A Dose-Finding Study of Vedolizumab for Treatment of Steroid-Refractory Acute Intestinal Graft-Versus-Host Disease (GvHD) in Participants Who Have Undergone Allogeneic Hematopoietic Stem Cell Transplantation (Allo-HSCT)

An Open-Label, Dose-Finding Study of Vedolizumab IV for Treatment of Steroid-Refractory Acute Intestinal Graft-Versus-Host Disease (GvHD) in Patients Who Have Undergone Allogeneic Hematopoietic Stem Cell Transplantation (Allo-HSCT)

The purpose of this study is to assess the initial activity, tolerability, safety and to identify a recommended dose and regimen of vedolizumab intravenous (IV) administered for treatment of steroid-refractory acute intestinal GvHD in participants who have undergone allo-HSCT.

Study Overview

• Status: Terminated
• Conditions: Allogeneic Hematopoietic Stem Cell Transplantation
• Intervention / Treatment: Drug: Vedolizumab

Detailed Description

The drug being tested in this study is called vedolizumab. This study will look at the tolerability and effectiveness of vedolizumab IV in participants with acute intestinal GvHD who have received no systemic therapy for the treatment of acute GvHD (prophylaxis acceptable) other than corticosteroids.

The study enrolled 17 participants. Participants will be randomly assigned (by chance, like flipping a coin) to one of the two treatment groups:

• Vedolizumab 300 mg
• Vedolizumab 600 mg

All participants will be infused intravenously at the same time each day throughout the study. Vedolizumab IV will be administered on Days 1, 15, 43, 71, and 99. After approximately 10 participants are enrolled at each dose level and have data available from the Day 28 evaluation, safety, tolerability, efficacy, and pharmacokinetic (PK), results will be assessed for each dose level, and the appropriate dose for subsequent participants in the study will be determined.

This multi-center trial will be conducted in multiple countries. The overall time to participate in this study is 32 weeks. Participants will make multiple visits to the clinic after last dose of study drug for a follow-up assessment.

• Study Type: Interventional
• Enrollment (Actual): 17
• Phase: Phase 2

Contacts and Locations

Study Locations

• Belgium
  • Antwerpen, Belgium, 2060
    • ZNA Stuivenberg
  • Brugge, Belgium, 8000
    • AZ Sint-Jan Brugge
  • Leuven, Belgium, 3000
    • UZ Leuven
• France
  • Loire Atlantique
    • Nantes cedex 1, Loire Atlantique, France, 44093
      • CHU Nantes - Hôtel Dieu
  • Nord
    • Lille cedex, Nord, France, 59037
      • Hopital Claude Huriez - CHU Lille
  • Paris
    • Paris cedex 12, Paris, France, 75571
      • Hopital Saint-Antoine
• Norway
  • Oslo, Norway, 3072
    • Oslo Universitetssykehus - Rikshospitalet
• Sweden
  • Lund, Sweden, 22185
    • Skånes universitetssjukhus, Lund
  • Uppsala, Sweden, 75185
    • Akademiska Sjukhuset
• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University
  • New York
    • Lake Success, New York, United States, 11041
      • Mount Sinai - PRIME
  • Ohio
    • Columbus, Ohio, United States, 43210
      • OSU - James Comprehensive Cancer Center
  • Texas
    • Dallas, Texas, United States, 75204
      • Baylor University Medical Center
  • Washington
    • Seattle, Washington, United States, 98109
      • Seattle Cancer Care Alliance

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Recipient of 1 allogeneic hematopoietic stem cell transplantation (allo-HSCT) but not more than 1 allo-HSCT.
2. Has primary steroid-refractory graft-versus-host disease (GvHD). Steroid-refractory disease is defined as worsening or no improvement in 5 to 7 days of treatment with methylprednisolone 2 milligram per kilogram (mg/kg) or equivalent or lack of a CR after 14 days of primary treatment with methylprednisolone 2 mg/kg or equivalent. Note that participants who develop intestinal GvHD while receiving systemic therapy for other GvHD are still eligible after 5 to 7 days, even if the intestinal GvHD has not been present for the entire duration. Participants who may have received an increase in their steroid dose treatment (example, increased methylprednisolone from 1 mg/kg to 2 mg/kg) before enrollment will be eligible, provided the participant has met the definition of steroid refractory above. Participants who develop toxicity on corticosteroids or who are otherwise medically unable to be dosed to this level, will also be eligible.
3. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 3.
4. Evidence of myeloid engraftment defined by absolute neutrophil count greater than or equal to (>=) 0.5*109/liter (L) on 3 consecutive days.

