Safety and Biological Activity of TroVax® Vaccine Given With IL-2 in Renal Cell Carcinoma
Safety and Biological Activity of TroVax® Vaccine Given With IL-2 in Renal Cell Carcinoma
The purpose of this study is to assess the safety and tolerability of TroVax® investigational
 vaccine injections when given as first or second line treatment in conjunction with
 subcutaneous low dose IL-2 to patients with locally advanced or metastatic clear cell or
 papillary cell renal carcinoma.

 TroVax® is the experimental product in this trial and its value as a medicine has not yet
 been proven. Interleukin-2 (IL-2) is a standard treatment for cancer, which means that it can
 be received even if one chooses not to participate in this study. TroVax® is being studied as
 a possible treatment for patients with cancer of the kidney.

 TroVax® belongs to a class of medicines called vaccines. A vaccine helps the body's immune
 system to recognize and kill foreign invading organisms effectively. It is believed that one
 of the reasons why cancer can spread through the body is that the immune system cannot
 recognize cancer cells as being different from normal tissues and therefore cannot kill the
 cancer cells. A vaccine that alerts the immune system to the presence of cancer cells in the
 body could lead to the immune system being able to target and kill those cancer cells
 effectively. This trial is of a completely new way of trying to treat cancer in the future by
 the use of vaccination injections. TroVax® consists of a virus that has been changed so that
 it is no longer infectious and carries a gene for a protein called 5T4. This protein is
 carried by many kidney cancer cells. When the virus is injected, it makes the protein, and
 the body's immune system is then able to recognize this protein and kill the cells that have
 it (i.e. the cancer cells).

 The purpose of this study is to assess the safety and tolerability of TroVax® injections and
 to understand whether TroVax® could make such an immune response happen in patients with
 renal cell cancer while receiving interleukin-2 (IL-2). This study will also observe and
 monitor any side effects experienced in patients who receive TroVax® while being treated with
 IL-2.
Objectives

 Primary:

 -  To assess the safety and tolerability of TroVax® injections when given as first or
 second line treatment in conjunction with subcutaneous low dose IL-2 to patients with
 locally advanced or metastatic clear cell or papillary cell renal carcinoma.

 -  To assess the immune responses induced by treatment with TroVax® and subcutaneous low
 dose IL-2.

 Secondary:

 -  To assess tumour response rates, time to progression, survival and progression free
 survival at 6, 12 and 24 months after commencement of treatment with subcutaneous low
 dose IL-2.

 -  To assess the ability of the reintroduction of low dose subcutaneous IL-2 to induce
 further disease responses or stabilisation in patients being treated with TroVax® alone.

 Study design:

 This will be an open label evaluation in patients with clear cell or papillary cell renal
 carcinoma requiring immunotherapy for locally advanced or metastatic disease. A single dose
 level of TroVax® in combination with a clinically accepted regimen of subcutaneous low dose
 IL-2 will be tested in 25 evaluable patients and their immunological responses to TroVax®
 (antibody and cellular) will be assessed. If immunological activity is observed after two
 cycles of TroVax®/IL-2 in 70% or more of these patients, further randomised trials will be
 undertaken to determine the clinical efficacy of TroVax® in this group of patients.

 The dosage schedule of subcutaneous low dose IL-2 will be an initial dose schedule of 250,000
 U/kg/dose for 5 days in week 1 followed by 125,000 U/kg/dose for 5 days in each of weeks 2
 though 6 inclusive. There will then be a two-week recovery period before the next cycle
 commences. The dosage regimen of TroVax® will be injections given prior to the first cycle on
 two occasions (weeks -2 and 1), and one injection given at the beginning of week 4 of the
 first cycle. In subsequent cycles, booster injections of TroVax® will be given at week 1
 only, prior to commencement of subcutaneous IL-2 therapy. After the first and second cycles
 of combined treatment, patients will be evaluated by CT scan for their response to treatment.
 If their disease has progressed after the second cycle, they will be withdrawn from the trial
 if they require alternative therapy (deterioration of one level of the Karnofsky score or
 appearance of disease in a new site). If they are experiencing progressive disease that does
 not require alternative therapy or stable disease or better, they will be treated with cycles
 of TroVax®/IL-2 as described above for up to a further four cycles. The tumour status will be
 evaluated by CT scan after every cycle.

