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Prevention and treatment of severe GVHD after allogeneic hematopoietic stem cell transplantation, applied as consolidation immunotherapy in patients with hematological malignancies. A prospective randomized phase III trial.


- candidate number7836
- NTR NumberNTR2252
- ISRCTNISRCTN wordt niet meer aangevraagd.
- Date ISRCTN created
- date ISRCTN requested
- Date Registered NTR15-mrt-2010
- Secondary IDs2008-003540-11 EudraCT
- Public TitlePrevention and treatment of severe GVHD after allogeneic hematopoietic stem cell transplantation, applied as consolidation immunotherapy in patients with hematological malignancies. A prospective randomized phase III trial.
- Scientific TitlePrevention and treatment of severe GVHD after allogeneic hematopoietic stem cell transplantation, applied as consolidation immunotherapy in patients with hematological malignancies. A prospective randomized phase III trial.
- ACRONYMHOVON 96 GVHD
- hypothesisRandomization 1:
The hypothesis to be tested is that the outcome in arm B is better than in arm A.

Randomization 2:
The hypothesis to be tested is that the outcome in arm B is better than in arm A.
- Healt Condition(s) or Problem(s) studiedGraft-versus-host disease, Hematological malignancy, Allogeneic stem cell transplantation
- Inclusion criteriaRandomization 1:
1. Age 18-65 inclusive;
2. AML, MDS, ALL, MM, CML, CLL, NHL, HL, or a myeloproliferative disease (MPD);
3. Planned allogeneic stem cell transplantation;
4. Related or unrelated donor with a 8/8 HLA match (HLA A, B, C, DRB1);
5. WHO performance status 0-2;
6. Written Informed Consent;
7. Negative pregnancy test (if applicable);
8. Patients who are willing and capable to use adequate contraception during Myfortic treatment (all pre-menopausal women).

Randomization 2:
1. Newly diagnosed acute GVHD grade II with gut involvement or grade III/IV within 1 year post allo-SCT according to appendix A, confirmed by histology of involved tissues;
2. Inclusion in randomization 1;
3. Written Informed Consent.
- Exclusion criteriaRandomization 1:
1. Renal dysfunction (serum creatinine > 150 µmol/L or clearance < 50 ml/min);
2. Patients with active, uncontrolled infection;
3. Cord Blood transplantation;
4. Patients receiving ATG pre-transplantation as part of the conditioning regimen;
5. Patients with progressive disease in case of MM, CLL, NHL, HL;
6. Patients with > 5% marrow blasts in case of AML, ALL, CML;
7. Patients with EMD in case of AML, ALL, CML.

Randomization 2:
1. Acute GVHD after donor lymphocyte infusion;
2. Patients with symptoms of classic chronic GVHD according to appendix A;
3. Patients with active, uncontrolled infection;
4. Patients requiring mechanical ventilation or vasopressor support;
5. Patients with progressive disease in case of NHL, HL, CLL, MM;
6. Patients with > 5% marrow blasts in case of AML, ALL, CML;
7. Patients with EMD in case of AML, ALL, CML.
- mec approval receivedyes
- multicenter trialyes
- randomisedyes
- masking/blindingNone
- controlActive
- groupParallel
- Type2 or more arms, randomized
- Studytypeintervention
- planned startdate 26-mrt-2010
- planned closingdate25-apr-2020
- Target number of participants500
- InterventionsPatients planned to undergo an allogeneic SCT for malignant hematological disorders and with a related or unrelated 8/8 HLA matched donor will be randomized to either standard immunosuppression (arm 1) or time restricted immunosuppression (arm 2). No ATG will be given pretransplantation as part of the conditioning regimen.

Patients who develop acute GVHD grade II with gut involvement or grade III/IV will be randomized to either standard treatment consisting of prednisolone monotherapy (arm A) or prednisolone plus ATG-Fresenius 15 mg/kg (arm B).
- Primary outcomeRandomization 1:
Proportion of patients with non-severe GVHD (acute GVHD grade I, grade II without gut infiltration, or chronic GVHD not requiring systemic treatment) within D180 after randomization.

Randomization 2:
Proportion of patients in each treatment arm who experience a CRGVHD or PRGVHD at day 28 without treatment failure (initiation of secondary treatment).
- Secondary outcomeRandomization 1:
1. Time to acute GVHD grade I, II, III, IV;
2. Cumulative incidence of progression;
3. Progression-free survival (defined as time from randomization 1 until progression or death, whichever occurs first);
4. Cumulative incidence of non-relapse mortality;
5. Overall survival (cause of death should be defined according to Appendix F);
6. Time to chronic GVHD limited and extensive;
7. Adverse events;
8. ƒ{ƒnQuality of life as defined by the EORTC QLQ-C30 and the FACT-BMT definitions.

