CERTICOEUR: A Secondary Prevention Study of Skin Cancers in Heart Transplant Patients. Everolimus Versus Calcineurin Inhibitors Multicenter Trial

• New skin cancer [ Time Frame: 2 years ] [ Designated as safety issue: No ]
• Number of patients with new skin cancers [ Time Frame: 2 years ] [ Designated as safety issue: No ]
• Time of recurrence [ Time Frame: 2 years ] [ Designated as safety issue: No ]
• Number and histology of other types of skin cancer [ Time Frame: 2 years ] [ Designated as safety issue: No ]
• Graft function (including acute rejection, graft loss, death) [ Time Frame: 2 years ] [ Designated as safety issue: No ]
• Renal function evolution as assessed using cockroft creatinine clearance and proteinuria [ Time Frame: 2 years ] [ Designated as safety issue: No ]
• Adverse events and serious adverse events [ Time Frame: 2 years ] [ Designated as safety issue: Yes ]
• Non skin cancer (Number and diagnostic) [ Time Frame: 2 years ] [ Designated as safety issue: No ]
• Schemes of calcineurin inhibitors reduction/withdrawal [ Time Frame: 2 years ] [ Designated as safety issue: No ]
• Immune response assessment through regulatory or effector function of blood and in situ T lymphocytes at baseline and following immusuppression switch [ Time Frame: 2 years ] [ Designated as safety issue: No ]

Heart transplant is a recognized therapeutic strategy in refractory heart failure. Its success is however hampered by severe cancer occurrence and recurrence. The new m-tor inhibiting drugs Sirolimus and Everolimus have shown potential for reducing the incidence of cancer in animal models. They are potent immunosuppressant, antiproliferative and antiangiogenic drugs. This open labelled randomized multicenter study aims at evaluating the beneficial antineoplastic effect of Everolimus in 159 heart transplant patients suffering of recurrent skin cancer. Primary objective is to demonstrate a reduction in the number of new skin cancers. Secondary end point will be time of recurrence, incidence of non skin cancer, graft function following switch (including death), renal function evolution following calcineurin inhibitors reduction or withdrawal, Everolimus tolerance profile, schemes of calcineurin inbitors reduction management in centers.

• Open labelled randomized Everolimus vs reduction of calcineurin inhibitors trial. 2:1 randomization design
• October 10, 2008
• 159 patients (106 everolimus vs 53 calcineurin inhibitors reduction)
• 175 patients (117 vs 58)
• X Not yet recruiting 0 recruiting 0 no longer recruiting
• Number of skin tumors per patients requiring surgery with histology control within 2 years

Within 2 years of Follow up:

• New skin cancer
• Number of patients with new skin cancers
• Time of recurrence
• Number and histology of other types of skin cancer
• Graft function (including acute rejection, graft loss, death)
• Renal function evolution as assessed using cockroft creatinine clearance and proteinuria
• Adverse events and serious adverse events
• Non skin cancer (Number and diagnostic)
• Schemes of calcineurin inhibitors reduction/withdrawal
• Immune response assessment through regulatory or effector function of blood and in situ T lymphocytes at baseline and following immusuppression switch

• Cardiac Transplantation
• Skin Cancer

• No Intervention: 1
  reduction of immunosuppression
• Experimental: 2
  switch to Everolimus : 50% reduction of calcineurin inbitors (ciclosporine or tacrolimus)
  Intervention: Drug: Everolimus

Inclusion Criteria:

• First orthotopic heart transplant after 1st year
• No rejection within previous 6 Months
• Occurrence within the three previous years of squamous cell carcinoma, basal cell carcinoma, in situ carcinoma, Bowen disease, premalignant keratosis.
• Recurrence of skin cancers leading to immunosuppressive regimen modifications
• Above 18 yrs and under contraceptive drugs if applicable
• Informed consent given
• Health coverage ongoing

Exclusion Criteria:

• Other non simultaneously transplanted organ
• recent biopsy proven acute rejection
• Proteinuria > 1g/l
• Ongoing infectious disease
• HIV positivity, Chronic active Hepatitis B or C.
• Abnormal blood tests: transaminases >= 3UNL, Bilirubine > 34 mmol.l, albumin<35 g/l, spontaneous INR >1,3
• Hemoglobin >= 8 g/dl, White Blood Count<= 2 giga/l, platelet count <= 50 giga/l
• Hypercholesterolemia>= 9 mmol/l, hypertriglyceridemia >= 8,5 mmol/l despite treatment
• History of macrolid or mTor inhibitor intolerance
• Previous cancer other than skin within last 5 years
• Medical or surgical condition unsuitable for the trial
• Breast feeding
• Positive pregnancy test
• Severe psychiatric disorder
• Communication or language disability