Overview
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
Eligibility
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.