PRednisone Plus EVerolimus in Patients With Metastatic Renal Cell Cancer After Failure of VEGFR -TKI

Phase II Study of Oral PRednisone 5 mg Bid Plus EVerolimus in Patients With Metastatic Renal Cell Cancer After Failure of Vascular Endothelial Growth Factor Receptor-tyrosine Kinase Inhibitors

This is a multicenter prospective study that includes all patients with metastatic Renal Cell Cancer (RCC) pre- treated with VEGFR TKI in eight Italian cancer centers.

Everolimus is formulated as tablets of 5-10 mg strength, blister-packed under aluminium foil in units of 10 tablets. Prednisone will be dispensed to patients at the dose of 5 mg twice daily (BID). Everolimus at dose of 10 mg (one 10 mg tablet or two 5 mg tablets). Both drugs will be self-administered orally, continuously from Day 1 (Visit 2) until progression of disease, unacceptable toxicity, death or discontinuation for any other reason.

A treatment cycle consists of 28 days.

Title Phase II study of oral PRednisone 5 mg bid plus EVerolimus in patients with metastatic renal cell cancer after failure of vascular endothelial growth factor receptor-tyrosine kinase inhibitor (PREV study).

Short Title/ Acronym PREV Protocol Code IRST189.04 Phase Phase 2 Study Design This is a multicenter prospective study that includes all patients with metastatic RCC pre- treated with VEGFR TKI in eight Italian cancer centers.

Study Duration 2 years of recruitment and 1 year of follow-up Study Center(s) multi-center: 8 centers involved

Objectives Primary objective:

To evaluate the safety and tolerability of prednisone 5 mg bid and everolimus 10 mg/day in RCC.

Secondary objectives:

To evaluate the activity and the clinical outcome of these patients.

Exploratory objectives:

To evaluate the influence of prednisone on trough concentration of everolimus and correlation with the incidence of side effects, in particular stomatitis and non-infectious pneumonitis.

Infiammation markers such as pentraxin 3 (PTX3), IL-6, TGF-β and neutrophil-lymphocyte ratio will be correlated with clinical outcome (ORR, PFS, OS).

Number of Subjects 42 subjects Diagnosis and Main Inclusion Criteria Patients with mRCC who failed at least one VEGFR TKI.

Main Inclusion Criteria:

• Patients with renal cell carcinoma who failed at least one VEGFR TKI
• Patients with adequate bone marrow function
• Patients with adequate liver function
• Patients with adequate renal function Diagnosis and Main Inclusion Criteria (continued) Main exclusion criteria:
• CNS disease OR patients with presence or history of central nervous system (CNS) lymphoma
• Patients receiving chronic, systemic treatment with corticosteroids or another immunosuppressive agent (except corticosteroids with a daily dosage equivalent to prednisone ≤ 20 mg for adrenal insufficiency). However, patients receiving corticosteroids must be on a stable dose for ≥ 4 weeks prior to the first dose of everolimus. Topical or inhaled corticosteroids are permitted.
• Patients with a known hypersensitivity to everolimus or other rapamycins (sirolimus, temsirolimus) or to its excipients
• Patients with uncontrolled hyperlipidemia (≥ Grade 3 hyperlipidemia despite optimal supportive medical therapy)
• Patients with an active, bleeding diathesis
• Previous organ transplantation
• Patients who have any severe and/or uncontrolled medical conditions or other conditions that could affect their participation in the study Study Product, Dose, Route, Regimen and duration of administration Everolimus is formulated as tablets of 5-10 mg strength, blister-packed under aluminium foil in units of 10 tablets. Prednisone will be dispensed to patients at the dose of 5 mg twice daily (BID). Everolimus at dose of 10 mg (one 10 mg tablet or two 5 mg tablets). Both drugs will be self-administered orally, continuously from Day 1 (Visit 2) until progression of disease, unacceptable toxicity, death or discontinuation for any other reason.

A treatment cycle consists of 28 days. Reference therapy Not applicable Statistical Methodology This is a multicenter prospective study that includes all patients with metastatic RCC pre- treated with VEGFR TKI in eight Italian cancer centers.

The study will be analyzed on an intent-to-treat basis. Secondary parameters will be analyzed exploratively for the intent-to-treat population.

Inclusion Criteria:

1. Age ≥ 18 years old
2. Patients with histopathologically confirmed diagnosis of renal cell carcinoma
3. Patients with renal cell carcinoma who failed at least one VEGFR TKI
4. Patients with adequate bone marrow function defined as ANC ≥ 1.5 x 109/L, Platelets ≥ 80 x 109/L, Hb >9 g/dL
5. Patients with adequate liver function defined as serum bilirubin ≤ 1.5 x ULN, ALT and AST ≤ 2.5x ULN. Patients with known liver metastases who have an AST and ALT ≤ 5x ULN
6. Patients with adequate renal function defined as serum creatinine ≤ 1.5 x ULN
7. Patients who give a written informed consent obtained according to local guidelines

Exclusion Criteria:

1. CNS disease OR patients with presence or history of central nervous system (CNS) lymphoma

2. Patients receiving chronic, systemic treatment with corticosteroids or another immunosuppressive agent (except corticosteroids with a daily dosage equivalent to prednisone ≤ 20 mg for adrenal insufficiency). However, patients receiving corticosteroids must be on a stable dose for ≥ 4 weeks prior to the first dose of everolimus. Topical or inhaled corticosteroids are permitted.

3. Patients with a known hypersensitivity to everolimus or other rapamycins (sirolimus, temsirolimus) or to its excipients

4. Patients with uncontrolled hyperlipidemia (≥ Grade 3 hyperlipidemia despite optimal supportive medical therapy)

5. Patients with an active, bleeding diathesis

6. Previous organ transplantation

7. Patients who have any severe and/or uncontrolled medical conditions or other conditions that could affect their participation in the study such as:

   • unstable angina pectoris, symptomatic congestive heart failure, myocardial infarction within 6 months of start of study drug, serious uncontrolled cardiac arrhythmia or any other clinically significant cardiac disease
   • severely impaired lung function (spirometry and DLCO that is 50% of the normal predicted value and/or Oxygen saturation that is 88% or less at rest, in room air)
   • uncontrolled diabetes as defined by fasting serum glucose >1.5 x ULN
   • any active (acute or chronic) or uncontrolled infections/disorders
   • non malignant medical illnesses that are uncontrolled or whose control may be jeopardized by the treatment with this study therapy
   • liver disease such as cirrhosis or severe hepatic impairment (Child-Pugh class C).
   • Note: a detailed assessment of Hepatitis B/C medical history and risk factors must be done at screening for all patients. HBV DNA and HCV RNA PCR testing are required at screening for all patients with a positive medical history based on risk factors and/or confirmation of prior HBV/HCV infection.

8. A known history of HIV seropositivity

9. Female patients who are pregnant or breast feeding, or adults of reproductive potential who are not willing to use effective birth control methods. If barrier contraceptives are used, they must be continued throughout the treatment by both sexes.

10. Patients unwilling to or unable to comply with the protocol