 All patients will be monitored for up to 6 cycles (48 weeks) to assess tolerability,
 induction of humoural and cellular immunity to 5T4 cell surface antigen, immune response to
 the vector, tumour response rates, survival, time to progression and progression free
 survival. Patients who are intolerant of further treatments with subcutaneous IL-2 during
 this part of the study will be withdrawn from the study.

 Patients who are still stable or experiencing a tumour response at 48 weeks will be offered
 further boosts with TroVax® without IL-2 every three months at weeks 52, 64, 76, 88 and 100.
 During this period, if disease progression recurs, two further cycles with subcutaneous IL-2
 as described above may be given in combination with TroVax® as described above with the
 objective of inducing further disease response or stabilisation.

 Following termination of all patients' participation in the trial (including those with
 progressive disease after two cycles of TroVax®/IL-2), contact will be kept by the
 Investigators with their families in order to determine the date of death.

 A total of 25 patients will be enrolled.

 Withdrawal criteria from the trial:

 1. Non-compliance with the protocol.

 2. Patient withdraws consent.

 3. Progressive disease with new sites of disease demonstrated on CT scan and/or requiring
 other cancer treatment (deterioration in Karnofsky performance score of 10% or more).

 4. Death.

 5. Serious IL-2 related adverse events or lack of tolerance to further treatment with IL-2

 6. Serious TroVax® related adverse events (DLT).

 Treatment plan and methods:

 Patients complying with the entry criteria will be invited to enter the study. After
 giving fully informed consent, patients will be subjected to a physical examination to
 document general fitness to proceed with the trial. Vital signs will be recorded.
 Performance status (Karnofsky) will be documented. At that time, metastases will be
 documented using chest, abdominal and pelvic CT scans and an MRI scan of the brain will
 be obtained. Blood samples will also be obtained for clinical pathology (10 mL; safety
 testing). A urine sample will be tested for protein and blood (safety testing). A 12
 lead ECG and echocardiogram will be obtained. This screen should not occur more than two
 weeks before treatment with TroVax® begins. If available, tumour tissue from earlier
 biopsies will be obtained and tested for the presence of tumour antigens, e.g. 5T4. CT
 scans must be compared with scans obtained within the previous three months in order to
 determine that the disease is progressing.

 Week -2, day 1:

 Obtain blood sample for HLA testing and immunological evaluation, (antibody and T-cell
 responses to the vector and the 5T4 surface antigen; 100 mL).

 Safety testing (blood, 10 mL and urine) TroVax® injection i.m. 1 mL

 Cycle 1, Week 1 day 1:

 Karnofsky score Vital signs TroVax® injection i.m. 1 mL (time 0) Vital signs (1 hour) /
 Vital signs (3 hours) IL-2 subcutaneous injection (250,000 U/kg/dose) safety testing

 Cycle 1, Week 1, days 2-5:

 IL-2 subcutaneous injection (250,000 U/kg/dose)

 Cycle 1, Week 2, day 1:

 Obtain samples for immunological evaluation (100 mL blood) and safety testing (blood 10
 mL and urine) IL-2 subcutaneous injection (125,000 U/kg/dose).

 Week 2, days 2-5:

 IL-2 injection subcutaneous (125,000 U/kg/dose).

 Week 3, days 1-5:

 Safety testing (blood and urine; day 1 only) IL-2 subcutaneous injection (125,000
 U/kg/dose).

 Week 4, day 1:

 Safety testing Vital signs TroVax® injection i.m. 1 mL (time 0) Vital signs (1 hour) /
 Vital signs (3 hours) IL-2 subcutaneous injection (125,000 U/kg/dose).

 Week 4, days 2-5:

 IL-2 subcutaneous injection (125,000 U/kg/dose).

 Week 5, days 1-5:

 Obtain sample for immunological evaluation (blood) and safety testing (blood 10 mL and
 urine; day 1 only) IL-2 subcutaneous injection (125,000 U/kg/dose).

