Decidua Stroma Cells for Steroid Resistent Acute Graft-versus-host Disease After Allo-HSCT (2017-00355)

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

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.

Study Overview

• Status: Recruiting
• Conditions: GVHD, Acute
• Intervention / Treatment: Biological: Decidua Stroma Cells (DSC); Drug: Best available Treatment (BAT)

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:

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

• Study Type: Interventional
• Enrollment (Estimated): 50
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Mats Remberger, Professor; Phone Number: +46-760165080; Email: mats.remberger@akademiska.se
• Study Contact Backup: Name: Ulla Olsson-Strömberg, AssProfessor; Phone Number: +46-709522667; Email: ulla.olsson.stromberg@akademiska.se

Study Locations

• Denmark
  • Copenhagen, Denmark, 2300
    • Recruiting
    • Copenhagen Univerity Hospital
    • Contact: Brian T Kornblit, AssProf; Email: brian.thomas.kornblit@regionh.dk
• Norway
  • Oslo, Norway, NO-0424
    • Recruiting
    • Oslo University Hospital
    • Contact: Tobias Gedde-Dahl, Professor; Email: tgeddeda@ous-hf.no
• Sweden
  • Göteborg, Sweden, SE-413 45
    • Withdrawn
    • Gothenburg University Hospital
  • Lund, Sweden, SE-221 85
    • Recruiting
    • Lund University Hospital
    • Contact: Stig Lenhoff, AssProf; Email: stig.lenhoff@skane.se
  • Stockholm, Sweden, SE-14186
    • Withdrawn
    • Karolinska University Hospital
  • Uppsala, Sweden, SE-75185
    • Recruiting
    • Uppsala University Hospital
    • Contact: Ulla Olsson-Strömberg, AssProf; Email: ulla.olsson.stromberg@akademiska.se

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Decidua Stroma Cells (DSC); 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); 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.
Active Comparator: Best Available Treatment (BAT); 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); 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.; Other Names: ECP, Everolimus, Sirolimus, Etanercept, Vedolizumab, Ruxolitinib, Infliximab.

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Mats Remberger
• Collaborators: The Swedish Research Council
• Investigators: Study Director: Mats Remberger, Professor, KFUE, Uppsala University Hospital, Uppsala, Sweden; Principal Investigator: Ulla Olsson-Strömberg, AssProfessor, Dep of Hematology, Uppsala University Hospital, Uppsala, Sweden

Publications and helpful links

General Publications

• Ringden O, Baygan A, Remberger M, Gustafsson B, Winiarski J, Khoein B, Moll G, Klingspor L, Westgren M, Sadeghi B. Placenta-Derived Decidua Stromal Cells for Treatment of Severe Acute Graft-Versus-Host Disease. Stem Cells Transl Med. 2018 Apr;7(4):325-331. doi: 10.1002/sctm.17-0167. Epub 2018 Mar 13.
• Sadeghi B, Remberger M, Gustafsson B, Winiarski J, Moretti G, Khoein B, Klingspor L, Westgren M, Mattsson J, Ringden O. Long-Term Follow-Up of a Pilot Study Using Placenta-Derived Decidua Stromal Cells for Severe Acute Graft-versus-Host Disease. Biol Blood Marrow Transplant. 2019 Oct;25(10):1965-1969. doi: 10.1016/j.bbmt.2019.05.034. Epub 2019 Jun 4.

Study record dates

Study Major Dates

• Study Start (Actual): December 1, 2021
• Primary Completion (Estimated): December 31, 2024
• Study Completion (Estimated): December 31, 2029

Study Registration Dates

• First Submitted: September 27, 2019
• First Submitted That Met QC Criteria: October 5, 2019
• First Posted (Actual): October 8, 2019

Study Record Updates

• Last Update Posted (Actual): October 6, 2023
• Last Update Submitted That Met QC Criteria: October 5, 2023
• Last Verified: October 1, 2023

More Information

Terms related to this study

• Keywords: GVHD; HSCT; BAT; DSC
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Peripheral Nervous System Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Gastrointestinal Agents; Dermatologic Agents; Anti-Bacterial Agents; Protein Kinase Inhibitors; Antibiotics, Antineoplastic; Antifungal Agents; Tumor Necrosis Factor Inhibitors; MTOR Inhibitors; Etanercept; Vedolizumab; Infliximab; Everolimus; Sirolimus
• Other Study ID Numbers: DSC-BROMS-1; 2019-002186-36 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No