Vedolizumab + Cyclophosphamide + Tacrolimus for Graft-versus-Host Disease

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: City of Hope Medical Center

Must not be taking: Herbal medications, others

Disqualifiers: Prior allogeneic HCT, active infection, 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: 181

35 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase II trial studies how well vedolizumab plus post-transplant cyclophosphamide (PTCy) and short course tacrolimus work for the prevention of graft versus host disease (GVHD) in patients undergoing allogeneic hematopoietic cell transplantation (HCT) after reduced intensity conditioning. Allogeneic HCT is a procedure in which a person receives blood-forming stem cells (cells from which all blood cells develop) from a donor. Giving reduced conditioning chemotherapy before an allogeneic HCT helps kill cancer cells in the body and helps make room in the patient's bone marrow for new stem cells to grow using less than standard doses of chemotherapy. Sometimes, the transplanted cells from a donor can attack the body's normal cells (called graft-versus-host disease). Vedolizumab is a monoclonal antibody, which is a type of protein that can bind to certain targets in the body, such as molecules that cause the body to make an immune response (antigens). It may reduce inflammation. Cyclophosphamide is in a class of medications called alkylating agents. It works by damaging the cell's deoxyribonucleic acid and may kill cancer cells. It may also lower the body's immune response. Tacrolimus suppresses the immune system by preventing the activation of certain types of immune cells. Giving vedolizumab plus PTCy and short course tacrolimus may be effective at preventing GVHD after allogeneic HCT.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but it does exclude those taking other investigational drugs for GVHD prophylaxis and herbal medications. It's best to discuss your current medications with the trial team to see if they are allowed.

What data supports the effectiveness of the drugs Vedolizumab, Cyclophosphamide, and Tacrolimus for treating graft-versus-host disease?

Research shows that Vedolizumab is effective for treating gastrointestinal symptoms of graft-versus-host disease, and Tacrolimus has been successful in preventing and treating this condition. Cyclophosphamide is also used in some regimens to prevent graft-versus-host disease, suggesting that these drugs may work well together for this purpose. ^{1 2 3 4 5}

Is the combination of Vedolizumab, Cyclophosphamide, and Tacrolimus safe for humans?

Vedolizumab has been studied for graft-versus-host disease and was generally well tolerated, with some participants experiencing adverse events. Tacrolimus has been associated with kidney problems in some patients. There is no specific safety data available for the combination of Vedolizumab, Cyclophosphamide, and Tacrolimus together. ^{3 6 7 8 9}

How is the drug Vedolizumab + Cyclophosphamide + Tacrolimus unique for treating graft-versus-host disease?

This treatment combines Vedolizumab, which targets specific immune cells in the gut, with Cyclophosphamide and Tacrolimus, which are used to suppress the immune system. This combination aims to prevent and treat graft-versus-host disease by reducing immune response and promoting tolerance, potentially offering a novel approach compared to standard treatments that may not be as effective for steroid-refractory cases. ^{3 10 11 12 13}

Research Team

Monzr M Al Malki

Principal Investigator

City of Hope Medical Center

Eligibility Criteria

This trial is for patients with certain blood cancers or disorders who are undergoing a stem cell transplant from a donor after receiving lower doses of chemotherapy. It aims to prevent the immune response where transplanted cells attack the patient's body (GVHD).

Inclusion Criteria

* Documented informed consent of the participant and/or legally authorized representative

* Assent, when appropriate, will be obtained per institutional guidelines

* Agreement to allow the use of archival tissue from diagnostic tumor biopsies

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Conditioning

Participants receive reduced intensity conditioning with fludarabine and melphalan before transplantation

1 week

Daily visits for conditioning

Transplantation and Initial Treatment

Participants undergo allogeneic HCT and receive vedolizumab, cyclophosphamide, and tacrolimus

14 weeks

Multiple visits for drug administration and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment

1 year

Follow-up visits at day +180 and 1 year post-HCT

Treatment Details

Interventions

• Cyclophosphamide
• Tacrolimus
• Vedolizumab

Trial Overview The study tests if vedolizumab, combined with cyclophosphamide and short-term tacrolimus after transplant, can prevent GVHD in patients receiving reduced intensity conditioning before allogeneic hematopoietic cell transplantation.

Participant Groups

Group I: Prevention (vedolizumab, cyclophosphamide, tacrolimus) Experimental Treatment 12 Interventions

Patients receive reduced intensity conditioning with fludarabine IV on days -7 to -3 and melphalan IV on day -2. Patients then undergo allogeneic HCT on day 0. Patients also receive vedolizumab IV over 30 minutes on days -1, +13, +41, +69, +97, +125, and +153, cyclophosphamide IV on days +3 and +4, and tacrolimus IV or PO on day +5 to day +95 in the absence of disease progression or unacceptable toxicity. Additionally, patients undergo CT and ECHO or MUGA during screening, blood sample collection on study, and bone marrow biopsy throughout the study.

