Vedolizumab Plus Post-transplant Cyclophosphamide and Short Course Tacrolimus for the Prevention of Graft Versus Host Disease in Patients Undergoing Allogeneic Hematopoietic Cell Transplantation After Reduced Intensity Conditioning

Phase-2 Study of Vedolizumab Plus Post-Transplant Cyclophosphamide and Short Course Tacrolimus for Graft-versus-Host Disease Prevention After Reduced Intensity Conditioning Peripheral Blood Stem Cell Allogeneic Hematopoietic Cell Transplantation

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.

Study Overview

• Status: Recruiting
• Conditions: Acute Myeloid Leukemia; Chronic Myelomonocytic Leukemia; Acute Lymphoblastic Leukemia; Myelodysplastic Syndrome; Myeloproliferative Neoplasm; Graft Versus Host Disease
• Intervention / Treatment: Other: Questionnaire Administration; Procedure: Computed Tomography; Procedure: Biospecimen Collection; Drug: Cyclophosphamide; Drug: Fludarabine; Drug: Melphalan; Procedure: Echocardiography; Procedure: Multigated Acquisition Scan; Drug: Tacrolimus; Procedure: Allogeneic Hematopoietic Stem Cell Transplantation; Procedure: Bone Marrow Biopsy; Biological: Vedolizumab

Detailed Description

PRIMARY OBJECTIVES:

I. Assess the safety and describe the toxicity profile of adding vedolizumab at a fixed dose level to post-transplant cyclophosphamide (PTCy) -based graft-versus-host disease (GVHD) prophylaxis with tacrolimus after mobilized peripheral blood stem cell (PBSC) allogeneic hematopoietic cell transplantation (HCT) from a matched related/unrelated donor. (Safety lead-in segment) II. Assess the efficacy of vedolizumab in combination with PTCy by grade 2-4 acute GVHD-free survival by day+180 after allogeneic hematopoietic cell transplantation (HCT). (Expansion segment)

SECONDARY OBJECTIVES:

I. Continue safety assessment of vedolizumab + PTCy combination as GVHD prophylaxis in the expansion cohort.

II. Estimate overall survival (OS), progression-free survival (PFS), cumulative incidences of relapse/disease progression, and non-relapse mortality (NRM) at 100 days, and 1-year post-transplant.

III. Estimate rates of acute GVHD (day 100 and 180 post-HCT), lower gastrointestinal (GI) GVHD (day 100 and day 180 post-HCT), chronic GvHD (1-year post-HCT), infections (100 and 180 days and 1 year post HCT).

IV. Estimate rates of complete remission, and neutrophil recovery. V. Evaluate and describe the cytokine release syndrome (CRS) post-HCT by assessing the incidence, frequency, and severity of CRS.

EXPLORATORY OBJECTIVES:

I. Donor cell engraftment will be assessed by count monitoring and short tandem repeat (STR) chimerism analysis on days +30 and day +100.

II. Describe the kinetics of immune cell recovery. III. Evaluate patient's quality of life on day +100, 6 months and one-year post-HCT.

IV. Describe the kinetics of GVHD biomarkers, and inflammatory cytokines for up to 100 days post-HCT.

V. Obtain a preliminary estimate of gut microbiome diversity at baseline (preferably before fludarabine administration), and then on days +14, +30, +60, +100, and +180 after HCT.

OUTLINE:

Patients receive reduced intensity conditioning with fludarabine intravenously (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 orally (PO) on day +5 to day +95 in the absence of disease progression or unacceptable toxicity. Additionally, patients undergo computed tomography (CT) and echocardiography (ECHO) or multigated acquisition scan (MUGA) during screening, blood sample collection on study, and bone marrow biopsy throughout the study.

After completion of study treatment, patients are followed up at 30 days after the last dose of vedolizumab, day +180 and at 1 year.

