure the adequacy of immunosuppression with polyclonal induction, flow cytometric analysis has been used to evaluate the suppression of CD3, CD4, and CD8 cells. Thy is currently undergoing pediatric trials at our center, and we have utilized ATG and ALG in previous pediatric induction protocols. ALG (20 mg/kg/day) and ATG (15 mg/kg/day) were administered over 10 days, whereas Thy (2 mg/kg/day) was given over 5 days. All inductions were accompanied by preoperative intravenous solumedrol (10 mg/kg) followed by oral prednisone (2 mg/kg/day) with taper. Preoperative (1.5 mg/kg/day) and post-operative (2 mg/kg/day) azathioprine was administered to patients receiving ALG or ATG. Mycophenolate mofetil (MMF) (1200 mg/m2/day) was given to the patients receiving Thy. Post-operative cyclosporin A (CsA) (14 mg/kg/day) was started (for all groups) once renal function permitted (creatinine

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] An anti-CD25 monoclonal antibody was added to thymoglobulin for induction therapy in simultaneous pancreas/kidney (SPK) recipients. T-cell subsets including CD3 and CD25 were assessed by flow cytometry analysis in the peripheral blood of SPK (n = 88), and for comparison kidney transplant (KT) recipients were assessed. KT recipients were treated with daclizumab (anti-CD25) alone (five doses; 1 mg/kg) (n = 27) or thymoglobulin alone (4-7 doses; 1 mg/kg) (n = 23). SPK recipients received daclizumab (two doses; 1 mg/kg) in addition to thymoglobulin (five doses; 1 mg/kg). The return of peripheral blood CD25+ cells was delayed for 45 d post-transplantation in the SPK recipients where anti-CD25 was added to thymoglobulin, compared to those KT recipients with thymoglobulin alone. This strategy may result in reduced allogeneic (donor-specific) T effector cells at the time of solid organ transplantation.