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)

Allogeneic Hematopoietic Stem Cell Transplantation Clinical Trial

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)

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT02993783
• Other study ID #: Vedolizumab-2004
• Secondary ID: 2016-002985-30U1
• Status: Terminated
• Phase: Phase 2
• Start date: April 28, 2017
• Est. completion date: May 9, 2018

Study information

• Verified date: May 2019
• Source: Takeda
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 17
• Est. completion date: May 9, 2018
• Est. primary completion date: May 9, 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Allogeneic Hematopoietic Stem Cell Transplantation
• Graft vs Host Disease

Intervention

Drug:
• Vedolizumab
Vedolizumab IV infusion

Locations

Country	Name	City	State
Belgium	ZNA Stuivenberg	Antwerpen
Belgium	AZ Sint-Jan Brugge	Brugge
Belgium	UZ Leuven	Leuven
France	Hopital Claude Huriez - CHU Lille	Lille cedex	Nord
France	CHU Nantes - Hotel Dieu	Nantes cedex 1	Loire Atlantique
France	Hopital Saint-Antoine	Paris cedex 12	Paris
Norway	Oslo Universitetssykehus - Rikshospitalet	Oslo
Sweden	Skanes Universitetssjukhus, Lund	Lund
Sweden	Akademiska Sjukhuset	Uppsala
United States	Massachusetts General Hospital	Boston	Massachusetts
United States	OSU - James Comprehensive Cancer Center	Columbus	Ohio
United States	Baylor University Medical Center	Dallas	Texas
United States	Mount Sinai - PRIME	Lake Success	New York
United States	Washington University	Saint Louis	Missouri
United States	Seattle Cancer Care Alliance	Seattle	Washington

Sponsors (1)

Lead Sponsor	Collaborator
Millennium Pharmaceuticals, Inc.

Countries where clinical trial is conducted

United States,  Belgium,  France,  Norway,  Sweden, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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	Percentage of Participants Who Died in the Absence of Primary Malignancy Relapse After Allo-HSCT at Month 6		Month 6
Secondary	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
Secondary	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
Secondary	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
Secondary	Percentage of Participants Alive Without GvHD or Primary Malignancy Relapse at Months 6 and 12		Months 6 and 12
Secondary	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
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	Ctrough: Trough Serum Concentrations of Vedolizumab		Day 99 (pre-dose)