• Study Type: Interventional
• Enrollment (Estimated): 35
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • California
    • Duarte, California, United States, 91010
      • Recruiting
      • City of Hope Medical Center
      • Contact: Monzr M. Al Malki; Phone Number: 626-218-2405; Email: malmalki@coh.org
      • Principal Investigator: Monzr M. Al Malki

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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

  • If unavailable, exceptions may be granted with study principal investigator (PI) approval

• Age: ≥ 18 and ≤ 80 years old

  • Note: Patients > 70 years of age must have Karnofsky performance status ≥ 80 and hematopoietic cell transplantation-comorbidity index (HCT-CI) ≤ 2
• Karnofsky performance status ≥ 70%

• Patients with the following diagnosis, eligible to undergo allogeneic HCT from an 8/8 match related/unrelated donor (A, B, C, DR by high resolution typing)

  • Acute Leukemias (acute myeloid leukemia [AML] or acute lymphoblastic leukemia [ALL]) in complete remission with bone marrow (BM) blast of < 5%
  • Myelodysplastic syndrome (blast < 10%)
  • Myeloproliferative neoplasm (MPN) other than myelofibrosis (MF) needing HCT
  • Chronic myelomonocytic leukemia (CMML)

• Hemoglobin ≥ 9g/dL (within 30 days prior to day 1 of protocol therapy)

  • NOTE: Red blood cell transfusions are not permitted within 14 days of hemoglobin assessment unless cytopenia is secondary to disease involvement
• Total bilirubin ≤ 2.0 mg/dL (unless has Gilbert's disease) AND serum glutamic oxaloacetic transaminase (SGOT) and serum glutamic pyruvic transaminase (SGPT) < 5 times the upper limit of normal (ULN) (within 30 days prior to day 1 of protocol therapy)
• Aspartate aminotransferase (AST) =< 3.0 x ULN (within 30 days prior to day 1 of protocol therapy)
• Alanine aminotransferase (ALT) =< 3.0 x ULN (within 30 days prior to day 1 of protocol therapy)
• Creatinine clearance of ≤ 1.5 mg/dL or ≥ 60 mL/min per 24 hour urine test or the Cockcroft-Gault formula (within 30 days prior to day 1 of protocol therapy)

• Left ventricular ejection fraction (LVEF) ≥ 50%

  • Note: To be performed within 28 days prior to day 1 of protocol therapy

• IF ABLE TO PERFORM PULMONARY FUNCTION TESTS: Forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC) and DLCO (diffusion capacity) ≥ 50% of predicted (corrected for hemoglobin)

  • Note To be performed within 28 days prior to day 1 of protocol therapy

• IF UNABLE TO PERFORM PULMONARY FUNCTION TESTS: Oxygen (O2) saturation > 92% on room air

  • Note To be performed within 28 days prior to day 1 of protocol therapy

• Seronegative for HIV antigen/antibody (Ag/Ab) combo, hepatitis C virus (HCV), active hepatitis B virus (HBV) (surface antigen negative) (within 30 days prior to day 1 of protocol therapy)

  • HIV-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial

• Tuberculosis test (within 30 days prior to day 1 of protocol therapy)

  • Patients with positive tuberculosis (TB) test results will have infectious disease (ID) evaluation and post HCT therapy with isoniazid (INH) for 6 months with ID follow up. Vaccinated patients will need negative chest X-ray results

• Meets other institutional and federal requirements for infectious disease titer requirements

  • Note Infectious disease testing to be performed within 28 days prior to day 1 of protocol therapy

• Women of childbearing potential (WOCBP): Negative urine or serum pregnancy test (within 30 days prior to day 1 of protocol therapy)

  • If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required

• Agreement by females and males of childbearing potential to use an effective method of birth control or abstain from heterosexual activity for the course of the study through at least 3 months after the last dose of protocol therapy

  • Childbearing potential defined as not being surgically sterilized (men and women) or have not been free from menses for > 1 year (women only)

Exclusion Criteria:

• Prior allogeneic HCT

• Chemotherapy, radiation therapy, biological therapy, immunotherapy within 14 days prior to day 1 of protocol therapy

  • Note: Conditioning regimen within 14 days prior to day 1 of protocol therapy is not considered as an exclusion criterion. Patients on maintenance chemotherapy with agents listed are not excluded
• Other investigational drugs for GVHD prophylaxis
• Herbal medications
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to study agent
• Clinically significant uncontrolled illness
• Active infection not responding to antibiotics
• Other active malignancy. Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial
• Females only: Pregnant or breastfeeding
• Patients not expected to be available for follow-up in our institution for at least 100 days after the transplant
• Any other condition that would, in the investigator's judgment, contraindicate the patient's participation in the clinical study due to safety concerns with clinical study procedures
• Prospective participants who, in the opinion of the investigator, may not be able to comply with all study procedures (including compliance issues related to feasibility/logistics)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Prevention (vedolizumab, cyclophosphamide, tacrolimus); 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.