Randomization 2:
1. Time to CR-GVHD or PR-GVHD;
2. Adverse events;
3. Immune reconstitution, including monitoring of absolute numbers of all T-cell subsets at day 28, 90, 180, and 270 from the start of treatment.
- TimepointsClinical and laboratory evaluations:

Randomization 1:
1. At entry (before start of conditioning);
2. At day 0, 14 and 28;
3. Thereafter monthly during first year after allo-SCT;
4. Every 6 months from 1-5 yr after allo-SCT.

Randomization 2:
1. At randomization;
2. Weekly until day 28;
3. At day 56, 90, 180, 270.

Pharmacokinetic analyses (30 patients):
1. 32 timepoints in the period from day 1-56.

Quality of life:
1. At entry, i.e. at admission prior to the initiation of the conditioning regimen;
2. At 180 days after allo-SCT;
3. At 1 year after allo-SCT;
4. At 2 years after allo-SCT;
5. At 5 years after allo-SCT.
The quality of life measurements will be stopped at progression.
- Trial web sitewww.hovon.nl
- statusopen: patient inclusion
- CONTACT FOR PUBLIC QUERIESMw. Dr. A.E.C. Broers
- CONTACT for SCIENTIFIC QUERIESMw. Dr. A.E.C. Broers
- Sponsor/Initiator HOVON Data Center, Stichting Hemato-Oncologie voor Volwassenen Nederland (HOVON), Erasmus Medical Center, Daniel den Hoed Cancer Center
- Funding
(Source(s) of Monetary or Material Support)
Dutch Cancer Society, Fresenius Medical Care, Novartis
- PublicationsN/A
- Brief summaryStudy phase:
Phase III.

Objectives R1:
1. To reduce the proportion of patients without GVHD within 180 days post-allo-SCT;
2. To reduce the progression rate;
3. To improve the progression free survival;
4. To asses the impact on the quality of life using a time restricted immunosuppressive regimen as compared to a prolonged, standard immunosuppressive regimen.

Objectives R2:
1. To improve the response rate to treatment of severe acute GVHD (grade II with gut involvement or grade III-IV) by adding ATG-Fresenius to standard high dose prednisolone;
2. To study the safety of the addition of ATG-Fresenius to standard treatment of severe acute GVHD as compared to standard treatment alone.

Additional objectives:
1. To develop a predictive score, by means of clinical and laboratory parameters (using genomic and proteomic approaches) that allows for accurate identification of patients at high risk of severe GVHD as well as for identification of patients, who will not develop GVHD.

Patient population:
All patients planned to undergo an allogeneic SCT for malignant hematological disorders and with a related or unrelated 8/8 HLA matched donor are eligible for randomization 1. No ATG will be given pre-transplantation as part of the conditioning regimen.
Patients with the diagnosis of acute GVHD grade II with gut involvement or grade III/IV and before the institution of any treatment are eligible for randomization 2.

Study design:
Prospective, multicenter, open-label randomized.

Duration of treatment:
The expected duration of full dose immunosuppressive treatment after randomization 1 will be 84 to 180 days. The expected maximum treatment duration after randomization 2 will be 4 weeks.
- Main changes (audit trail)13-Aug-2012: There has been an amendment, with the following changes:

Public title en Scientific title is changed to:
Prevention of severe GVHD after allogeneic hematopoietic stem cell transplantation, applied as consolidation immunotherapy in patients with hematological malignancies. A prospective randomized phase III trial.

Hypothesis, Inclusion criteria, Exclusion criteria, Primary outcome, Secondary outcome, time points regarding randomization 2 are no longer applicable.

Time point: No longer applicable is:
Pharmacokinetic analyses (30 patients): 1. 32 timepoints in the period from day 1-56.

Objectives R2:
4. to asses the impact of allogeneic SCT on the quality of life in a prospectively treated cohort of patients.
Objectives 1, 2 and 3: using a time restricted immunosuppressive regimen as compared to a prolonged, standard immunosuppressive regimen.

Interventions: The following randomization is no longer active:
Patients who develop acute GVHD grade II with gut involvement or grade III/IV will be randomized to either standard treatment consisting of prednisolone monotherapy (arm A) or prednisolone plus ATG-Fresenius 15 mg/kg (arm B).

Contact for public and scientific queries is Dr. A.E.C. Broers.

Brief summary: Objectives R2 are no longer applicable.
Patient population: no longer applicable is: Patients with the diagnosis of acute GVHD grade II with gut involvement or grade III/IV and before the institution of any treatment are eligible for randomization 2.

Duration of treatment:
‘The expected maximum treatment duration after randomization 2 will be 4 weeks.’ is no longer applicable.
- RECORD15-mrt-2010 - 16-aug-2012


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