 Week 6, days 1-5:

 Obtain sample for safety testing (blood 10 mL and urine; day 1 only) IL-2 subcutaneous
 injection (125,000 U/kg/dose).

 Week 8 day 1:

 CT scan for information. Physician examination. Safety blood (10 mL) and urine

 Cycles 2-6 week 1, day 1:

 Obtain sample for safety testing (blood 100 mL and urine) Vital signs Karnofsky score
 TroVax® injection i.m. 1 mL (time 0) Vital signs (1 hour) / Vital signs (3 hours) IL-2
 subcutaneous injection (250,000 U/kg/dose)

 Cycle 2-6, week 1, days 2-5:

 IL-2 subcutaneous injection (250,000 U/kg/dose)

 Cycles 2-6, Week 2, day 1:

 Obtain sample for immunological evaluation (blood) and safety testing (blood and urine).

 IL-2 subcutaneous injection (125,000 U/kg/dose).

 Cycles 2-6, Week 2, days 2-5:

 IL-2 subcutaneous injection (125,000 U/kg/dose).

 Cycles 2-6, Weeks 3-6, days 1-5:

 Safety testing (blood 10 mL and urine day 1 only) IL-2 subcutaneous injection (125,000
 U/kg/dose)

 Cycles 2-6, Week 8, day 1:

 Obtain blood for safety testing (blood and urine) CT scan. Physician examination.

 At the end of cycle 2 to 6 inclusive, if disease has progressed and requires other
 treatment (deterioration in Karnofsky performance score by 10% or more, disease appears
 in a new site), withdraw patient from trial. Also withdraw patient if intolerant of
 subcutaneous low dose IL-2 at the lowest permissible dose or if the patient experiences
 DLT. Patients withdrawing before they receive the first four doses of TroVax® and give
 blood for immunology testing in cycle 2, week 2 will be replaced.

 If disease is stable, responding or progressing (but Karnofsky score unchanged, no new
 disease sites) and patient is tolerant of treatment, continue with further therapy.

 After six cycles of combined study drugs (48 weeks), assess with CT scan at week 48 day
 1:

 If disease has progressed and requires alternative treatment (deterioration in Karnofsky
 performance score by 10% or more or disease appears in a new site), withdraw patient
 from trial.

 If disease is stable or responding or progressing (but Karnofsky score stable and no new
 disease sites) and patient is tolerant of treatment, continue with further therapy. This
 therapy will be TroVax® injection every three months, on weeks 52, 64, 76, 88, 100.
 Perform physician examination on each occasion and assess Karnofsky score prior to
 injection. Obtain samples for safety testing (blood 10 mL and urine) and immunological
 evaluation (10 mL sample only for antibody testing) prior to each injection. A further
 10 mL sample for immunological evaluation will be obtained one week after each TroVax®
 injection. CT scans will be obtained at weeks 63, 75, 87, 99. At each CT scan, assess:

 If disease has progressed, recommence subcutaneous low dose IL-2 treatment (6 weeks on,
 two weeks off IL-2) at week 64, 76, 88 as appropriate and give a further 2 cycles of
 subcutaneous low dose IL-2.

 If IL-2 restarted at week 64 (76, 88), schedule is:

 Week 64 (or 76, 88), day 1:

 Safety testing (blood 10 mL and urine) TroVax® injection i.m. 1 mL Karnofsky score IL-2
 subcutaneous injection (250,000 U/kg/dose) Physical examination

 Week 64 (or 76, 88), days 2-5:

 IL-2 subcutaneous injection (250,000 U/kg/dose)

 Week 65 (or 77, 89), days 1-5:

 Safety testing (blood 10 mL and urine, day 1 only). Immunological evaluation, 10 mL
 sample only (day 1 only) IL-2 subcutaneous injection (125,000 U/kg/dose).

 Weeks 66-69 (or 78-81, or 90-93), days 1-5:

 Safety testing (blood 10 mL and urine, day 1 only). IL-2 subcutaneous injection (125,000
 U/kg/dose).