Other: Questionnaire Administration; Ancillary studies; Procedure: Computed Tomography; Undergo CT; Other Names: CT; CAT; CAT Scan; Computed Axial Tomography; Computerized Axial Tomography; Computerized Tomography; CT Scan; tomography; Computerized axial tomography (procedure); Computerized Tomography (CT) scan; Procedure: Biospecimen Collection; Undergo blood sample collection; Other Names: Biological Sample Collection; Biospecimen Collected; Specimen Collection; Drug: Cyclophosphamide; Given IV; Other Names: Cytoxan; CTX; (-)-Cyclophosphamide; 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate; Carloxan; Ciclofosfamida; Ciclofosfamide; Cicloxal; Clafen; Claphene; CP monohydrate; CYCLO-cell; Cycloblastin; Cycloblastine; Cyclophospham; Cyclophosphamid monohydrate; Cyclophosphamide Monohydrate; Cyclophosphamidum; Cyclophosphan; Cyclophosphane; Cyclophosphanum; Cyclostin; Cyclostine; Cytophosphan; Cytophosphane; Fosfaseron; Genoxal; Genuxal; Ledoxina; Mitoxan; Neosar; Revimmune; Syklofosfamid; WR- 138719; Asta B 518; B-518; WR-138719; B 518; B518; WR 138719; WR138719; Drug: Fludarabine; Given IV; Other Names: Fluradosa; Drug: Melphalan; Given IV; Other Names: CB-3025; L-PAM; L-Sarcolysin; Alanine Nitrogen Mustard; L-Phenylalanine Mustard; L-Sarcolysin Phenylalanine mustard; L-Sarcolysine; Melphalanum; Phenylalanine Mustard; Phenylalanine Nitrogen Mustard; Sarcoclorin; Sarkolysin; WR-19813; Melphalan for Injection-Hepatic Delivery System; Procedure: Echocardiography; Undergo ECHO; Other Names: EC; Procedure: Multigated Acquisition Scan; Undergo MUGA; Other Names: Blood Pool Scan; Equilibrium Radionuclide Angiography; Gated Blood Pool Imaging; MUGA; Radionuclide Ventriculography; RNVG; SYMA Scanning; Synchronized Multigated Acquisition Scanning; MUGA Scan; Multi-Gated Acquisition Scan; Radionuclide Ventriculogram Scan; Gated Heart Pool Scan; RNV Scan; Drug: Tacrolimus; Given IV or PO; Other Names: Prograf; FK506; Hecoria; FK 506; Fujimycin; Protopic; FK-506; Tacforius; Procedure: Allogeneic Hematopoietic Stem Cell Transplantation; Undergo allogeneic HCT; Other Names: Allogeneic; Allogeneic Hematopoietic Cell Transplantation; Allogeneic Stem Cell Transplantation; HSC; HSCT; Stem Cell Transplantation, Allogeneic; Procedure: Bone Marrow Biopsy; Undergo bone marrow biopsy; Other Names: Biopsy of Bone Marrow; Biopsy, Bone Marrow; Biological: Vedolizumab; Given IV; Other Names: Entyvio; MLN0002; MLN02; LDP-02; LDP 02; LDP02; Immunoglobulin G1, anti-(human integrin LPAM-1 (lymphocyte Peyer's patch adhesion molecule 1)) (human-Mus musculus heavy chain), disulfide with human-Mus musculus kappa-chain, dimer

