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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)

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: NCT02993783
Recruitment Status : Terminated (Lack of efficacy of the drug; no safety concern)
First Posted : December 15, 2016
Results First Posted : May 24, 2019
Last Update Posted : May 24, 2019
Sponsor:
Information provided by (Responsible Party):
Takeda ( Millennium Pharmaceuticals, Inc. )

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.

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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

Resource links provided by the National Library of Medicine

Drug Information available for: Vedolizumab

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




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) ]


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 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.

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): NCT02993783


Locations
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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
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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

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

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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 ( Millennium Pharmaceuticals, Inc. ):
Drug Therapy
Additional relevant MeSH terms:
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Graft vs Host Disease
Immune System Diseases
Vedolizumab
Gastrointestinal Agents