Dose Finding Study of Vedolizumab for GvHD in Participants Undergoing Allogeneic HSCT

Phase 1

Completed

• Conditions: Allogeneic Hematopoietic Stem Cell Transplantation
• Interventions: Drug: Vedolizumab

• Registration Number: NCT02728895
• Lead Sponsor: Takeda

Brief Summary

The purpose of this study is to assess the initial tolerability, safety and recommended phase 2 dose of vedolizumab intravenous (IV) administered for GvHD prophylaxis along with standard GvHD prophylaxis therapy (in participants undergoing allogeneic hematopoietic stem cell transplantation \[allo-HSCT\]).

Detailed Description

The drug being tested in this study is called Vedolizumab. Vedolizumab (also called MLN0002) is approved for the treatment of adult participants with moderately to severely active ulcerative colitis (UC) and Crohn's disease (CD) who achieved an inadequate response, had a loss of response, or were intolerant to conventional and/or biologic treatments. This study will look at the tolerability and pharmacokinetics of Vedolizumab in participants undergoing allo-HSCT when added to standard GvHD prophylaxis (tacrolimus plus short-term methotrexate) for the prevention of acute GvHD (major complication in allo-HSCT).

The study will enroll approximately 36 participants. Participants will be assigned to different dose-escalating cohorts in order to find out the recommended phase 2 dose (RP2D) of the study:

* Cohort 1: Vedolizumab 75 mg

* Cohort 2: Vedolizumab 300 mg

* Cohort 3: Vedolizumab Dose 1

All participants have to receive 1 injection of Vedolizumab on Day -1 before allo-HSCT and on Days 13 and 42 after allo-HSCT. If none of the participants receiving vedolizumab at 75 mg experience dose-limiting toxicities (DLTs), dose escalation will continue to 300 mg on Day -1 before allo-HSCT and on Days +13 and +42 after allo-HSCT. If the first 3 participants at 300 mg tolerate the treatment without experiencing DLTs, then the decision on whether to increase the vedolizumab IV dose in the next cohort will be guided by the PK results.

Cohorts will be escalated in same manner until the identification of RP2D. The cohort at that dose level may be expanded to include approximately 18 additional participants undergoing myeloablative conditioning or reduced-intensity conditioning (RIC) and receiving either related or unrelated allo-HSCT for the treatment of hematologic malignancies or myeloproliferative neoplasms. This group of participants will allow the further assessment of the tolerability and clinical activity of vedolizumab.

This multi-center trial will be conducted in the United States. The overall time to participate in this study will be approximately 2 years. Following the treatment period, participants who remain in remission will be followed for development of acute and chronic GvHD and safety during clinic visits at 4, 5, 6, 9, and 12 months after allo-HSCT or until death or withdrawal of consent or termination of the study by the sponsor. Participants who complete the study will attend a 12-month follow-up visit. Patients who have been discontinued from treatment will attend an end of treatment visit 30 to 40 days after the last dose of study drug using all study procedures outlined for the 12-month follow-up visit.

Study Timeline

• Study First Submitted: 2016-03-31
• Study First Submitted QC: 2016-03-31
• Study First Posted: 2016-04-05
• Study Start: 2016-06-15
• Primary Completion: 2018-07-10
• Study Completion: 2018-07-10
• Status Verified: 2019-07
• Results First Submitted: 2019-07-09
• Results First Submitted QC: 2019-07-09
• Last Update Submitted: 2019-07-09
• Results First Posted: 2019-08-26
• Last Update Posted: 2019-08-26

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 24

Inclusion Criteria

1. Is undergoing matched or single-antigen mismatched unrelated-donor myeloablative transplant for the treatment of acute lymphoblastic leukemia (ALL) or acute myeloid leukemia (AML); Is less than or equal to (<=) 60 years of age.

   For the cohort after RP2D

2. Is undergoing matched or single-antigen mismatched related or unrelated-donor transplant and receiving myeloablative conditioning or RIC for the treatment of hematologic malignancies or myeloproliferative neoplasms; Is less than or equal to (<=) 75 years of age.

Exclusion Criteria

1. Has received prior allogeneic transplants or who are planned to undergo umbilical cord blood transplant, receive ex vivo T-cell-depleted hematopoietic stem cells (HSCs), received any in vivo T-cell depleting antibodies, or non-myeloablative conditioning.
2. Has active cerebral/meningeal disease, active cytomegalovirus (CMV) colitis, or signs and symptoms of progressive multifocal leukoencephalopathy (PML) or any history of PML.
3. Is undergoing transplant for the treatment of nonmalignant hematological disorders (for example: aplastic anemia, sickle cell anemia, thalassemias, Fanconi anemia).

