E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Steroid-Refractory Acute Intestinal Graft-Versus-Host Disease (GvHD) |
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E.1.1.1 | Medical condition in easily understood language |
Acute Intestinal Graft-Versus-Host Disease (GvHD), a complication of bone marrow transplantation, that has not responded to steroid treatment. |
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E.1.1.2 | Therapeutic area | Diseases [C] - Immune System Diseases [C20] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10066264 |
E.1.2 | Term | Acute graft versus host disease in intestine |
E.1.2 | System Organ Class | 10021428 - Immune system disorders |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The primary objective is to describe the initial activity, tolerability, and safety and to identify a recommended dose and regimen of vedolizumab IV administered for treatment of steroid-refractory acute intestinal GvHD in patients who have undergone allo-HSCT. |
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E.2.2 | Secondary objectives of the trial |
The secondary objectives are:
To evaluate overall response to vedolizumab treatment at Day 28.
To determine the nonrelapse mortality at 6 months after treatment with vedolizumab.
To evaluate overall survival (OS).
To determine the GvHD-free, relapse-free survival at 6 and 12 months after treatment with vedolizumab.
To characterize the PK in patients treated with vedolizumab. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Male or female patients aged 18 years or older.
2. Recipient of 1 allo-HSCT but not more than 1 allo-HSCT.
3. Patients with primary steroid-refractory GvHD as defined in the protocol. Patients who develop toxicity on corticosteroids or who are otherwise medically unable to be dosed to this level, will also be eligible.
4. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 3 as per Appendix E of the protocol.
5. Acute GvHD with intestinal disease involvement with a severity index of B, C, or D using the Blood and Marrow Transplant Clinical Trials Network (BMT CTN)-modified International Bone Marrow Transplant Registry Database (IBMTR) index (See Appendix F of the protocol).
6. Evidence of myeloid engraftment defined by absolute neutrophil count ≥0.5×109/L on 3 consecutive days.
7. This inclusion criteria is deleted in amendment 02.
8. Sufficient cognitive ability to reliably complete the PML checklist at Baseline.
9. Female patients who:
Are postmenopausal for at least 1 year before the Screening visit, OR
Are surgically sterile, OR
If they are of childbearing potential, agree to practice one highly effective method of contraception and one additional effective (barrier) method at the same time, from the time of signing the informed consent 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 together.)
Male patients, even if surgically sterilized (ie, status postvasectomy), who:
Agree to practice effective barrier contraception during the entire study treatment period 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 together.)
10. Voluntary written consent must be given before performance of any study-related procedure not part of standard medical care, with the understanding that consent may be withdrawn by the patient at any time without prejudice to future medical care.
11. Suitable venous access for the study-required blood sampling, including PK and biomarker sampling. |
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E.4 | Principal exclusion criteria |
1. Presence of chronic GvHD at Screening (including acute-chronic overlap syndrome).
2. Relapsed disease after allo-HSCT.
3. Patients with 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 (eg, calcineurin inhibitors) may be continued.
5. This exclusion criterion is deleted in amendment 02.
6. Patients with a positive PML subjective checklist must be evaluated by a neurologist for possible PML before enrollment. Patients will be excluded if PML cannot be ruled out.
7. Evidence of encephalopathy at Screening.
8. Evidence of severe hepatic veno-occlusive disease/sinusoidal obstruction syndrome.
9. Life expectancy of <3 weeks.
10. History of any major neurological disorders, including multiple sclerosis or neurodegenerative disease. Patients with a history of stroke or brain tumor within the past 3 years are also excluded.
11. Patients with active cytomegalovirus (CMV) colitis.
12. The patient has chronic hepatitis B (HBV) or hepatitis C (HCV) infection indicated by testing for positive HBV surface antigen, and/or HCV RNA.
13. Any identified congenital or acquired immunodeficiency (eg, common variable immunodeficiency, human immunodeficiency virus [HIV] infection, organ transplantation).
14. Positive Clostridium difficile toxin test on a stool sample or evidence of other intestinal pathogens (eg, adenovirus) during Screening.
15. Evidence of uncontrolled active systemic infection.
16. Any serious medical or psychiatric condition that could, in the investigator’s or medical monitor’s opinion, potentially interfere with the completion of treatment according to this protocol.
17. Any unstable or uncontrolled cardiovascular, pulmonary, hepatic, renal, GI, genitourinary, hematological, coagulation, immunological, endocrine/metabolic, neurologic, or other medical disorder that, in the opinion of the investigator or medical monitor, would confound the study results or compromise patient safety.
18. History of hypersensitivity or allergies to vedolizumab or its components.
19. If female, the patient is pregnant or lactating 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. If male, the patient intends to donate sperm during the course of this study or for 18 weeks thereafter. |
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E.5 End points |
E.5.1 | Primary end point(s) |
1. The proportion of subjects with overall response (partial response [PR]+very good partial response [VGPR]+CR) at Day 28.
2. The number and percentage of patients who experience SAEs from administration of the first dose of vedolizumab IV through Day 28. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
1. evaluated at Day 28
2. evaluated from administration of the first dose of vedolizumab IV
through Day 28 |
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E.5.2 | Secondary end point(s) |
1. The proportion of subjects who have died in the absence of primary malignancy relapse after allo-HSCT at 6 months.
2. The proportion of subjects with CR at Day 28.
3. The proportion of subjects with intestinal overall response at Day 28.
4. OS at 6 and 12 months.
5. The proportion of subjects alive without GvHD or relapse of primary malignancy at 6 and 12 months.
6. The number and percentage of patients who experience TEAEs from administration of the first dose of vedolizumab IV through 18 weeks after administration of the last dose of vedolizumab IV.
7. The number and percentage of patients who experience SAEs from administration of the first dose of vedolizumab IV through 18 weeks after administration of the last dose of vedolizumab IV.
8. Mean serum concentrations of vedolizumab before dosing (Ctrough) on Day 99.
9. The total dose of steroids administered (mg/kg/day of methylprednisolone or equivalent) from the start of the first IV infusion of vedolizumab through both 6 and 12 months. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. evaluated at 6 months
2. & 3. evaluated at Day 28
4. & 5. evaluated at 6 and 12 months
6. & 7. evaluated from administration of the first dose of vedolizumab IV
through 18 weeks after administration of the last dose of vedolizumab
IV
8. evaluated at Day 99
9. evaluated from the start of the first IV infusion of vedolizumab
through both 6 and 12 months |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
Comparison between different doses of vedolizumab |
|
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 9 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Belgium |
France |
Norway |
Sweden |
United States |
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E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 0 |
E.8.9.1 | In the Member State concerned months | 36 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 0 |
E.8.9.2 | In all countries concerned by the trial months | 36 |
E.8.9.2 | In all countries concerned by the trial days | 0 |