Sirolimus in Kidney Transplant Patients With Squamous Cell Skin Carcinoma

• Evaluation of skin tumor for squamous cell skin carcinoma after sirolimus therapy. [ Time Frame: At baseline and time of surgical removal. ] [ Designated as safety issue: No ]
  Tumor will be analyzed at baseline and time of surgical removal by both laboratory and microscopic testing.
• Tumor recurrence. [ Time Frame: Every 3 months for 1 year. ] [ Designated as safety issue: No ]
  Full skin exam done by dermatology.
• Response rate of squamous cell carcinomas to sirolimus therapy verses calcineurin-based immunosuppressant therapy. [ Time Frame: At baseline and time of surgical removal. ] [ Designated as safety issue: No ]
  Tumor will be analyzed by pathology.
• Other cancer development. [ Time Frame: From time of enrollment and every 3 months for 1 year. ] [ Designated as safety issue: No ]
• Tumor evaluation by western blot analysis. [ Time Frame: At baseline and time of surgical removal. ] [ Designated as safety issue: No ]
  Baseline results will be recorded and and then results at time of surgical removal will be reported as increased or decreased expression in comparison to the baseline results.
• Acute and/or chronic transplant rejection. [ Time Frame: At baseline and 1 year. ] [ Designated as safety issue: Yes ]
  Evaluating for safety reasons of sirolimus.
• Pre-treatment biopsy immunohistochemistry and PCR testing for oncogenic viruses. [ Time Frame: Baseline. ] [ Designated as safety issue: No ]
  p16 will be assessed for HPV integration and analysis for presence of other oncogenic viruses, EBV, HTLV-1, HHV-8, and the Merkel Cell Virus will be done.

• Evaluation of skin tumor for squamous cell skin carcinoma after sirolimus therapy. [ Time Frame: At baseline and time of surgical removal. ] [ Designated as safety issue: No ]
  Tumor will be analyzed at baseline and time of surgical removal by both laboratory and microscopic testing.
• Tumor recurrence. [ Time Frame: Every 3 months for 1 year. ] [ Designated as safety issue: No ]
  Full skin exam done by dermatology.
• Response rate of squamous cell carcinomas to sirolimus therapy verses calcineurin-based immunosuppressant therapy. [ Time Frame: At baseline and time of surgical removal. ] [ Designated as safety issue: No ]
  Tumor will be analyzed by pathology.
• Other cancer development. [ Time Frame: From time of enrollment and every 3 months for 1 year. ] [ Designated as safety issue: No ]
• Tumor evaluation by western blot analysis. [ Time Frame: At baseline and time of surgical removal. ] [ Designated as safety issue: No ]
  Baseline results will be recorded and and then results at time of surgical removal will be reported as increased or decreased expression in comparison to the baseline results.
• Acute and/or chronic transplant rejection. [ Time Frame: At baseline and 1 year. ] [ Designated as safety issue: Yes ]
  Evaluating for safety reasons of sirolimus.
• Pre-treatment biopsy immunohistochemistry and PCR testing for oncogenic viruses.. [ Time Frame: Baseline. ] [ Designated as safety issue: No ]
  p16 will be assessed for HPV integration and analysis for presence of other oncogenic viruses, EBV, HTLV-1, HHV-8, and the Merkel Cell Virus will be done.

Solid organ transplant recipients (SOTR) have a 3-5x increased occurrence of cancer in contrast to the general population with basal and squamous cell skin cancer. The use of immunosuppressant or anti-rejection drugs that are needed after SOTR is known to increase the risk of developing certain kinds of cancer. The purpose of this study is to compare sirolimus (an immunosuppressant drug) and calcineurin inhibitors (CNIs: also immunosuppressant drugs) and how they affect invasive squamous cell carcinomas in renal transplant patients.

This is a Phase II randomized study to evaluate the effectiveness of sirolimus in treating and preventing squamous cell skin cancer carcinoma using a Simon's 2-stage design. Once a pathological diagnosis of squamous cell skin carcinoma has been made and patients consent, they will be randomized to either continue on their current immunosuppressive regimen or switch to sirolimus. The patients will participate in the study for one year. They will be seen once a week over the first 3 weeks of the study to evaluate immunosuppressant drug levels. At week 5 of the study, or sooner if determined by dermatology, patients will receive surgery to treat their squamous cell carcinomas. Patients will continue to be evaluated by dermatology for new skin cancers every 3 months for 1 year.

• Drug: Sirolimus
  Patients randomized to this arm of the study will receive sirolimus from the time of randomization at least until 5 weeks or the removal of the skin tumor. Nephrology will determine/manage the immunosuppressant therapy.
  Other Name: Rapamune
• Drug: Calcineurin inhibitor-based immunosuppressant (CNI)
  Patients randomized to this arm of the study will continue to receive their CNI as prescribed by Nephrology. The Nephrology team will determine/manage the immunosuppressant medications for these patients.
  Other Names:

  • Tacrolimus (Prograf)
  • Cyclosporine (Sandimmune)

• Active Comparator: Sirolimus treatment
  Patients will receive sirolimus 5 weeks prior to removal of squamous cell skin carcinoma. After the 5 weeks of treatment, nephrology will determine/manage each patient's immunosuppressant therapy.
  Intervention: Drug: Sirolimus
• Active Comparator: Calineurin inhibitor-based immunosuppressant (CNI)
  This group will be considered the control group and will have the same time points of tumor measurement at randomization and 5 weeks later. After tumor removal, patients may be switch to sirolimus treatment. Nephrology will determine/manage the patient's immunosuppressant therapy.
  Intervention: Drug: Calcineurin inhibitor-based immunosuppressant (CNI)

Inclusion Criteria:

• Histologically or cytologically proven squamous cell skin carcinoma
• Recipient of a renal organ transplant at least one year prior to study enrollment
• Receiving a CNI for at least 6 months prior to diagnosis of skin cancer
• No current evidence of graft rejection, except low-grade, chronic graft rejection
• Measurable disease by caliper measurement
• Life expectancy > 6 months
• Age of at least 18 years
• Adequate organ and marrow function as determined by ANC, HGB, PLT, Total Bili, AST, and creatinine clearance
• Ability to understand/willingness to sign a written informed consent form

Exclusion Criteria:

• Inability to give informed consent
• Major surgery within 4 week prior to starting study drug
• Chronic or non-healing open wounds
• Pregnant and nursing women
• Women and men of child-bearing potential must agree to use adequate contraception prior to study entry and for the study duration
• Prior use of an mTOR inhibitor
• Pre-existing clinically significant cardiac, hepatic, pulmonary, or renal dysfunction
• HIV-positive patients
• Proteinuria (> 1 gram)
• Prior or current history of uncontrolled hyperlipidemia (cholesterol > 7.8 mmol/l or triglycerides > 4 mmol/l)
• Currently receiving any investigational agents
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to sirolimus (mTOR inhibitors)
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrythmia, or psychiatric illness/social situations that would limit compliance with study requirements