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

A study of 2,905 patients who developed grade II-IV acute graft-versus-host disease (GVHD) after hematopoietic cell transplantation showed a significant decrease in the proportion of severe grade III-IV GVHD over time, from 56% in 1999-2001 to 37% in 2006-2010.

Patients treated with tacrolimus-based prophylaxis experienced notable improvements in overall survival and reduced treatment-related mortality, particularly among those with grade II acute GVHD, indicating that this treatment regimen may enhance outcomes for transplant recipients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Improved survival after acute graft-versus-host disease diagnosis in the modern era. Khoury, HJ., Wang, T., Hemmer, MT., et al.[2019]

Tacrolimus has been found to be effective in preventing graft-versus-host disease (GVHD) in patients undergoing allogeneic bone marrow transplants, highlighting its potential as a critical intervention in this high-risk population.

Further research is necessary to refine dosage schedules and establish therapeutic ranges to ensure both efficacy and safety in the use of tacrolimus for GVHD prevention.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tacrolimus: an alternative for graft-versus-host disease prevention. Lee, TJ., Kennedy, LA.[2017]

A patient with severe graft versus host disease (GVHD) after a bone marrow transplant showed no improvement with standard treatments like cyclosporine and high-dose steroids.

However, treatment with tacrolimus and Psoralen plus ultraviolet light (PUVA) led to complete resolution of GVHD symptoms, suggesting this combination could be effective for other patients with treatment-resistant GVHD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Successful therapy of refractory graft versus host disease with tacrolimus and Psoralen plus ultraviolet light. Jubran, RF., Dinndorf, PA.[2019]

High-dose cyclophosphamide used as a single-agent prophylaxis after myeloablative allogeneic bone marrow transplantation significantly reduced the incidence of acute graft-versus-host disease (GVHD), with rates of 43% for grades II-IV and 10% for grades III-IV among 117 patients.

The treatment also demonstrated promising long-term outcomes, with a 2-year overall survival rate of 55% and a low cumulative incidence of chronic GVHD at 10%, indicating its efficacy and safety in patients with advanced hematologic malignancies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

High-dose cyclophosphamide as single-agent, short-course prophylaxis of graft-versus-host disease. Luznik, L., Bolaños-Meade, J., Zahurak, M., et al.[2022]

References

1. Italy pubmed.ncbi.nlm.nih.gov

Improved survival after acute graft-versus-host disease diagnosis in the modern era. [2019]

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

Three prophylaxis regimens (tacrolimus, mycophenolate mofetil, and cyclophosphamide; tacrolimus, methotrexate, and bortezomib; or tacrolimus, methotrexate, and maraviroc) versus tacrolimus and methotrexate for prevention of graft-versus-host disease with haemopoietic cell transplantation with reduced-intensity conditioning: a randomised phase 2 trial with a non-randomised contemporaneous control group (BMT CTN 1203). [2023]

3. Switzerland pubmed.ncbi.nlm.nih.gov

Vedolizumab for acute gastrointestinal graft-versus-host disease: A systematic review and meta-analysis. [2022]

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

Tacrolimus: an alternative for graft-versus-host disease prevention. [2017]

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

Successful therapy of refractory graft versus host disease with tacrolimus and Psoralen plus ultraviolet light. [2019]

6. Germany pubmed.ncbi.nlm.nih.gov

[Drug interactions of tacrolimus]. [2013]

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

Vedolizumab for prevention of graft-versus-host disease after allogeneic hematopoietic stem cell transplantation. [2020]

8. England pubmed.ncbi.nlm.nih.gov

Tacrolimus and methotrexate for the prophylaxis of acute graft-versus-host disease in allogeneic bone marrow transplantation in patients with hematologic malignancies. [2013]

9. England pubmed.ncbi.nlm.nih.gov

Anti-α4β7 integrin monoclonal antibody (vedolizumab) for the treatment of steroid-resistant severe intestinal acute graft-versus-host disease. [2020]

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

Single-Agent High-Dose Cyclophosphamide for Graft-versus-Host Disease Prophylaxis in Human Leukocyte Antigen-Matched Reduced-Intensity Peripheral Blood Stem Cell Transplantation Results in an Unacceptably High Rate of Severe Acute Graft-versus-Host Disease. [2015]

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

Targeting Integrin α4β7 in Steroid-Refractory Intestinal Graft-versus-Host Disease. [2018]

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

High-dose, post-transplantation cyclophosphamide to promote graft-host tolerance after allogeneic hematopoietic stem cell transplantation. [2021]

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

High-dose cyclophosphamide as single-agent, short-course prophylaxis of graft-versus-host disease. [2022]