Exclusion Criteria:

1. Presence of chronic GvHD at Screening (including acute-chronic overlap syndrome).
2. Relapse of underlying malignant disease after allo-HSCT.
3. Hyperacute GvHD defined as onset of GvHD within the first 15 days following hematopoietic stem cell infusion.
4. Received systemic agents other than corticosteroids for treatment of acute GvHD. GvHD prophylaxis agents (example, calcineurin inhibitors) may be continued.
5. Life expectancy of <3 weeks.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Vedolizumab 300 mg; Vedolizumab 300 mg, intravenous (IV) infusion, once on Days 1, 15, 43, 71 and 99.	Drug: Vedolizumab; Vedolizumab IV infusion; Other Names: Entyvio; MLN0002
Experimental: Vedolizumab 600 mg; Vedolizumab 600 mg, IV infusion, once on Days 1, 15, 43, 71 and 99.	Drug: Vedolizumab; Vedolizumab IV infusion; Other Names: Entyvio; MLN0002

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants With Overall Response (Partial Response [PR]+Very Good Partial Response [VGPR]+Complete Response [CR]) at Day 28	CR is defined as the resolution of all signs and symptoms of acute graft-versus-host-disease (GvHD). VGPR is defined as resolution of the signs and symptoms of the GvHD: 1) Skin: no rash, or residual erythematous rash involving <25% of the body surface, without bullae (excluding residual faint erythema and hyperpigmentation). 2) Liver: total serum bilirubin concentration <2 mg/dL or <25% of baseline at enrollment. 3) Gut: a) participant tolerates food or enteral feeding; b) predominantly formed stools; c) no overt gastrointestinal bleeding or abdominal cramping; d) no more than occasional nausea or vomiting. PR is defined as improvement of 1 GvHD stage in 1 or more organs without progression in any organ.	Day 28
Number of Participants Who Experienced Serious Adverse Events (SAEs) Through Day 28	An Adverse Event (AE) is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. An SAE is defined as an untoward medical occurrence, significant hazard, contraindication, side effect or precaution that at any dose: results in death, is life-threatening, required in-patient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect or is medically significant.	From first dose up to Day 28

