Intestinal acute graft-versus-host disease (aGvHD) MedDRA version: 20.1 Level: PT Classification code 10066264 Term: Acute graft versus host disease in intestine System Organ Class: 10021428 - Immune system disorders
Conditions
Sponsors
Millennium Pharmaceuticals, Inc.
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. The subject or, when applicable, the subject’s legally acceptable representative voluntarily signs and dates a written, informed consent form (ICF) and any required privacy authorization before performance of any study-related procedures not part of standard medical care, with the understanding that consent may be withdrawn by the subject at any time without prejudice to future medical care. As applicable, a parent/both parents or legally acceptable representative must provide signature of informed consent, and there must be documentation of ageappropriate assent by the subject. 2. Male or female subjects =18 years of age, in selected countries (where local requirements permit and based on feasibility), adolescents aged 12 years and greater and weighing =30 kg at time of randomization. 3. Subjects must undergo DNA-based HLA matching and be 8 of 8 or 7 of 8 HLA-matched (single allele or antigen mismatch at HLA-A, -B, and -C,and HLA-DRB1 is allowable) unrelated hematopoietic stem cell transplantation (HSCT) from either peripheral blood or bone marrow stem cells for a hematologic malignancy or myeloproliferative disorder. Subjects should follow local practice for additional HLA-match, for example France, 9/10 or 10/10 HLA match. 4. Subjects for whom a myeloablative conditioning or RIC is planned. 5. Allo-HSCT eligible (meeting institutional criteria)-subjects planned medical care should include aGvHD prophylaxis with a combination of CNI (CYS or TAC) and MTX or CNI and MMF. With the exception of ATG (ATG-F or thymoglobulin), all other therapies, approved or investigational, for GvHD prophylaxis are excluded. 6. Status of the primary disease as follows: a. Subjects with acute leukemia or chronic myelogenous leukemia: no circulating blasts and <5% blasts in the bone marrow. b. Subjects with myelodysplasia: no circulating blasts and <10% blasts in the bone marrow. c. Subjects with chronic lymphocytic leukemia or small lymphocytic lymphoma with chemosensitive disease at the time of transplantation (partial or complete response to last salvage therapy). d. Subjects with other nonHodgkin or Hodgkin lymphoma with a response to last salvage therapy or chemo-sensitive disease per institutional standards at the time of transplantation. e. For subjects with myelofibrosis and other myeloproliferative disorders: <5% blasts in the blood and bone marrow. 7. Eastern Cooperative Oncology Group (ECOG) performance status of =2 for subjects aged =18 years at randomization or =60% using the Karnofsky performance status for adolescent subjects aged =16 years at randomization or the Lansky performance status for adolescent subjects aged 12 to <16 years at randomization. 8. Sufficient cognitive ability to reliably complete the PML checklist at baseline. 9. Female subjects who are: • Postmenopausal for at least 1 year before signing of the informed consent, OR • Surgically sterile, OR • If they are aged 12 years and greater and not postmenopausal or surgically sterilized , must use a highly effective method of contraception during the study and through 18 weeks after the last dose of study drug, OR • Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence [eg, calendar, ovulation, symptothermal, postovulation methods], withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception. Female and male condoms should not be used t
Exclusion criteria
Exclusion criteria: 1. Prior allo-HSCT. 2. Planned umbilical cord blood transplant or planned to receive posttransplant cyclophosphamide, in vivo or ex vivo T-cell depleted hematopoietic stem cells (HSCs) with the exception of ATG (ATG-F or thymoglobulin). 3. Planned allo-HSCT for nonmalignant hematological disorders (eg, aplastic anemia, sickle cell anemia, thalassemias, Fanconi anemia or immunodeficiency). 4. Known active cerebral/meningeal disease (including central nervous system involvement of the primary disease), or signs or symptoms of PML, any history of PML, or a positive PML subjective checklist before the administration of study drug on Day -1. 5. Evidence of encephalopathy at screening. 6. History of any major neurological disorder, including stroke, multiple sclerosis, brain tumor, or neurodegenerative disease. 7. Prior or current therapy with a4 and/or ß7 integrin inhibitors (including, but not limited to natalizumab, etrolizumab, AMG-181), MAdCAM-1-antibodies, anti-CD11a mAb (eg, efalizumab) within 60 days or 5 half-lives, whichever is longer from randomization. 