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

GVHD, Acute Clinical Trial

— 2017-00355  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04118556
• Other study ID #: DSC-BROMS-1
• Secondary ID: 2019-002186-36
• Status: Recruiting
• Phase: Phase 1/Phase 2
• Start date: December 1, 2021
• Est. completion date: December 31, 2029

Study information

• Verified date: October 2023
• Source: Uppsala University Hospital
• Contact: Mats Remberger, Professor
• Phone: +46-760165080
• Email: mats.remberger[@]akademiska.se
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

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

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 50
• Est. completion date: December 31, 2029
• Est. primary completion date: December 31, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• GVHD, Acute

Intervention

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.

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.

Locations

Country	Name	City	State
Denmark	Copenhagen Univerity Hospital	Copenhagen
Norway	Oslo University Hospital	Oslo
Sweden	Gothenburg University Hospital	Göteborg
Sweden	Lund University Hospital	Lund
Sweden	Karolinska University Hospital	Stockholm
Sweden	Uppsala University Hospital	Uppsala

Sponsors (2)

Lead Sponsor	Collaborator
Mats Remberger	The Swedish Research Council

Countries where clinical trial is conducted

Denmark,  Norway,  Sweden, 

References & Publications (2)

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 — View Citation

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 Bloo — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	Durable Response to treatment	Durable Overall Response (DOR) day 56.	56 days
Secondary	Number of patients with overall response (CR+PR) at day 28	Overall Response Rate (ORR) at day 28.	28 days
Secondary	Rate of Survival	Death within 1 year after inclusion in study.	1 year
Secondary	Incidence of Non-Relapse Mortality (NRM)	Death of any cause with enduring complete remission.	1 year
Secondary	Incidence of infections	Serious infections occurring after inclusion in study.	1 year
Secondary	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
Secondary	Incidence of Relapse	Recurrence of the disease the patient were transplanted for.	5 year
Secondary	Incidence of secondary malignancies	Occurrence of other malignancies than the patient were transplanted for.	5 year
Secondary	Incidence of chronic GVHD	Occurrence of chronic GVHD.	5 year