Myelodysplastic Syndromes Clinical Trial
Official title:
Multicenter Trials to Evaluate the Efficacy and Toxicity of Sirolimus/Tacrolimus Combination as a GVHD Prophylaxis After HLA Matched Related PBSCT
Study Design: To evaluate the efficacy of the combination of sirolimus and tacrolimus as a
graft-versus-host disease prophylaxis, the investigators are going to perform a phase II,
multicenter clinical trial after human leukocyte antigen (HLA)-matched, related peripheral
blood stem cell transplants (PBSCT) in patients with hematologic malignancies. Total 116
patients will be accrued.
Objective: The primary objective is to evaluate the rates of 100 day Grade II-IV acute GVHD.
Secondary objectives include the time to neutrophil and platelet engraftment, the incidence
of grade III-IV acute GVHD, non-relapse mortality during 100 days after transplant,
mucositis severity, all infectious complications including cytomegalovirus (CMV)
reactivation, vascular complications (venoocclusive disease of liver; VOD, thrombotic
microangiopathy; TMA), disease-free survival, and overall survival at 1 year after
transplant.
Eligibility Criteria: Eligible patients are between 20 and 60 years of age, have acute
leukemia, myelodysplastic syndrome (MDS), chronic myelogenous leukemia (CML), and adequate
organ function. For available sibling donor, a serologic (or higher resolution) 6/6 Class I
HLA-A and B and molecular Class II DRB1 must be matched.
Treatment Description: Conditioning regimens will vary by center and donor will donate
peripheral blood stem cells according to local institutional practices. Peripheral blood
stem cells will not be manipulated or T-depleted prior to infusion. Tacrolimus will be
administered at 0.05 mg/kg/day intravenously by continuous infusion beginning on day -1 with
a target serum concentration of 5 to 10 ng/mL. Sirolimus will be administered as a 6 mg oral
loading dose on day -1, followed by a 3 mg/day single dose, with a target serum
concentration of 3 to 12 ng/mL. Levels will be monitored weekly during hospitalization and
then as clinically indicated. Intravenous tacrolimus will be converted to an oral equivalent
dose prior to discharge and both immunosuppressives will be tapered beginning at day +100
after transplantation and eliminated by day +180 when clinically feasible.
Accrual Period: The estimated accrual period is three years. Patients will be followed for
100 days post transplantation for evaluation of the primary endpoint, with additional
follow-up to two years after transplantation for evaluation of secondary endpoints.
Rationale: Graft-versus-host disease (GVHD) remains a major cause of morbidity and mortality
after allogeneic HSCT. The combination of a calcineurin inhibitor and methotrexate has been
the standard GVHD prophylactic regimen for the past 20 years. However, the incidence of
acute GVHD remains high, with reported cumulative incidence of grade II-IV up to 60%.
Serious acute GVHD or chronic GVHD has detrimental consequences in patients including death,
disability, infections, or prolonged hospitalization.
Sirolimus is the first available inhibitor of the mammalian target of rapamycin (mTOR). And
sirolimus binds uniquely to FK-binding protein (FKBP12) and forms a complex with mTOR. This
complex inhibits several biochemical pathways, resulting in a reduction in DNA
transcription, DNA translation, protein synthesis, and cell cycling, ultimately leading to
T-cell immunosuppression. Sirolimus has been used alone and in combination with calcineurin
inhibitors for prevention of allograft rejection after solid organ transplantation. In the
field of hematopoietic stem cell transplantation, the combination of sirolimus and
tacrolimus has also resulted in a low incidence of acute GVHD and reduced transplant-related
toxicity.
In addition, the investigators demonstrated previously that the combination of tacrolimus
and sirolimus is effective as a GVHD prophylaxis and well tolerated in cases of high risk
transplantation using mismatched related or unrelated donor.
As discussed above, sirolimus has emerged as one of the most promising immunosuppressive
agents in allogeneic hematopoietic stem cell transplantation. However, the benefit of GVHD
prophylaxis regimens including sirolimus has not been confirmed consistently and there is
controversy that the incorporation of sirolimus into GVHD prophylaxis results in improved
survival.
Efficacy measures: Patients will be followed for 100 days post transplantation for
evaluation of the primary endpoint (the incidence and severity of acute GVHD) and clinical
data will be collected at 100 day after HSCT using case report form. And patients will be
recommended additional follow-up to one year after HSCT for evaluation of secondary
endpoints or parameters including clinical outcomes (disease-free survival and overall at 1
year after transplant). The investigators will perform the interim analyses at the time when
31 patients are enrolled during phase 1.
Acute GVHD will be graded according to the consensus grading scale (appendix-1). The broad
category of acute GVHD includes:
1. Classic acute GVHD (maculopapular rash, nausea, vomiting, anorexia, profuse diarrhea,
illus, or cholestatic hepatitis) occurring within 100 days after transplantation
(without diagnostic or distinctive signs of chronic GVHD)
2. Persistent, recurrent, or late acute GVHD: Features of classic acute GVHD without
diagnostic or distinctive manifestations of chronic GVHD occurring beyond 100 days of
transplantation (often seen after withdrawal of immune suppression).