8. Prior known exposure of the transplant recipient to vedolizumab. 9. Any serious medical or psychiatric condition that could, in the investigator or medical monitor’s opinion, potentially interfere with the completion of treatment according to this protocol. 10. Any unstable or uncontrolled cardiovascular, pulmonary, hepatic, renal, GI, genitourinary, coagulation, immunological, endocrine/metabolic, neurologic or other medical disorder not related to the subject’s primary disease that, in the opinion of the investigator, would confound the study results or compromise subject safety. 11. Clinically active systemic infection during screening. 12. Clinically active cytomegalovirus (CMV) colitis during screening. 13. Clinically active Clostridium difficile infection or other intestinal pathogen during screening. 14. Active or latent tubercolosis (TB), regardless of treatment history, as evidenced by any of the following: history of TB, OR positive QuantiFERON test, OR T-Spot or 2 successive indeterminate QuantiFERON tests, OR T-Spot tests OR a tuberculin skin test reaction =10 mm (=5 mm in subjects receiving the equivalent of >15 mg/day prednisone). 15. Chronic hepatitis B (hepatitis B surface antigen [HBsAg] positive [HBsAg+]) or hepatitis C infection (evident by active viral replication by polymerase chain reaction [PCR] if hepatitis C virus antibody positive). Hepatitis B core antibody (HBcAb) positive (HBcAb+) and negative for hepatitis B surface antigen (HBsAg-) may be enrolled if viral DNA is undetectable. 16. History of human immunodeficiency virus (HIV) positive test. 17. Treatment with anti-T-cells antibody such as alemtuzumab (anti-CD52), excluding ATG (ATG-F or thymoglobulin), within 4 months before the first dose of study drug on Day -1. 18. Treatment with any live vaccinations within 30 days before randomization. 19. If female, the subject is pregnant, lactating or breastfeeding, or intending to become pregnant before, during or within 18 weeks after participating in this study, or intending to donate ova during such time period. 20. Diagnosed or treated for another malignancy within 2 years before the first dose of study drug or previously diagnosed with another malignancy and have any evidence of residual disease. Subjects with nonmelanoma skin cancer or carcinoma in situ of any type are not excluded if they have undergone complete resection.
Design outcomes
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): • Intestinal aGvHD-free and relapse-free (of the underlying malignancy) survival by Day +180. • Grade C-D aGvHD-free (any organ involvement) survival by Day +180. • NRM by Day +180. • OS by Day +180. • Grade B-D aGvHD-free (any organ involvement) survival by Day +180. ;Timepoint(s) of evaluation of this end point: Day +180 | — |
Primary
| Measure | Time frame |
|---|---|
| Primary end point(s): The primary endpoint is intestinal aGvHD-free survival by Day +180 after allo HSCT. Intestinal aGvHD is defined as Stage 1-4 intestinal involvement per Acute Graft versus-Host Disease Clinical Stage criteria.;Timepoint(s) of evaluation of this end point: Day +180;Main Objective: To evaluate the efficacy of vedolizumab when added to background aGvHD prophylaxis regimen compared to placebo and background aGvHD prophylaxis regimen on intestinal aGvHD-free survival by Day +180 in subjects who receive allo-HSCT as treatment for a hematologic malignancy or myeloproliferative disorder. ;Secondary Objective: Safety Objective: To evaluate the safety of vedolizumab when added to background aGvHD prophylaxis regimen compared to placebo and background aGvHD prophylaxis regimen. Secondary Objectives: • To evaluate the effect of vedolizumab compared to placebo on intestinal aGvHD free, relapse-free (free of underlying malignancy) survival by Day +180. • To evaluate the effect of vedolizumab compared to placebo on Grade C-D aGvHD free (any organ involvement) survival by Day +180. • To evaluate the effect of vedolizumab compared to placebo on NRM in subjects by Day +180. • To evaluate the effect of vedolizumab compared to placebo on OS by Day +180. • To evaluate the effect of vedolizumab compared to placebo on Grade B-D aGvHD-free (any organ involvement) survival by Day +180. | — |
Countries
Argentina, Australia, Austria, Belgium, Brazil, Canada, France, Germany, Greece, Hungary, Israel, Italy, Japan, Korea, Republic of, Norway, Poland, Portugal, Romania, Russian Federation, Singapore, Spain, Sweden, Switzerland, Taiwan, Turkey, United Kingdom, United States
Contacts
Public ContactTakeda Study Registration Call Cent
Takeda
Outcome results
None listed