Trial Information

Multicenter Trials to Evaluate the Efficacy and Toxicity of Sirolimus/Tacrolimus Combination as a GVHD Prophylaxis After HLA Matched Related PBSCT

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.