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Cohort 1: Vedolizumab 75 mg	Vedolizumab	Vedolizumab 75 mg, injection, intravenously once on Days -1, 13 and 42.
Cohort 2: Vedolizumab 300 mg	Vedolizumab	Vedolizumab 300 mg, injection, intravenously once on Days -1, 13 and 42.
Cohort 3: Vedolizumab Dose 1	Vedolizumab	Vedolizumab first decided dose as determined from Cohort 1 or 2, injection, intravenously once on Days -1, 13 and 42.

Primary Outcome Measures

Name	Time	Method
Number of Participants With Dose-Limiting Toxicities (DLTs)	Baseline up to Day 28	DLTs was based on National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03 and was defined as any of following events: Grade 3 or higher toxicity assessed by the investigator as related to vedolizumab treatment; Grade 4 or higher regimen-related organ toxicities; and failure to engraft by Day +28. Engraftment was defined as absolute neutrophils count (ANC) greater than (\>) 500 per cubic millimeter (/mm\^3) for 3 consecutive days or \>2000/mm\^3 for 1 day.
Number of Participants Reporting One or More Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)	Up to 18 weeks after last dose of study drug
Mean Serum Concentrations of Vedolizumab That Helped the Likelihood of Alpha4Beta7 Target Saturation on Day 100 Following Allo-HSCT	Day 100

Secondary Outcome Measures

Name	Time	Method
Time to Neutrophil Engraftment	Baseline up to Day 100	Time to neutrophil engraftment (recovery of ANC) was defined by an ANC \>500/mm\^3 for 3 consecutive days or \>2000/mm\^3 for 1 day. Time to neutrophil engraftment was calculated using Kaplan-Meier estimate and presented with 2-sided 95% confidence interval.
Percentage of Participants With Overall Grade 2 to 4 Acute Graft-Versus-Host Disease (GvHD)	Baseline up to Day 100	GvHD grading scale was based on the modified Glucksberg criteria. The grades are defined as: Grade 1 (skin stage 1 or 2 only); Grade 2 (skin stage 3 or liver stage 1 or lower or gastrointestinal \[GI\] stage 1 or upper GI involvement); Grade 3 (skin stage 0 to 3 plus liver stage 2 to 4 or lower GI stage 2 to 3); Grade 4 (skin stage 4 or lower GI stage 4).
Percentage of Participants With Maximum Severity of Acute GvHD Based on Modified Glucksberg Criteria	Baseline up to Day 100	Maximum severity was assessed using GvHD grading scale based on the modified Glucksberg criteria. The grades are defined as: Grade 1 (skin stage 1 or 2 only); Grade 2 (skin stage 3 or liver stage 1 or lower or GI stage 1 or upper GI involvement); Grade 3 (skin stage 0 to 3 plus liver stage 2 to 4 or lower GI stage 2 to 3); Grade 4 (skin stage 4 or lower GI stage 4).
Percentage of Participants With Maximum Severity of Acute GvHD Based on Blood and Marrow Transplant Clinical Trials Network (BMT CTN) Modified International Bone Marrow Transplant Registry Database (IBMTR) Index	Baseline up to Day 100	Maximum severity of acute GvHD was assessed by using BMT CTN modified IBMTR index. The severity index are defined as: Grade A (skin stage 1: extent of rash less than \[\<\] 25%); Grade B (skin stage 2: extent of rash 25 to 50% or liver stage 1 to 2: total bilirubin 34 to 102 micromole per liter \[mcmol/L\] or intestinal tract stage 1 to 2: volume of diarrhea 550 to 1500 milliliter per day \[mL/day\]); Grade C (skin stage 3: extent of rash greater than (\>) 50% or liver stage 3: total bilirubin 103 to 255 mcmol/L or intestinal tract stage 3: volume of diarrhea \>1500 mL/day); Grade D (skin stage 4: extent of rash bullae or liver stage 4: total bilirubin \>255 or intestinal tract stage 4: volume of diarrhea severe pain and ileus).
Ctrough: Serum Concentration Before Dosing for Vedolizumab	Days 13 and 42 pre-dose

Trial Locations

Locations (5)

Dana-Farber Cancer Institute; 🇺🇸 Boston, Massachusetts, United States

Massachusetts General Hospital; 🇺🇸 Boston, Massachusetts, United States

OSU - James Comprehensive Cancer Center; 🇺🇸 Columbus, Ohio, United States

Medical College of Wisconsin, Inc.; 🇺🇸 Milwaukee, Wisconsin, United States

Icahn School of Medicine at Mount Sinai; 🇺🇸 New York, New York, United States