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants Who Died in the Absence of Primary Malignancy Relapse After Allo-HSCT at Month 6		Month 6
Percentage of Participants With Acute GvHD Complete Response (CR) at Day 28	CR is defined as the resolution of all signs and symptoms of acute GvHD.	Day 28
Percentage of Participants With Intestinal Overall Response at Day 28	Symptoms of acute intestinal GvHD were measured using the BMT CTN-modified International Bone Marrow Transplant Registry Database (IBMTR) index. Intestinal overall response is either CR, VGPR or PR for intestine only. CR is defined as the resolution of all signs and symptoms of GvHD. VGPR is defined as resolution of the majority of signs and symptoms of intestinal GvHD: a) participant tolerates food or enteral feeding; b) predominantly formed stools; c) no overt gastrointestinal bleeding or abdominal cramping; d) no more than occasional nausea or vomiting. PR is defined as improvement of intestinal GvHD by at least 1 stage.	Day 28
Kaplan-Meier Estimate of Percentage of Participants Achieving Survival at Months 6 and 12	The Kaplan-Meier estimate reports the percentage of participants surviving at Months 6 and 12.	Months 6 and 12
Percentage of Participants Alive Without GvHD or Primary Malignancy Relapse at Months 6 and 12		Months 6 and 12
Total Dose of Steroids Administered	Total Steroids administered in mg/kg/day of methylprednisolone or equivalent	From first dose of study drug up to Months 6 and 12
Number of Participants Who Experienced Treatment Emergent Adverse Events (TEAEs)	An AE is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (example, a clinically significant abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug, whether or not it is considered related to the drug. A TEAE is defined as an adverse event with an onset that occurs after receiving study drug.	From first dose of study drug to 18 weeks after last dose (Up to Week 32)
Number of Participants Who Experienced Serious Adverse Events (SAEs) Through Week 32	An AE is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. An SAE is defined as an untoward medical occurrence, significant hazard, contraindication, side effect or precaution that at any dose: results in death, is life-threatening, required in-patient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect or is medically significant.	From first dose of study drug to 18 weeks after last dose (Up to Week 32)
Number of Participants With Markedly Abnormal Laboratory Parameters Values	Clinical Laboratory parameters included tests for chemistry, hematology and urinalysis. Markedly abnormal values during treatment period were categorized as:alanine aminotransferase (ALT)>3.0 U/L*upper limit of normal(ULN),albumin<25 g/L*lower limit of normal(LLN),alkaline phosphatase >3.0 U/L*ULN,aspartate aminotransferase >3.0 U/L*ULN,bilirubin >2 umol/L*ULN,blood urea nitrogen(BUN) >10.7 mmol/L,calcium <1.75 mmol/L, >2.88 mmol/L,chloride <75 mmol/L, >126 mmol/L,creatinine >177umol/L,gamma glutamyl transferase (GGT) >3 U/L*ULN,glucose <2.8 mmol/L, >19.4 mmol/L,phosphate <0.52 mmol/L, >2.10 mmol/L,potassium<3 mmol/L, >6 mmol/L,sodium <130 mmol/L, >150 mmol/L,basophils >3(10^9/L)*ULN,eosinophils >2(10^9/L)*ULN,hematocrit (%) <0.8*LLN, >1.2*ULN,hemoglobin <0.8 g/L*LLN, >1.2 g/L*ULN,leukocytes <0.5 (10^9/L)*LLN, >1.5 (10^9/L)*ULN,lymphocytes <0.5 (10^9/L)*LLN, >1.5(10^9/L)*ULN,monocytes >2 (10^9/L)*ULN,neutrophils <0.5(10^9/L)*LLN, >1.5 (10^9/L)*ULN,platelets <75(10^9/L), >600(10^9/L).	From Baseline up to last dose of study drug (Day 99)
Number of Participants With Markedly Abnormal Vital Signs	Vital signs included heart rate, respiratory rate, systolic and diastolic blood pressure, temperature and weight. The vital sign values outside the range: systolic blood pressure (SBP) <85 mmHg and change from Baseline (BL) <=-20 mmHg, >180 mmHg and change from Baseline >=20 mmHg,diastolic blood pressure (DBP) <50 mmHg and change from Baseline <=-15 mmHg, >110 mmHg and change from Baseline >=15 mmHg, heart rate <50 beats per minute (bpm),>120 beats per minute, temperature <35.6 Degree C, >37.7 Degree C and weight change from Baseline <=-7 % and weight change from Baseline >=7 % assessed during treatment period were considered markedly abnormal.	From Baseline up to last dose of study drug (Day 99)
Ctrough: Trough Serum Concentrations of Vedolizumab		Day 99 (pre-dose)

Collaborators and Investigators

• Sponsor: Millennium Pharmaceuticals, Inc.
• Investigators: Study Director: Study Director, Millennium Pharmaceuticals, Inc.

Publications and helpful links

General Publications

• Floisand Y, Schroeder MA, Chevallier P, Selleslag D, Devine S, Renteria AS, Mohty M, Yakoub-Agha I, Chen C, Parfionovas A, Quadri S, Jansson J, Akbari M, Chen YB. A phase 2a randomized clinical trial of intravenous vedolizumab for the treatment of steroid-refractory intestinal acute graft-versus-host disease. Bone Marrow Transplant. 2021 Oct;56(10):2477-2488. doi: 10.1038/s41409-021-01356-0. Epub 2021 Jun 9.

Study record dates

Study Major Dates

• Study Start (Actual): April 28, 2017
• Primary Completion (Actual): May 9, 2018
• Study Completion (Actual): May 9, 2018

Study Registration Dates

• First Submitted: December 8, 2016
• First Submitted That Met QC Criteria: December 13, 2016
• First Posted (Estimate): December 15, 2016

Study Record Updates

• Last Update Posted (Actual): May 24, 2019
• Last Update Submitted That Met QC Criteria: May 1, 2019
• Last Verified: May 1, 2019

More Information

Terms related to this study

• Keywords: Drug Therapy
• Additional Relevant MeSH Terms: Immune System Diseases; Graft vs Host Disease; Gastrointestinal Agents; Vedolizumab
• Other Study ID Numbers: Vedolizumab-2004; 2016-002985-30 (EudraCT Number); U1111-1185-6832 (Other Identifier: WHO)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD 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.

Drug and device information, study documents

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