Decidua Stroma Cells for Steroid Resistent Acute Graft-versus-host Disease After Allo-HSCT

Study Overview
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Brief Summary
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A two-stage design. An open, non-randomized, 3+3 dose escalating scheme will be used in the first stage of the study. 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 in each phase will receive 2 doses of DSC. In the second part (Phase II) additional doses (up to 6 doses) may be given depending on response. No cross-over are planned in the second stage of the study.

Detailed Description
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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: This is a phase I/II, multicenter, open-label trial of DSC in patients with steroid refractory acute GvHD grades II-IV. The trial will consist of 2 main parts: Phase 1 (open, non-randomized, 3+3 DSC dose escalating scheme), and 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. Phase I dose escalating study. The main objective of the first part of the study is safety and tolerability of two different doses of DSC and to establish the optimal dose for the second, Phase II, part of the study. Six patients will be enrolled, 3 patients given the lower dose (1x10^6 DSC/kg) and 3 patients given the higher dose (3x10^6 DSC/kg). Patients will receive 2 doses of DSC (low or high) one week apart. If none of the initial 3 patients in the low-dose cohort experience a Severe Adverse Event (SAE), enrolment into the high dose level will commence. If the low and high dose in the Phase I study show similar safety results, the lower dose will be chosen for the Phase II, randomized study. The reason for the chosen doses in the phase I part is that in the pilot study, 1x10^6/kg showed very promising clinical results without any significant side-effects. The higher dose is chosen as this is the highest dose used clinically without any severe side-effects. The dose proposed for cohort 2 may change pending review of the data from the previous cohort by the Safety committee. In the second part of the study (Phase II) 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 In the phase I part: Assess the safety and tolerability profile of DSC Select the recommended DSC dose for the phase II study. In the phase II part: 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

Official Title
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A Multicenter, Open-label, Randomized, Phase I/II Clinical Trial Comparing Safety and Durable Overall Response Day 56 in Patients With Steroid Resistent Acute GvHD After Allogeneic Hematopoietic Stem Cell Transplant Treated With DSC or BAT

Conditions
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GVHD, Acute

Intervention / Treatment
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* Biological: Decidua Stroma Cells (DSC)
* Drug: Best available Treatment (BAT)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult patients (age ≥ 18 years) with steroid refractory acute GvHD grades II-IV after allo-HSCT. Signed written study informed consent once SR-aGvHD is confirmed. Exclusion Criteria: Presence of an active uncontrolled infection including significant bacterial, fungal, viral or parasitic infection requiring treatment. Has received systemic treatment for aGvHD apart from steroids. Clinical presentation resembling de novo chronic GvHD or GvHD overlap syndrome. Pregnant or lactating women. Significant respiratory disease. Presence of severely impaired renal function Any corticosteroid therapy for indications other than aGvHD Previous participation in a study of any investigational treatment agent within 30 days Known human immunodeficiency virus infection (HIV). Patients suffering on active tuberculosis or viral hepatitis Significant respiratory disease Presence of severely impaired renal or liver function History of progressive multifocal leuko-encephalopathy Patients with coagulopathy History of severe chronic history of heart disease Any condition that would, in the Investigator's judgment, interfere with full participation in the study.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: A two-stage design. An open, non-randomized, 3+3 dose escalating scheme will be used in the first stage of the study. 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 in each phase will receive 2 doses of DSC. In the second part (Phase II) additional doses (up to 4 doses) may be given depending on response. No cross-over are planned in the second stage of the study.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Decidua Stroma Cells (DSC)<br>Placenta derived decidua stroma cells (DSC). In the first phase I part, two different dose levels will be used, 1x10^6/kg and 3x10^6/kg. Two doses, one week apart, will be given. The decision to proceed to the next dose level will depend on results observed at the previous dose level. The dose in the randomized part will be based on the findings in the phase I part. In the Phase II study all patients will receive 2 doses, one week apart. Depending on response, up to 6 doses in total may be given. Additional doses (beyond the first 2 doses) may be given one week apart until response. | Biological: Decidua Stroma Cells (DSC)<br>* 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.<br>|
| Active Comparator: Best Available Treatment (BAT)<br>The BAT in this study will freely be identified by the Investigator prior to patient randomization and may include treatments such as: anti-thymocyte globulin (ATG), 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. | Drug: Best available Treatment (BAT)<br>* 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.<br>* Other names: ECP, Everolimus, Sirolimus, Etanercept, Vedolizumab, Ruxolitinib, Infliximab.;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and tolerability evaluation including Severe Adverse Events (SAE). | Adverse events will be assessed and graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. | 5 years | 
| Durable Response to treatment | Durable Overall Response (DOR) day 56. | 56 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of patients with overall response (CR+PR) at day 28 | Overall Response Rate (ORR) at day 28. | 28 days | 
| Rate of Survival | Death within 1 year after inclusion in study. | 1 year | 
| Incidence of Non-Relapse Mortality (NRM) | Death of any cause with enduring complete remission. | 1 year | 
| Incidence of infections | Serious infections occurring after inclusion in study. | 1 year | 
| Change of Quality of Life | 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. | 1 year | 
| Incidence of Relapse | Recurrence of the disease the patient were transplanted for. | 5 year | 
| Incidence of secondary malignancies | Occurrence of other malignancies than the patient were transplanted for. | 5 year | 
| Incidence of chronic GVHD | Occurrence of chronic GVHD. | 5 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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DSC, BAT, GVHD, HSCT