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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02728895
Recruitment Status : Completed
First Posted : April 5, 2016
Results First Posted : August 26, 2019
Last Update Posted : August 26, 2019
Sponsor:
Information provided by (Responsible Party):
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]).

Condition or disease Intervention/treatment Phase
Allogeneic Hematopoietic Stem Cell Transplantation Drug: Vedolizumab Phase 1

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 24 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: An Open-Label, Dose-Finding Study of Vedolizumab IV Plus Standard of Care for Graft-Versus-Host Disease (GvHD) Prophylaxis in Patients Undergoing Allogeneic Hematopoietic Stem Cell Transplantation (HSCT)
Actual Study Start Date : June 15, 2016
Actual Primary Completion Date : July 10, 2018
Actual Study Completion Date : July 10, 2018

Resource links provided by the National Library of Medicine

Drug Information available for: Vedolizumab

Arm Intervention/treatment
Experimental: Cohort 1: Vedolizumab 75 mg
Vedolizumab 75 mg, injection, intravenously once on Days -1, 13 and 42.
Drug: Vedolizumab
Vedolizumab Injection.

Experimental: Cohort 2: Vedolizumab 300 mg
Vedolizumab 300 mg, injection, intravenously once on Days -1, 13 and 42.
Drug: Vedolizumab
Vedolizumab Injection.

Experimental: Cohort 3: Vedolizumab Dose 1
Vedolizumab first decided dose as determined from Cohort 1 or 2, injection, intravenously once on Days -1, 13 and 42.
Drug: Vedolizumab
Vedolizumab Injection.




Primary Outcome Measures :
  1. Number of Participants With Dose-Limiting Toxicities (DLTs) [ Time Frame: 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.

  2. Number of Participants Reporting One or More Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) [ Time Frame: Up to 18 weeks after last dose of study drug ]
  3. Mean Serum Concentrations of Vedolizumab That Helped the Likelihood of Alpha4Beta7 Target Saturation on Day 100 Following Allo-HSCT [ Time Frame: Day 100 ]

Secondary Outcome Measures :
  1. Time to Neutrophil Engraftment [ Time Frame: 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.

  2. Percentage of Participants With Overall Grade 2 to 4 Acute Graft-Versus-Host Disease (GvHD) [ Time Frame: 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).

  3. Percentage of Participants With Maximum Severity of Acute GvHD Based on Modified Glucksberg Criteria [ Time Frame: 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).

  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 [ Time Frame: 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).

  5. Ctrough: Serum Concentration Before Dosing for Vedolizumab [ Time Frame: Days 13 and 42 pre-dose ]


Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 60 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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).

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02728895


Locations
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United States, Massachusetts
Massachusetts General Hospital
Boston, Massachusetts, United States, 02114
Dana-Farber Cancer Institute
Boston, Massachusetts, United States, 2215
United States, New York
Icahn School of Medicine at Mount Sinai
New York, New York, United States, 10029
United States, Ohio
OSU - James Comprehensive Cancer Center
Columbus, Ohio, United States, 43210
United States, Wisconsin
Medical College of Wisconsin, Inc.
Milwaukee, Wisconsin, United States, 53266
Sponsors and Collaborators
Takeda
Investigators
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Study Director: Medical Director Takeda
  Study Documents (Full-Text)

Documents provided by Takeda:
Statistical Analysis Plan  [PDF] June 4, 2018
Study Protocol  [PDF] January 13, 2016


Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Takeda
ClinicalTrials.gov Identifier: NCT02728895    
Other Study ID Numbers: Vedolizumab-1015
U1111-1184-1822 ( Registry Identifier: WHO )
First Posted: April 5, 2016    Key Record Dates
Results First Posted: August 26, 2019
Last Update Posted: August 26, 2019
Last Verified: July 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Takeda makes patient-level, de-identified data sets and associated documents available after applicable marketing approvals and commercial availability have been received, an opportunity for the primary publication of the research has been allowed, and other criteria have been met as set forth in Takeda's Data Sharing Policy (see www.TakedaClinicalTrials.com/Approach for details). To obtain access, researchers must submit a legitimate academic research proposal for adjudication by an independent review panel, who will review the scientific merit of the research and the requestor's qualifications and conflict of interest that can result in potential bias. Once approved, qualified researchers who sign a data sharing agreement are provided access to these data in a secure research environment.

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Takeda:
Drug Therapy
Additional relevant MeSH terms:
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Vedolizumab
Gastrointestinal Agents