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.
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
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
35
Undergo allogeneic HCT
Undergo blood sample collection
Undergo bone marrow biopsy
Undergo CT
Given IV
Undergo ECHO
Given IV
Given IV
Undergo MUGA
Ancillary studies
Given IV or PO
Given IV
City of Hope Medical Center
Duarte, California, United States
RECRUITINGIncidence 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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
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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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
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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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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).
Time frame: 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.
Time frame: 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.
Time frame: Up to 1 year post-HCT