Safety Trial, DSC vs. BAT in SR acute GvHD

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Oslo Universitetssykehus HF

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Immune System Diseases [C20]

Trial duration

20 Nov 2024 → 21 Apr 2026

Decision date (initial)

2024-11-22

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

No

External identifiers

EU CT number

2024-511768-97-01

EudraCT number

2019-002186-36

ClinicalTrials.gov

NCT04118556

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Safety

To assess the safety and tolerability of DSC
To assess Durable Overall Response Rate (DOR) at Day 56

Secondary objectives 12

1. To assess Overall Response Rate at day 28 (ORR)
2. To assess 1-year Overall Survival (OS)
3. To assess 1-year Non-Relapse Mortality (NRM)
4. To assess incidence of infections
5. To evaluate the safety of DSC and BAT.
6. For Norway: To assess 1-year Event-free survival (EFS) per randomization arm
7. Exploratory objective: To assess the cumulative steroid dose until Day 56 and Day 84.
8. Exploratory objective: To assess incidence of malignancy relapse/progression (MR).
9. Exploratory objective: Cumulative incidences and severity of chronic GvHD. Chronic GvHD is diagnosed clinically according to previously published criteria (Przepiorka 1994).
10. Exploratory objective: To evaluate effect of DSC on immune reconstitution per randomization arm.
11. Exploratory endpoint: To evaluate Quality of Life (QoL) at 3, 6 and 12 months after randomization per randomization arm.
12. Exploratory for Denmark and Sweden: To assess 1-year Event-free survival (EFS) per randomization arm. Endpoint: Event-free

Conditions and MedDRA coding

Graft vs Host Disease

Regulatory references

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 5

1. Study informed consent form signed by the patient her-/himself.
2. Male or female patients aged 18 or older at the time of informed consent
3. Have undergone HSCT from any donor source (unrelated, sibling, haploidentical) using bone marrow, peripheral blood stem cells, or cord blood. Recipients of non- myeloablative, myeloablative, and reduced intensity conditioning are eligible
4. Clinically diagnosed Grades II to IV acute GvHD as per standard criteria (Appendix 1) occurring after HSCT requiring systemic immune suppressive therapy. Biopsy of involved organs with aGvHD is encouraged but not required for study screening.
5. Confirmed diagnosis of steroid refractory aGvHD defined as patients administered high dose systemic corticosteroids (methylprednisolone ≥1 mg/kg/day (±20%) [or equivalent prednisone dose ≥1.25 mg/kg/day]), given alone or combined with calcineurin inhibitors (CNI) and either: A. A Progression based on organ assessment after at least 3 days compared to organ stage at the time of initiation of high-dose systemic corticosteroid +/- CNI for the treatment of Grade II-IV aGvHD, OR B. Failure to achieve at a minimum partial response based on organ assessment after 5-7 days compared to organ stage at the time of initiation of high-dose systemic corticosteroid +/- CNI for the treatment of Grade II-IV aGvHD, OR C. Patients who fail corticosteroid taper defined as fulfilling either one of the following criteria: 1. Requirement for an increase in the corticosteroid dose to methylprednisolone ≥1 mg/kg/day (or equivalent prednisone dose ≥1.25 mg/kg/day) OR 2. Failure to taper the methylprednisolone dose to <0.5 mg/kg/day (or equivalent prednisone dose <0.6 mg/kg/day) for a minimum 7 days

