TroVax Renal Immunotherapy Survival Trial

This is an international, randomised, double blind, placebo controlled, parallel group study to investigate whether a minimum of three doses of TroVax® added to first-line standard of care therapy, prolongs the survival of patients with locally advanced or metastatic renal clear cell adenocarcinoma.

The primary endpoint is survival. The study is designed to be pragmatic, limiting additional study related investigations to a minimum. Protocol mandated scans and X-rays are limited to two time points (baseline and week 26) to permit comparison of the percentage of patients with progressive disease at 6 months as a secondary efficacy endpoint. Six months was selected based on review of published literature indicating that progressive disease was commonly observed by 26 weeks in patients with renal cancer. Endpoints such as tumour response by RECIST are considered of secondary importance to survival and will be determined by radiological examinations ordered at the discretion of the investigator based on the clinical status of the patient and will be based the interpretation of the patient's care-team (investigator and local radiologist).

After signing the study informed consent form and meeting the baseline enrolment criteria patients will be assigned by the investigator (their physician) to one of the following defined first-line standard of care regimens based on what is best for the patient and consistent with local practice:

• subcutaneous low dose IL-2
• interferon-α (excluding pegylated IFNα)
• sunitinib

TroVax® is administered at a dose of 1E9TCID50/ml in 1ml by injection into the deltoid muscle of the upper arm at regular intervals up to 8 weeks apart up to a maximum of 13 doses.

Inclusion criteria

• Signed informed consent. The patient must be competent to give written informed consent and comply with the protocol requirements.
• Locally advanced or metastatic, histologically proven clear cell renal carcinoma.
• Primary tumour surgically removed (some residual advanced primary tumour may remain).
• At least four weeks post surgery or radiotherapy.
• First-line. No prior therapy for renal cancer except surgery or radiotherapy.
• Measurable disease.
• Aged 18 years or more.
• Patient expected to survive a minimum of 12 weeks (i.e. in the opinion of the investigator there is a >90% probability that the patient will survive >12 weeks if treated with the selected standard of care).
• Free of clinically apparent autoimmune disease (including no prior confirmed diagnosis or treatment for autoimmune disease including Systemic Lupus Erythematosis, Grave's disease, Hashimoto's thyroiditis, multiple sclerosis, insulin dependant diabetes mellitus or systemic (non-joint) manifestations of rheumatoid disease).
• Total white cell count ≥ 3 x 109/L and lymphocyte count ≥1 x 109/L.
• Serum creatinine ≤1.5 times the upper limit of normal.
• Bilirubin ≤ 2 times the upper limit of normal and an SGPT of ≤ 4 times the upper limit of normal.
• Women must be either post menopausal, or rendered surgically sterile or, if of child bearing potential, must have been practising a reliable form of contraception (oral contraception + a barrier method) for at least three months prior to the first dose of TroVax® and must continue while they are being treated with TroVax®. Men must practise a reliable form of contraception (barrier or vasectomy) while they are being treated with TroVax®.
• No acute changes on 12-lead ECG.
• Ejection fraction documented as not less than 45% or no clinical suspicion that cardiac ejection fraction is less than 45%.(If clinical suspicion exists the ejection fraction should be measured according to local site procedures).
• Karnofsky performance status of ≥ 80%.

Exclusion criteria

• Cerebral metastases. (Known from previous investigations or clinically detectable).
• Previous exposure to TroVax®.
• Serious infections within the 28 days prior to entry to the trial.
• Known to test positive for HIV or hepatitis B or C.
• Life threatening illness unrelated to cancer.
• History of allergic response to previous vaccinia vaccinations.
• Known allergy to egg proteins.
• Known hypersensitivity to neomycin.
• Participation in any other clinical trial of a licensed or unlicensed drug within the previous 30 days or during the course of this trial.
• Previous malignancies within the last 10 years other than successfully treated squamous carcinoma of the skin or in situ carcinoma of the cervix treated with cone biopsy.
• Previous history of major psychiatric disorder requiring hospitalization or any current psychiatric disorder that would impede the patient's ability to provide informed consent or to comply with the protocol.
• Oral corticosteroid use unless prescribed as replacement therapy in the case of adrenal insufficiency.
• Ongoing use of agents listed in locally approved prescribing information as causing immunosuppression.
• Prior history of organ transplantation.
• Pregnancy or lactation.