Radiotherapy As an Immunological Booster in Patients with Metastatic Melanoma or Renal Cell Carcinoma Treated with High-dose Interleukin-2

Title: Radiotherapy as an immunological booster in patients with metastatic melanoma or renal cell carcinoma treated with High-dose Interleukin-2: evaluation of biomarkers of immunologic and therapeutic response

Phase: Proof of Principle phase II study

Study Design: Single center, open-label trial to assess the immune response and potential biomarkers predictive of response

Study Duration:

Total duration: 36 months Enrollment: 20 months Treatment: 5 months per patient Follow-up every three months

Number of Subjects:

Mini-max two-stage Simon design:

• Step 1: 7 patients enrolled

If tumor antigen-specific immune response is observed in at least 3 patients:

• Step 2: recruitment of an additional 12 patients

Title: Radiotherapy as an immunological booster in patients with metastatic melanoma or renal cell carcinoma treated with High-dose Interleukin-2: evaluation of biomarkers of immunologic and therapeutic response

Phase: Proof of Principle phase II study

Study Design: Single center, open-label trial to assess the immune response and potential biomarkers predictive of response

Study Duration:

Total duration: 36 months Enrollment: 20 months Treatment: 5 months per patient Follow-up every three months

Primary objectives:

1. to determine the tumor antigen-specific immune response induced by the treatment
2. to prospectively determine the predictive/prognostic value of pretreatment biological features in identifying patients who will benefit from HDIL-2-based therapy

Secondary end points:

1. Toxicity
2. Response Rate
3. Overall Survival.

Number of Subjects:

Mini-max two-stage Simon design:

• Step 1: 7 patients enrolled

If tumor antigen-specific immune response is observed in at least 3 patients:

• Step 2: recruitment of an additional 12 patients

Study Product, Dose, Route, Regimen and duration of administration:

Three daily doses boost radiotherapy (XRT) at 6-12 Gy to at least 1, and up to a maximum of 5, metastatic fields, will be administrated on days -4 -3 -2 or -3 -2 -1 before the first and the third cycle of IL-2. The first day of administration of IL-2 of each cycle is the day +1.

Treatment with IL-2 (dose 18 MIU/m2/day in 500cc by continuous IV infusion for 72 hours) will start on day +1 and will be administered every 3 weeks up to 4 cycles, than every 3-4 weeks for a further 2 cycles.

IL-2 will be withheld for refractory hypotension (hypotension where isotropic or vasoactive therapy is ineffective and that persists despite specific medical therapy set), anuria for \> 24 hours, respiratory distress, confusion, sustained ventricular tachycardia, signs of myocardial ischemia or myocarditis, persistant metabolic acidosis, atrial fibrillation and documented systemic infection.

Patients will be evaluated every 8 weeks with computed tomography to determine the response, and every 3 months after completion of treatment until death (the time of disease progression and the initiation of alternative therapies will also be documented).

Statistical Methodology:

A minimax two-stage Simon design will be employed. A 40% immune response will preclude further study, whereas a 70% response rate will indicate that further study would be warranted. Using alfa and beta errors of 0.10, 7 patients will be enrolled during the first stage, and if an immune response is observed in at least 3 patients the study will go on, and an additional 12 patients will be treated. The treatments will be considered active if a tumor antigen-specific immune response is observed in 11 out of 19 patients treated. The analysis will be performed on an intention to treat population, i.e. all patients having received at least one cycle of therapy.

Eligibility Criteria:
Inclusion Criteria:

1. Patients must have histologically or cytologically confirmed non resectable stage III or IV advanced melanoma or Renal Cell Carcinoma (RCC).
2. Patients must have a minimum of two lesions and one of which must be measurable, (it can be accurately measured in at least one dimension (longest diameter to be recorded) as \>20 mm with conventional techniques or as \>10 mm with spiral CT scan).
3. At least one tumor lesion accessible for bioptic sampling.
4. Prior lines (maximum 4) of chemotherapy, immunotherapy or biological therapy (e.g. inhibitors of B-Raf or c-Kit, Ipilimumab, etc.) for advanced disease are allowed (patients must have finished prior treatments at least 4 weeks before the first IL2 dose);
5. Male or Female, aged \>= 18 years.
6. Life expectancy of greater than 3 months.
7. ECOG performance status \<=1
8. Patients must have normal organ and marrow function as defined below:

   * leukocytes \>=3,500/microL
   * absolute neutrophil count \>=1,500/microL
   * platelets \>= 100,000/microL
   * total bilirubin within normal institutional limits
   * AST(SGOT)/ALT(SGPT) \<=2.5 X institutional upper limit of normal
   * creatinine \< 1,2 mg/dl
   * haemoglobin \> 9.0 gm/dl
   * ECG and echocardiogram within normal institutional limits
   * Pulmonary function tests within normal institutional limits (to be performed only in patients with lung metastases or history of impaired lung function)
9. no contraindication for the use of vasopressor agents
10. Female participants of child bearing potential and male participants whose partner is of child bearing potential must be willing to ensure that they or their partner use effective contraception during the study and for 3 months thereafter
11. Participant is willing and able to give informed consent for participation in the study.

Exclusion Criteria:

1. Patient with stage I or II melanoma or RCC
2. Patients who have had chemotherapy or radiotherapy or immunotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier.
3. Participation in another clinical trial with any investigational agents within 30 days prior to study screening.
4. Patients with known brain metastases should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events.
5. History of allergic reactions attributed to compounds of similar chemical or biologic composition to IL-2 or other agents used in the study.
6. Any autoimmune disease which could be exacerbated by IL-2
7. A medical illness requiring chronic treatments with corticosteroids or other immunosuppressive agents
8. A history of significant cardiovascular disease, including myocardial infarction, congestive heart failure, primary cardiac arrhythmias, angina pectoris or cerebrovascular accident
9. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
10. Other known malignant neoplastic diseases in the patient's medical history with a disease-free interval of less than 5 years (except for previously treated basal cell carcinoma and in situ carcinoma of the uterine cervix);
11. HIV-positivity, whether or not symptomatic.