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of primary engraftment failure (Safety lead-in segment)	Will be assessed as an unacceptable toxicity (UT). Will include type, severity, duration, and attribution/association with the study regimen and dose limiting toxicity (DLT) occurrence. Tables will be constructed to summarize the observed incidence, severity, and type of toxicity, including, but not limiting infections, other adverse events of special interest, and severe adverse events. Point estimates and corresponding exact 90% confidence intervals (CIs) will be provided for each measure of toxicity/adverse events.	From starting the first dose of vedolizumab to the first observation of event, day +30, whichever comes first
Incidence of severe infusion reaction (Safety lead-in segment)	Will be assessed as a UT. Will assess severe infusion reactions, grade 4 per Common Terminology Criteria for Adverse Events (CTCAE) version (v) 5.0, after receiving the 1st or 2nd dose of vedolizumab. Will include type, severity, duration, and attribution/association with the study regimen and DLT occurrence. Tables will be constructed to summarize the observed incidence, severity, and type of toxicity, including, but not limiting infections, other adverse events of special interest, and severe adverse events. Point estimates and corresponding exact 90% CIs will be provided for each measure of toxicity/adverse events.	From starting the first dose of vedolizumab to the first observation of event, day +30, whichever comes first
Incidence of grade 4-5 adverse events (Safety lead-in segment)	Will be assessed as a UT. Will assess grade 4-5 adverse events based on CTCAE v 5.0 probably or definitely attributable to vedolizumab. Will include type, severity, duration, and attribution/association with the study regimen and DLT occurrence. Tables will be constructed to summarize the observed incidence, severity, and type of toxicity, including, but not limiting infections, other adverse events of special interest, and severe adverse events. Point estimates and corresponding exact 90% CIs will be provided for each measure of toxicity/adverse events.	From starting the first dose of vedolizumab to the first observation of event, day +30, whichever comes first
Non-relapse mortality (NRM) (Safety lead-in segment)	Will be assessed as a UT. Defined as death occurring in a patient from causes other than relapse or progression. Deaths from relapse/progression will be considered a competing risk. NRM will be censored at last follow-up if patients are alive and remain disease free. Will be analyzed using the Kaplan-Meier curves.	From date of stem cell infusion until non-disease related death, assessed up to 1 year post-hematopoietic cell transplant (HCT)
Incidence of grade 2-4 acute graft versus host disease (GVHD)-free survival	Will be assessed among patients in the safety lead-in and dose expansion segments. Will be estimated using Kaplan-Meier curve.	From start of HCT to first occurrence of grade 2-4 acute GVHD followed until day +180 or death from any cause, whichever occurs first, assessed up to 1 year post-HCT