Exclusion criteria 21

1. Has received systemic treatment for aGvHD apart from steroids. Standard aGvHD prophylaxis and treatment medications initiated before randomization including systemic corticosteroids, calcineurin inhibitors (CNI) (cyclosporine, tacrolimus or Mycofenolate Mofetil (MMF)), and topical corticosteroid therapy may be continued, per institutional guidelines.
2. Clinical presentation resembling de novo chronic GvHD or GvHD overlap syndrome with both acute and chronic GvHD features (as defined by Jagasia, et al. 2015)
3. Presence of an active uncontrolled infection including significant bacterial, fungal, viral (CMV, EBV, HHV-6, HBV, or HCV) or parasitic infection requiring treatment. Infections are considered controlled if appropriate therapy has been instituted and, at the time of screening, no signs of progression are present. Progression of infection is defined as hemodynamic instability attributable to sepsis, new symptoms, worsening physical signs or radiographic findings attributable to infection. Persisting fever without other signs or symptoms will not be interpreted as progressing infection.
4. Known human immunodeficiency virus infection (HIV).
5. Patients suffering on active tuberculosis or viral hepatitis
6. Significant respiratory disease including patients who are on mechanical ventilation or who have resting O2 saturation <90% by pulse-oximetry.
7. Presence of severely impaired renal function defined by serum creatinine > 2 mg/dL (>176.8 μmol/L), renal dialysis requirement, or have estimated creatinine clearance <30 ml/min measured or calculated by Cockroft Gault equation (confirmed within 48h prior to study treatment start).
8. Presence of severely impaired liver function not due to liver GVHD defined by ALT / AST> 5 times the upper limit of the normal.
9. Malignancy (except the HSCT indication) that has required treatment in the previous two years (excluding non-melanoma skin malignancies treated by excision, or cryotherapy)
10. Any corticosteroid therapy for indications other than aGvHD at doses > 1 mg/kg/day methylprednisolone (or equivalent prednisone dose 1.25 mg/kg/day) within 7 days of Screening. Routine corticosteroids administered during conditioning or cell infusion is allowed.
11. History of progressive multifocal leuko-encephalopathy (PML).
12. Previous participation in a study of any investigational treatment agent within 30 days or within 5 half-lives of the study treatment, whichever is greater.
13. Any condition that would, in the Investigator's judgment, interfere with full participation in the study, including administration of study treatment and attending required study visits; pose a significant risk to the patient; or interfere with interpretation of study data.
14. Known allergies, hypersensitivity, or intolerance to systemic immunosuppressive therapy
15. Known hypersensitivity to dimethyl sulfoxide (DMSO) or to porcine or bovine proteins
16. Known hypersensitivity to trace amounts of Gentamycin
17. Patients with coagulopathy (eg. hemofilia), history of past thrombo-embolic event (eg. deep venous thrombosis, lung embolism, cerebral thrombo-embolism) in the previous 3 months
18. Uncontrolled hypertension
19. History of severe chronic heart disease (documented ejection fraction ≤ 30% or NYHA > II), recent MI (6 months) or unstable angina, clinically significant (symptomatic) cardiac arrhythmias, lung disease (requiring home oxygen), pulmonary hypertension (RVSP > 50 on prior ECHO), or liver comorbidities (MELD score <10).
20. Pregnant or nursing (lactating) women OR Female patients ≥ 18 years of age and of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception as defined below, throughout the study and for up to 90 days after stopping treatment.
21. Sexually active men and male adolescents who do not agree to use condom during intercourse, if applicable and for up to 90 days after stopping treatment and/or wish to father a child in this period. A condom is required to be used also by vasectomized men as well as during intercourse with a male partner to prevent delivery of the drug via seminal fluid.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. Documenting AEs and SAEs and determining causality in relation to DSC. Causality of AEs and SAEs will be assessed by the Investigator.
2. Durable Overall response rate (DOR) at Day 56 after randomization, defined as the proportion of patients in each arm demonstrating a complete response (CR) or partial response (PR) at day 28 and maintain a CR or PR at day 56 without requirement for additional systemic therapies for an earlier progression, mixed response or nonresponse.

Secondary endpoints 12

1. Proportion of patients in each arm who achieve a complete response (CR) or partial response (PR) at Day 28.
2. Overall survival (OS), defined as the time from the date of randomization to the date of death due to any cause.
3. Non-relapse mortality (NRM), defined as the time from date of randomization to death not preceded by hematologic disease relapse/progression.
4. Proportion of patients in each treatment arm who develop infections or other transplant related complications.
5. Safety and tolerability including myelosuppression, infections and bleeding will be assessed by monitoring the frequency, duration and severity of Adverse Events including occurrence of any secondary malignancies, infections, by performing physical exams and evaluating changes in vital signs from baseline, routine serum chemistry, hematology results and coagulation profile.
6. For Norway: Event-free survival, defined as the time from the date of randomization to the date of hematologic disease relapse/ progression, graft failure or death due to any cause.>
7. Exploratory endopint: Weekly cumulative steroid dose for each patient up to Day 56 and Day 84 or end of treatment will be calculated.
8. Exploratory endpoing: Malignancy relapse/progression (MR), defined as the time from date of randomization to hematologic malignancy relapse or progression. Calculated for patients with underlying hematologic malignant disease.
9. Exploratory endpoint: Chronic GvHD, defined as the diagnosis of any cGvHD including mild, moderate and severe according to NIH criteria. (see Appendix 3)
10. Exploratory endpoint: Changes in immune reconstitution after aGvHD per randomization arm.
11. Exploratory endpoint: Evaluation of patients´ self-experienced well-being (Quality of Life)(FACT-BMT version 4).
12. Exploratory endpoint for Sweden and Denmark: Event-free survival, defined as the time from the date of randomization to the date of hematologic disease relapse/ progression, graft failure or death due to any cause.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 3

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Oslo Universitetssykehus HF

Sponsor organisation

Oslo Universitetssykehus HF

Address

P. O. Box 4950

City

Oslo

Postcode

0424

Country

Norway

Scientific contact point

Organisation

Uppsala University Hospital

Contact name

Mats Remberger

Public contact point

Organisation

Uppsala University Hospital

Contact name

Mats Remberger

Third parties 1

Locations

3 EU/EEA countries · 4 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 10 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

4 submissions — initial application plus substantial / non-substantial modifications