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)

• ClinicalTrials.gov Identifier: NCT02993783
• Recruitment Status: Terminated
• First Posted: December 15, 2016
• Results First Posted: May 24, 2019
• Last Update Posted: May 24, 2019
• Sponsor: Millennium Pharmaceuticals, Inc.
• Information provided by (Responsible Party): Takeda ( Millennium Pharmaceuticals, Inc. )

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Allogeneic Hematopoietic Stem Cell Transplantation	Drug: Vedolizumab	Phase 2

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 17 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: 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)
• Actual Study Start Date: April 28, 2017
• Actual Primary Completion Date: May 9, 2018
• Actual Study Completion Date: May 9, 2018

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures :

1. Percentage of Participants With Overall Response (Partial Response [PR]+Very Good Partial Response [VGPR]+Complete Response [CR]) at Day 28 [ Time Frame: 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.
2. Number of Participants Who Experienced Serious Adverse Events (SAEs) Through Day 28 [ Time Frame: From first dose up to 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.

Secondary Outcome Measures :

1. Percentage of Participants Who Died in the Absence of Primary Malignancy Relapse After Allo-HSCT at Month 6 [ Time Frame: Month 6 ]
2. Percentage of Participants With Acute GvHD Complete Response (CR) at Day 28 [ Time Frame: Day 28 ]
   CR is defined as the resolution of all signs and symptoms of acute GvHD.
3. Percentage of Participants With Intestinal Overall Response at Day 28 [ Time Frame: 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.
4. Kaplan-Meier Estimate of Percentage of Participants Achieving Survival at Months 6 and 12 [ Time Frame: Months 6 and 12 ]
   The Kaplan-Meier estimate reports the percentage of participants surviving at Months 6 and 12.
5. Percentage of Participants Alive Without GvHD or Primary Malignancy Relapse at Months 6 and 12 [ Time Frame: Months 6 and 12 ]
6. Total Dose of Steroids Administered [ Time Frame: From first dose of study drug up to Months 6 and 12 ]
   Total Steroids administered in mg/kg/day of methylprednisolone or equivalent
7. Number of Participants Who Experienced Treatment Emergent Adverse Events (TEAEs) [ Time Frame: From first dose of study drug to 18 weeks after last dose (Up to 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 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.
8. Number of Participants Who Experienced Serious Adverse Events (SAEs) Through Week 32 [ Time Frame: From first dose of study drug to 18 weeks after last dose (Up to 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.
9. Number of Participants With Markedly Abnormal Laboratory Parameters Values [ Time Frame: From Baseline up to last dose of study drug (Day 99) ]
   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).
10. Number of Participants With Markedly Abnormal Vital Signs [ Time Frame: From Baseline up to last dose of study drug (Day 99) ]
    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.
11. Ctrough: Trough Serum Concentrations of Vedolizumab [ Time Frame: Day 99 (pre-dose) ]

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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.

Contacts and Locations

Locations

United States, Massachusetts

Massachusetts General Hospital

Boston, Massachusetts, United States, 02114

United States, Missouri

Washington University

Saint Louis, Missouri, United States, 63110

United States, New York

Mount Sinai - PRIME

Lake Success, New York, United States, 11041

United States, Ohio

OSU - James Comprehensive Cancer Center

Columbus, Ohio, United States, 43210

United States, Texas

Baylor University Medical Center

Dallas, Texas, United States, 75204

United States, Washington

Seattle Cancer Care Alliance

Seattle, Washington, United States, 98109

Belgium

ZNA Stuivenberg

Antwerpen, Belgium, 2060

AZ Sint-Jan Brugge

Brugge, Belgium, 8000

UZ Leuven

Leuven, Belgium, 3000

France

CHU Nantes - Hotel Dieu

Nantes cedex 1, Loire Atlantique, France, 44093

Hopital Claude Huriez - CHU Lille

Lille cedex, Nord, France, 59037

Hopital Saint-Antoine

Paris cedex 12, Paris, France, 75571

Norway

Oslo Universitetssykehus - Rikshospitalet

Oslo, Norway, 3072

Sweden

Skanes Universitetssjukhus, Lund

Lund, Sweden, 22185

Akademiska Sjukhuset

Uppsala, Sweden, 75185

Sponsors and Collaborators

Millennium Pharmaceuticals, Inc.

Investigators

• Study Director: Study Director; Millennium Pharmaceuticals, Inc.

  Study Documents (Full-Text)

Documents provided by Takeda ( Millennium Pharmaceuticals, Inc. ):

Statistical Analysis Plan  [PDF] September 13, 2018

Study Protocol  [PDF] November 27, 2017

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

• Responsible Party: Millennium Pharmaceuticals, Inc.
• ClinicalTrials.gov Identifier: NCT02993783
• Other Study ID Numbers: Vedolizumab-2004; 2016-002985-30 ( EudraCT Number ); U1111-1185-6832 ( Other Identifier: WHO )
• First Posted: December 15, 2016
• Results First Posted: May 24, 2019
• Last Update Posted: May 24, 2019
• Last Verified: May 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.

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Takeda ( Millennium Pharmaceuticals, Inc. ):

Drug Therapy

Additional relevant MeSH terms:

Graft vs Host Disease; Immune System Diseases; Vedolizumab; Gastrointestinal Agents