Safety: All the safety analyses will be based on safety population. The assessment of safety
will be based mainly on the frequency of adverse events and on the number of laboratory
values that fall outside of predetermined ranges. Adverse events will be summarized by
presenting the number and percentage of patients having any adverse event as well as by
severity to study treatment. In addition the summary of grade 3 and 4 will be presented.
During administration of drugs as a GVHD prophylaxis, toxicities related to drugs will be
graded according to the Common Terminology Criteria for Adverse Events (CTCAE v3.0).
Patients will also be assessed regularly by physical examination and laboratory tests
including CBC, biochemistry including liver function test and chest X-ray.
Statistical Methods: Descriptive statistical analysis will be performed to assess patient
baseline characteristics, engraftment, acute GVHD, and non-relapse mortality. Overall
survival and relapse-free survival will be calculated using the Kaplan-Meier method and
estimated using a competing risk of 100-day mortality for cumulative incidence rate of
grades II-IV acute GVHD.
;
Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Prevention
Status | Clinical Trial | Phase | |
---|---|---|---|
Recruiting |
NCT05400122 -
Natural Killer (NK) Cells in Combination With Interleukin-2 (IL-2) and Transforming Growth Factor Beta (TGFbeta) Receptor I Inhibitor Vactosertib in Cancer
|
Phase 1 | |
Terminated |
NCT04313881 -
Magrolimab + Azacitidine Versus Azacitidine + Placebo in Untreated Participants With Myelodysplastic Syndrome (MDS)
|
Phase 3 | |
Recruiting |
NCT05088356 -
Reduced Intensity Allogeneic HCT in Advanced Hematologic Malignancies w/T-Cell Depleted Graft
|
Phase 1 | |
Recruiting |
NCT04003220 -
Idiopathic Chronic Thrombocytopenia of Undetermined Significance : Pathogenesis and Biomarker
|
||
Completed |
NCT02916979 -
Myeloid-Derived Suppressor Cells and Checkpoint Immune Regulators' Expression in Allogeneic SCT Using FluBuATG
|
Phase 1 | |
Active, not recruiting |
NCT03755414 -
Study of Itacitinib for the Prophylaxis of Graft-Versus-Host Disease and Cytokine Release Syndrome After T-cell Replete Haploidentical Peripheral Blood Hematopoietic Cell Transplantation
|
Phase 1 | |
Completed |
NCT00003270 -
Chemotherapy, Radiation Therapy, and Umbilical Cord Blood Transplantation in Treating Patients With Hematologic Cancer
|
Phase 2 | |
Recruiting |
NCT04904588 -
HLA-Mismatched Unrelated Donor Hematopoietic Cell Transplantation With Post-Transplantation Cyclophosphamide
|
Phase 2 | |
Terminated |
NCT04866056 -
Jaktinib and Azacitidine In Treating Patients With MDS With MF or MDS/MPN With MF.
|
Phase 1/Phase 2 | |
Recruiting |
NCT04701229 -
Haploinsufficiency of the RBM22 and SLU7 Genes in Del(5q) Myelodysplastic Syndromes
|
||
Suspended |
NCT04485065 -
Safety and Efficacy of IBI188 With Azacitidine in Subjects With Newly Diagnosed Higher Risk MDS
|
Phase 1 | |
Recruiting |
NCT04174547 -
An European Platform for Translational Research in Myelodysplastic Syndromes
|
||
Enrolling by invitation |
NCT04093570 -
A Study for Participants Who Participated in Prior Clinical Studies of ASTX727 (Standard Dose), With a Food Effect Substudy at Select Study Centers
|
Phase 2 | |
Completed |
NCT02508870 -
A Study of Atezolizumab Administered Alone or in Combination With Azacitidine in Participants With Myelodysplastic Syndromes
|
Phase 1 | |
Completed |
NCT04543305 -
A Study of PRT1419 in Patients With Relapsed/Refractory Hematologic Malignancies
|
Phase 1 | |
Recruiting |
NCT05384691 -
Efficacy of Luspatercept in ESA-naive LR-MDS Patients With or Without Ring Sideroblasts Who do Not Require Transfusions
|
Phase 2 | |
Recruiting |
NCT05365035 -
A Phase II Study of Cladribine and Low Dose Cytarabine in Combination With Venetoclax, Alternating With Azacitidine and Venetoclax, in Patients With Higher-risk Myeloproliferative Chronic Myelomonocytic Leukemia or Higher-risk Myelodysplastic Syndromes With Excess Blasts
|
Phase 2 | |
Recruiting |
NCT06008405 -
Clinical Trial Evaluating the Safety of the TQB2928 Injection Combination Therapy
|
Phase 1 | |
Not yet recruiting |
NCT05969821 -
Clonal Hematopoiesis of Immunological Significance
|
||
Withdrawn |
NCT05170828 -
Cryopreserved MMUD BM With PTCy for Hematologic Malignancies
|
Phase 1 |