Prevention of the Graft-Versus-Host-Disease in Patients After Stem Cell Transplantation With Tacrolimus and Everolimus

Prophylaxis of the Graft-Versus-Host-Disease in Patients After Allogeneic Stem Cell Transplantation With a Combination of Tacrolimus and Everolimus

The purpose of this pilot study is to provide preliminary data about the efficacy and the safety of the combination of tacrolimus with everolimus in the prophylaxis of the graft-versus-host-disease (GvHD) in patients after allogeneic stem cell transplantation.

The allogeneic stem cell transplantation is a successful therapeutic approach in the treatment of a number of hematologic diseases. Nevertheless, it is associated with substantial risks and complications. A major life-threatening complication that occurs in the post transplantation period is the graft versus host disease, especially its severe forms (Grade III and Grade IV). For this reason, a combined immunosuppressive therapy is standard in patients after a stem cell transplantation. In this regard, the combination between cyclosporin A and methotrexate in the prevention of GvHD has been particularly successful. However, the incidence rate of GvHD and consequent mortality are still fairly high. Besides, the therapy itself is accompanied by serious side effects. Therefore, there is a need for a more efficient, less toxic, combined immunosuppressive therapy. The purpose of this pilot study is to test a new combination of immunosuppressives (tacrolimus and everolimus) for the prevention of GvHD after an allogeneic stem cell transplantation. Tacrolimus is a macrolide immunosuppressant that acts as a calcineurin inhibitor, thereby preventing the activation and proliferation of the T-lymphocytes. Everolimus is a semisynthetic macrocyclic lactone that inhibits the activity of a key protein involved in the regulation of the cell cycle, the so called m-TOR protein. Both medicaments act complementary and potently inhibit the proliferation of immune cells. Previous studies have shown that the combination of tacrolimus with everolimus decreases significantly the rejection rate after solid organ transplantation and this combination is generally well tolerated.

This study is designed as a prospective, single-center, non-randomized, open-label non-controlled pilot study. Study related visits are scheduled to take place at regular time intervals and the patients will be followed up to one year after the stem cell transplantation. The study is designed and will be conducted in accordance with the ICH-GCP guidelines and the respective national and international laws.

Inclusion Criteria:

• Male and female patients between 18 and 70 years of age
• Planned allogeneic stem cell transplantation either from a related or an unrelated donor
• Written informed consent

Exclusion Criteria:

• Previous stem cell transplantation
• Use of antibody Campath (anti CD-52) or ATG during the conditioning
• In vitro T-cell depleted graft
• Known hypersensitivity to everolimus or other constituents of the study medication
• Symptomatic infectious disease
• Hepatic disease (ASAT > 2 x ULN)
• Renal insufficiency (creatinine > 2 x ULN)
• HIV infection
• Life expectancy < 3 months
• Severe lung disease (FEV1 < 50% of the normal value)
• Severe psychiatric disorder
• Subjects unlikely to comply with the requirements of the protocol
• Known or current alcohol, medication or drug abuse
• Pregnancy or lactation
• Women of child-bearing potential without reliable contraception unless they meet the following criteria: postmenopausal (12 months of natural amenorrhea);postoperation status (6 weeks after surgical bilateral oophorectomy with or without hysterectomy);use of highly effective birth control method (defined as one which results in a low failure rate i.e. less than 1% per year when used consistently and correctly such as implants, injectables, combined oral contraceptives, IUDs, sexual abstinence or vasectomized partner)
• Men that do not use one of the following methods for prevention of conception:sexual abstinence; condom; vasectomy
• Participation of the subject in another clinical trial within the last 4 weeks