Primary objective* To improve the response rate to treatment of severe steroid-refractory acute GvHD grade II-IV (with gut and/or liver involvement) by early addition of MSC to standardized second line treatmentSecondary objectives* To study the…
ID
Source
Brief title
Condition
- Haematological disorders NEC
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Proportion of patients responding to treatment of acute GvHD grade II-IV (with
gut and/or liver involvement) at day 29
Secondary outcome
1. Cumulative incidence of treatment-related mortality, defined as death not
due to relapse of hematological malignancy (non-relapse mortality), at six
months and beyond
2. Overall survival, defined as time from randomization until death from any
cause. Patients alive at the date of last contact will be censored
3. Progression-free survival, defined as time from randomization until
progression or relapse of hematological malignancy or death, whichever comes
first
4.Duration of acute GvHD response, defined as time from response of acute GvHD
until relapse of acute GvHD or death, whichever comes first
5. Time from end of systemic immunosuppressive treatment for GvHD until
re-initiation of systemic immunosuppression for GvHD
6. Adverse events
7. Incidence of chronic GvHD
8. Quality of life
9. Immunological monitoring including monitoring of absolute numbers of all
T-cell subsets, B-cells, and NK-cells as well as biomarkers of acute GvHD
Background summary
Allogeneic stem cell transplantation (SCT) is the only curative option for many
patients suffering from hematological malignancies. Although providing cure for
many patients, SCT may be accompanied by severe treatment-related side-effects,
including acute Graft-versus-Host Disease (GvHD). Acute GvHD is a major cause
of SCT-related morbidity and mortality. First line treatment consists of often
protracted immuno-suppressive therapy with high dose corticosteroids often in
combination with calcineurin inhibitors. A variety of second line
immunosuppressive agents has been investigated for patients failing on
corticosteroids, but no optimal treatment has emerged. Steroid-refractory acute
GvHD has a high mortality rate and surviving patients often develop chronic
GvHD, which severely reduces quality of life. Therefore, there is an urgent
need for new and better treatment modalities. Several studies have indicated
that third-party mesenchymal stromal cells (MSC) might be an effective therapy
for steroid-refractory GvHD.
Study objective
Primary objective
* To improve the response rate to treatment of severe steroid-refractory acute
GvHD grade II-IV (with gut and/or liver involvement) by early addition of MSC
to standardized second line treatment
Secondary objectives
* To study the safety of MSC addition to standardized second line treatment
* To assess the incidence of treatment-related mortality
* To assess the overall survival
* To assess the progression-free survival
* To reduce the time required for continued pharmacological immune suppression
* To assess the incidence of severe bacterial, viral and fungal infections
* To assess the incidence and severity of chronic GvHD
* To evaluate the quality of life of patients treated with MSC in comparison
with controls up to two years after MSC treatment
* To establish the economic impact of MSC for the treatment of severe
steroid-refractory acute GvHD (with gut and/or liver involvement)
* To develop a score by means of clinical and laboratory parameters that allows
for identification of patients with severe acute GvHD that will respond on MSC
treatment
Study design
Phase 3, randomized, placebo-controlled, double-blind
Intervention
Patients are randomized for
- treatment with mycophenolate mofetil (MMF) and MSC, or
- treatment with MMF and placebo
Study burden and risks
There is no established treatment for steroid-refractory acute GvHD. Treatment
with bone marrow-derived expanded MSC may induce responses of acute GvHD. Based
on pilot studies in over 100s of patients, the infusional toxicity is expected
to be minimal and restricted to fever. Potential adverse events, that have not
been observed in pilot studies so far, include suppression of immune responses
increasing risk of infection and relapse of malignant disease. Moreover, MSC
mediated immunosuppression could result in an increased rate of relapse. These
potential risks, however, are balanced by the expected benefit of MSC therapy
namely resolution of GvHD with its known high mortality rate both from GvHD
itself and from the opportunistic infections associated with the current
immunosuppressive GvHD treatment strategies.
HOVON Centraal Bureau, VUMC, De Boelelaan 1117
Amsterdam 1081 HV
NL
HOVON Centraal Bureau, VUMC, De Boelelaan 1117
Amsterdam 1081 HV
NL
Listed location countries
Age
Inclusion criteria
• Grade II-IV acute GvHD with gut and/or liver involvement, confirmed by histology of involved tissues (in case of gut and liver involvement histology of either one of these tissues is considered sufficient);
• Steroid-refractory defined as progressive disease, mixed response, or grade IV disease after at least 5 days, or stable grade II-III disease after at least 7 days of consecutive systemic treatment with steroids at a dose of >= 2 mg/kg prednisolone or steroid equivalent and a calcineurin-inhibitor at therapeutic trough levels;
• Any age;
• Lansky / Karnofsky score of >=20;
• Signed informed consent by the patient and/or parent(s) or legal guardian(s).
Exclusion criteria
• Use of intravenous prophylactic MMF <= 6 days prior to development of acute GvHD;
• Systemic treatment for acute GvHD other than steroids and a calcineurin inhibitor (budesonide is considered a local treatment);
• Consecutive treatment with steroids >= 2 mg/kg prednisolone or steroid equivalent > 10 days directly prior to inclusion;
• Previous treatment with advanced therapy medicinal products (ATMP) potentially interfering with the endpoints of this study;
• Known progressive or relapsing malignant disease in case of NHL, HL, CLL, MM, and >= 5% blasts in the bone marrow in case of AML, ALL, CML;
• Requiring ventilator or vasopressor support;
• Poor performance not expected to survive 14 days;
• Known uncontrolled hypersensitivity to DMSO;
• History of any other malignancy, unless diagnosed and treated > 5 years ago with curative intent and without recurrence or nonmelanoma skin cancer and/or carcinoma in situ of any type following complete resection.
• Known pregnancy, a positive higly sensitive pregnancy test at screening, or lactation for female patients; unwillingness to practice highly effective means of contraception for both female and male patients of reproductive potential, as described in paragraph 9.4.
• Any psychological, familial, sociological and /or geographical condition potentially hampering compliance with the study protocol and follow-up schedule.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2012-004915-30-NL |
| CCMO | NL42497.000.12 |