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of adverse events (Expansion segment)	Will be assessed using CTCAE v5.0. Will assess grade 4-5 adverse events probably or definitely attributable to study regiment by day +30 post-HCT and grade 3-5 adverse events probably or definitely attributed to study regimen by day +130 that are not UT. Will include type, severity, duration, and attribution/association with the study regimen and DLT occurrence. Tables will be constructed to summarize the observed incidence, severity, and type of toxicity, including, but not limiting infections, other adverse events of special interest, and severe adverse events. Point estimates and corresponding exact 90% CIs will be provided for each measure of toxicity/adverse events.	From the start of first dose of vedolizumab to day +130 post-HCT
Incidence of grade 3-5 adverse events at least probably attributable to vedolizumab, but not UT	Will be assessed using CTCAE v5.0. Will include type, severity, duration, and attribution/association with the study regimen and DLT occurrence. Tables will be constructed to summarize the observed incidence, severity, and type of toxicity, including, but not limiting infections, other adverse events of special interest, and severe adverse events. Point estimates and corresponding exact 90% CIs will be provided for each measure of toxicity/adverse events.	Up to day +180 post-HCT
Overall survival	Patients are considered a failure for this endpoint if they die, regardless of cause. Will be censored at last follow-up if the last known status is alive. Will be analyzed using the Kaplan-Meier curves.	From the day of stem cell infusion until death, assessed up to 1 year post-HCT
Progression free survival	Patients are considered a failure for this endpoint if they die (regardless of cause) or experience disease progression or relapse. Will be censored at last follow-up if patients are alive and remain disease free. Will be analyzed using the Kaplan-Meier curves.	From the date of stem cell infusion to the date of death, disease relapse/progression, whichever occurs first, assessed up to 1 year post-HCT
Relapse/progression rate	Deaths without relapse/progression will be considered a competing risk. Surviving patients with no history of relapse/progression will be censored at time of last follow-up. Will be analyzed using the Kaplan-Meier curves.	From day of stem cell infusion (day 0) to 1 year post-HCT
NRM	Defined as death occurring in a patient from causes other than relapse or progression. Deaths from relapse/progression will be considered a competing risk. NRM will be censored at last follow-up if patients are alive and remain disease free. Will be analyzed using the Kaplan-Meier curves.	From date of stem cell infusion until non-disease related death, assessed up to 1 year post-HCT
Incidence of acute GVHD	Will be graded and staged according to Mount Sinai Acute GVHD International Consortium (MAGIC) criteria. The first day of acute GVHD onset at a certain grade will be used to calculate the cumulative incidence (grades II-IV). Will be evaluated among all patients treated with study regimen. Will be estimated using Kaplan-Meier curve.	From day 0 to days +100 and +180 post-HCT
Incidence of lower gastrointestinal GVHD	Will be graded and staged according to MAGIC criteria. The first day of acute GVHD onset at a certain grade will be used to calculate the cumulative incidence (grades II-IV). Will be evaluated among all patients treated with study regimen. Will be estimated using Kaplan-Meier curve.	From day 0 to days +100 and +180 post-HCT
Incidence chronic GVHD	Will be evaluated and scored according to National Institutes of Health Consensus Staging. The first day of chronic GVHD onset will be used to calculate the cumulative incidence. Will be evaluated among all patients treated with study regimen. Will be estimated using Kaplan-Meier curve.	From day +80 post-HCT to 1 year post-HCT
Incidence of infections	Microbiologically documented infections will be reported by site of disease, date of onset, severity and resolution, if any.	At days +100 and +180 post-HCT and 1 year post-HCT
Hematologic recovery	Will be defined as absolute neutrophil count (ANC) ≥ 0.5 x 10^3/μL achieved and sustained for 3 consecutive lab values on different days with no subsequent decline and platelets ≥ 20 K/μL independent of platelet transfusion support (date should reflect no transfusions in previous 7 days, and the first of 3 consecutive lab values on different days).	Up to 1 year post-HCT
Primary graft failure	Will be defined as failure to achieve ANC of 500 or more for 3 days and, hypocellular marrow, and donor chimerism of < 5% all by day 28.	Up to 28 days post-HCT
Incidence of cytokine release syndrome	Will be defined and graded per American Society for Transplantation and Cellular Therapy criteria.	Up to 1 year post-HCT

Collaborators and Investigators

• Sponsor: City of Hope Medical Center
• Collaborators: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Monzr M. Al Malki, City of Hope Medical Center

Study record dates

Study Major Dates

• Study Start (Actual): April 18, 2025
• Primary Completion (Estimated): October 15, 2028
• Study Completion (Estimated): October 15, 2028

Study Registration Dates

• First Submitted: February 4, 2025
• First Submitted That Met QC Criteria: February 4, 2025
• First Posted (Actual): February 7, 2025

Study Record Updates

• Last Update Posted (Actual): June 27, 2025
• Last Update Submitted That Met QC Criteria: June 24, 2025
• Last Verified: June 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms; Chronic Disease; Disease Attributes; Immune System Diseases; Neoplasms by Histologic Type; Hematologic Diseases; Lymphatic Diseases; Lymphoproliferative Disorders; Immunoproliferative Disorders; Leukemia, Myeloid; Myelodysplastic-Myeloproliferative Diseases; Bone Marrow Diseases; Leukemia, Lymphoid; Leukemia; Leukemia, Myelomonocytic, Chronic; Leukemia, Myelomonocytic, Juvenile; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Myelodysplastic Syndromes; Myeloproliferative Disorders; Graft vs Host Disease; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Gastrointestinal Agents; Enzyme Inhibitors; Antirheumatic Agents; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Calcineurin Inhibitors; Cyclophosphamide; Fludarabine; Melphalan; Immunoglobulins; Immunoglobulin G; Tacrolimus; Mechlorethamine; Nitrogen Mustard Compounds; Vedolizumab
• Other Study ID Numbers: 24473 (Other Identifier: City of Hope Medical Center); P30CA033572 (U.S. NIH Grant/Contract); NCI-2025-00341 (Registry Identifier: CTRP (Clinical Trial Reporting Program))

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No