 Week 71 (or 83 or 95) day 1:

 Physician examination. CT scan.

 Second Cycle:

 Week 72 (or 84, 96), day 1:

 Safety testing (blood 10 mL and urine) TroVax® injection i.m. 1 mL Karnofsky score IL-2
 injection (250,000 U/kg/dose)

 Week 72 (or 84, 96), days 2-5:

 IL-2 injection (250,000 U/kg/dose)

 Week 73 (or 85, 97), days 1-5:

 Safety testing (blood 10 mL and urine, day 1 only). Immunological evaluation, 10 mL
 sample only (day 1 only) IL-2 subcutaneous injection (125,000 U/kg/dose).

 Weeks 74-77 (or 86-89, or 98-101), days 1-5:

 Safety testing (blood and urine, day 1 only). IL-2 subcutaneous injection (125,000
 U/kg/dose).

 Week 79 (or 91 or 103) day 1:

 Physician examination. CT scan.

 After the second cycle of IL-2, if disease has progressed and requires other treatment
 (deterioration in Karnofsky score by 10% or more, disease appears in a new site),
 withdraw patient from trial.

 If the treatment cycles with IL-2 end before week 104 and the patient is responding,
 stable or progressing but not in need of alternative therapies (Karnofsky stable, no new
 disease sites), recommence TroVax® on the original schedule (see Flow Chart). If disease
 is progressing and requires further therapy (deterioration in Karnofsky score by 10% or
 more, disease appears in a new site), withdraw patient from trial.

 Four weeks after the final treatment, all patients will, if possible, attend for a final
 follow up visit. The following will be obtained:

 Physical examination. Karnofsky score Safety testing (blood 10 mL and urine).

 All study visits must occur within +/- 3 days of the day stipulated in the protocol.

 If patients withdraw at any time during the trial, a final follow up visit, if possible,
 will be obtained four weeks after withdrawal.

 Concomitant medication and adverse events will be recorded at each visit.
Inclusion Criteria:

 1. Locally advanced or metastatic, histologically proven clear cell or papillary cell
 renal carcinoma.

 2. Primary tumour surgically removed.

 3. Progressive disease

 4. At least four weeks from any previous therapy for renal cancer.

 5. Fit for first or second line immunotherapy with subcutaneous low dose IL-2

 6. Measurable disease

 7. Aged 18 years or more.

 8. Patients must comply with the following:

 -  Karnofsky score ≥ 80%

 -  Corrected calcium ≥ 10 g/dL (2.5 mmols/L)

 9. Clinically immunocompetent

 10. Free of clinically apparent autoimmune disease.

 11. Haemoglobin ≥ 9 g/dL, total white cell count ≥ 3 x 10^9/L and lymphocyte count ≥ 1 x
 10^9/dL

 12. Serum creatinine up to 1.5 times upper limit of normal.

 13. Bilirubin ≤ 2 mg% and an SGPT of ≤ 4 times the upper limit of normal.

 14. Able to give written informed consent and to comply with the protocol.

 15. 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 while they are being treated with TroVax®.

 16. No acute changes on 12-lead electrocardiogram (ECG)

 17. Ejection fraction on echocardiogram ≥ 45%

 Exclusion Criteria:

 1. Previous immunotherapy with any schedule of IL-2.

 2. Intercurrent serious infections within the 28 days prior to entry into the trial.

 3. Life threatening illness unrelated to cancer.

 4. Cerebral metastases on MRI scan.

 5. History of allergic response to previous vaccinia vaccinations.

 6. Participation in any other clinical trial of a licensed or unlicensed drug within the
 previous 30 days or during the course of this trial.

 7. 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.

 8. Previous history of major psychiatric disorder requiring hospitalisation or any
 current psychiatric disorder that would impede the patient's ability to provide
 informed consent or to comply with the protocol.

 9. Known allergy to egg proteins

 10. Chronic oral corticosteroid use unless prescribed as replacement therapy in the case
 of adrenal insufficiency.

 11. Known to test positive for HIV or hepatitis B or C

 12. Known hypersensitivity to neomycin

 13. Pregnancy or lactation