GVHD, Acute
Conditions
Keywords
DSC, BAT, GVHD, HSCT
Brief summary
A randomized (1:1) phase II open label study of DSC compared to Investigator choice Best Available Therapy (BAT) in allogeneic hematopoietic stem cell transplant recipients with Grades II-IV steroid refractory acute graft vs. host disease in the second part of the study. Patients will receive 2 doses of DSC. Additional doses (up to 4 doses) may be given depending on response. No cross-over are planned in the second stage of the study.
Detailed description
Main inclusion criteria: Adult patients (age ≥ 18 years) with steroid refractory (SR) acute GvHD (aGVHD) grades II-IV after allo-HSCT. Signed written study informed consent once SR-aGvHD is confirmed. Main exclusion criteria: Presence of an active uncontrolled infection requiring treatment. Has received systemic treatment for aGvHD apart from steroids. Clinical presentation resembling de novo chronic GvHD or GvHD overlap syndrome. Known human immunodeficiency virus infection (HIV). Patients suffering on active tuberculosis or viral hepatitis. Significant respiratory disease Presence of severely impaired renal function Patients with coagulopathy Pregnant or nursing (lactating) women Malignancy that has required treatment in the previous two years Any condition that would, in the Investigator's judgment, interfere with full participation in the study. Design: The trial is a Phase II, randomized (1:1), open label study investigating the efficacy and safety of DSC vs. BAT added to the patient's immunosuppressive regimen in adults with SR-aGvHD. The primary objectives will be safety and to compare durable overall response (DOR) at 56 days after randomization between patients receiving DSC with patients receiving BAT as treatment for SR acute GvHD grades II-IV. Target enrollment is 50 patients, 25 in the DSC treatment-arm and 25 in the BAT arm. Patients will be given the optimal dose of DSC from the Phase I, dose escalating part of the study, as mentioned above. At least 2 doses of DSC will be given one week apart. Additional doses of DSC (maximum 4 doses) may be given depending on response. Additional doses (beyond the first 2 doses) may be given one week apart until response, or whenever needed if aGVHD flare occur within 6 months after randomization (EOT). BAT: Investigator's choice Best Available Therapy (BAT) will vary depending upon Investigator's choice identified prior to randomization. Dose and frequency will depend on label (where approved) and institutional guidelines for various BAT. Primary objective * Assess the Safety of DSC. * Durable Overall Response (DOR) at Day 56. Secondary objectives * To assess Overall Response Rate (ORR) at day 28 * To assess 1-year Overall Survival (OS) * To assess 1-year Non-Relapse Mortality (NRM) * To assess incidence of infections Exploratory objectives * To assess the cumulative steroid dose until Day 56 and Day 90 * To assess Event-Free Survival (EFS) * To assess incidence of Malignancy Relapse/Progression * To measure the incidence of chronic GvHD * To measure immune reconstitution * To evaluate changes in Patient Reported Outcomes
Interventions
BIOLOGICALDecidua Stroma Cells (DSC)
Placenta-derived Decidua Stroma Cells. The product consists of a viable allogeneic DSCs frozen in 5% of human serum albumin (HSA) in sodium chloride (NaCl) 0.9% and 10% dimethylsulfoxide (DMSO), that is thawed and immediately diluted in 40 mL sodium chloride (NaCl) 0.9% prior to infusion. That will give a final concentration of 2.2% HSA and 2% DMSO. DSC will be infused when steroid-refractory acute GVHD after allogenic stem-cell transplantation has been diagnosed. Two doses, one week apart, will be given to all patients. Additional doses will be used depending on response.
The BAT in this study will freely be identified by the Investigator prior to patient randomization and may include treatments such as: extracorporeal photopheresis (ECP), low-dose methotrexate (MTX), mycophenolate mofetil (MMF), mTOR inhibitors (everolimus or sirolimus), etanercept, vedolizumab, ruxolitinib or infliximab. Dose and frequency will depend on label (where approved) and institutional guidelines for various BAT.
Sponsors
The Swedish Research Council
Mats Remberger
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
A randomized (1:1) phase II open label study of DSC compared to Investigator choice Best Available Therapy (BAT) in allogeneic hematopoietic stem cell transplant recipients with Grades II-IV steroid refractory acute graft vs. host disease. Patients will receive 2 doses of DSC. Additional doses (up to 4 doses) may be given depending on response. No cross-over are planned in the second stage of the study.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Adult patients (age ≥ 18 years) with steroid refractory acute GvHD grades II-IV after allo-HSCT. 2. Signed written study informed consent once SR-aGvHD is confirmed.
Exclusion criteria
1. Presence of an active uncontrolled infection including significant bacterial, fungal, viral or parasitic infection requiring treatment. 2. Has received systemic treatment for aGvHD apart from steroids. 3. Clinical presentation resembling de novo chronic GvHD or GvHD overlap syndrome. 4. Pregnant or lactating women. 5. Significant respiratory disease. 6. Presence of severely impaired renal function 7. Any corticosteroid therapy for indications other than aGvHD 8. Previous participation in a study of any investigational treatment agent within 30 days 9. Known human immunodeficiency virus infection (HIV). 10. Patients suffering on active tuberculosis or viral hepatitis 11. Significant respiratory disease 12. Presence of severely impaired renal or liver function 13. History of progressive multifocal leuko-encephalopathy 14. Patients with coagulopathy 15. History of severe chronic history of heart disease 16. Any condition that would, in the Investigator's judgment, interfere with full participation in the study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Safety and tolerability evaluation including Severe Adverse Events (SAE). | 5 years | Adverse events will be assessed and graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. |
| Durable Response to treatment | 56 days | Durable Overall Response (DOR) day 56. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of Non-Relapse Mortality (NRM) | 1 year | Death of any cause with enduring complete remission. |
| Incidence of infections | 1 year | Serious infections occurring after inclusion in study. |
| Change of Quality of Life | 1 year | Change of self-experienced well-being (Quality of Life)(FACT-BMT version 4) at four time-points after inclusion. Scoring procedures consist of summing the items with reversed scoring (0-4p where 0=best and 4=worst) for several items which produces individual subscale scores (0-24/28p) and an overall score (0-200p). The FACT-BMT (Functional Assessment of Cancer Therapy-Bone Marrow Transplant) has a total of 50 questions. This is a questionnaire of general questions divided into four primary quality of life domains: physical well-being (PWB; 7-items), social/family well-being (SWB; 7-items), emotional well-being (EWB; 6-items); and functional well-being (FWB; 7-items), 18 items address the BMT related side effects, specifically designed to assess the BMT patients' quality of life. Five other questions from different QoL questionnaire were added as they were considered relevant to FACT-BMT. |
| Number of patients with overall response (CR+PR) at day 28 | 28 days | Overall Response Rate (ORR) at day 28. |
| Incidence of secondary malignancies | 5 year | Occurrence of other malignancies than the patient were transplanted for. |
| Incidence of chronic GVHD | 5 year | Occurrence of chronic GVHD. |
| Incidence of Relapse | 5 year | Recurrence of the disease the patient were transplanted for. |
| Rate of Survival | 1 year | Death within 1 year after inclusion in study. |
Countries
Denmark, Norway, Sweden
Contacts
Primary ContactMats Remberger, Professor
Backup ContactUlla Olsson-Strömberg, AssProfessor
Outcome results
None listed