Efficacy and Safety of Bevacizumab/Temsirolimus Combination to Treat Advanced Renal Cell Carcinoma

• Progression Free Survival (PFS) [ Time Frame: Tumor assessments will be performed every 8 weeks during treatment and at discontinuation, unless it was performed within the last 4 weeks ] [ Designated as safety issue: No ]
  PFS will be calculated from date of treatment initiation until disease progression or death (whichever occurs first)
• Overall Survival (OS) [ Time Frame: 48 months ] [ Designated as safety issue: No ]
  OS will be calculated from the date of treatment initiation to the date of death or last contact
• Response Rate (RR) [ Time Frame: Tumor assessments will be performed every 8 weeks during treatment and at discontinuation, unless it was performed within the last 4 weeks ] [ Designated as safety issue: No ]
  RR is defined as the overall percentage of patients with partial (PR) or complete response (CR). The evaluation of responses will be performed according to RECIST criteria
• Tumor Shrinkage [ Time Frame: Tumor assessments will be performed every 8 weeks during treatment and at discontinuation, unless it was performed within the last 4 weeks ] [ Designated as safety issue: No ]
  Tumor shrinkage will be computed using waterfall plots
• Adverse Events (AEs) of all participants will be recorded and assessed upon signature of the informed consent form, until 30 days after the last administration of study treatment. [ Time Frame: 3 years ] [ Designated as safety issue: Yes ]
  Adverse Events will be graded according to the NCI CTCAE v3.0 criteria and will be reported in a frequency table according to the highest severity grade observed per patient
• Quality of Life (QoL) assessment [ Time Frame: At baseline and every 8 weeks during treatment ] [ Designated as safety issue: No ]
  QoL will be assessed using the EORTC QLQ C-30 questionnaire. The change in the QoL during treatment will be estimated using the Wilcoxon paired t-test
• Investigation of antiangiogenic factors (FGF, VEGF, VEGFRR) [ Time Frame: 36 months ] [ Designated as safety issue: No ]
  Changes in serum levels of antiangiogenic factors during treatment and correlation to the outcome of study treatment.

• Progression Free Survival (PFS) [ Time Frame: Tumor assessments will be performed every 8 weeks during treatment and at discontinuation, unless it was performed within the last 4 weeks ] [ Designated as safety issue: No ]
  PFS will be calculated from date of treatment initiation until disease progression or death (whichever occurs first)
• Overall Survival (OS) [ Time Frame: 42 months ] [ Designated as safety issue: No ]
  OS will be calculated from the date of treatment initiation to the date of death or last contact
• Response Rate (RR) [ Time Frame: Tumor assessments will be performed every 8 weeks during treatment and at discontinuation, unless it was performed within the last 4 weeks ] [ Designated as safety issue: No ]
  RR is defined as the overall percentage of patients with partial (PR) or complete response (CR). The evaluation of responses will be performed according to RECIST criteria
• Tumor Shrinkage [ Time Frame: Tumor assessments will be performed every 8 weeks during treatment and at discontinuation, unless it was performed within the last 4 weeks ] [ Designated as safety issue: No ]
  Tumor shrinkage will be computed using waterfall plots
• Adverse Events (AEs) of all participants will be recorded and assessed upon signature of the informed consent form, until 30 days after the last administration of study treatment. [ Time Frame: 3 years ] [ Designated as safety issue: Yes ]
  Adverse Events will be graded according to the NCI CTCAE v3.0 criteria and will be reported in a frequency table according to the highest severity grade observed per patient
• Quality of Life (QoL) assessment [ Time Frame: At baseline and every 8 weeks during treatment ] [ Designated as safety issue: No ]
  QoL will be assessed using the EORTC QLQ C-30 questionnaire. The change in the QoL during treatment will be estimated using the Wilcoxon paired t-test
• Investigation of antiangiogenic factors (FGF, VEGF, VEGFRR) [ Time Frame: 36 months ] [ Designated as safety issue: No ]
  Changes in serum levels of antiangiogenic factors during treatment and correlation to the outcome of study treatment.

The purpose of this study is to determine whether the combination of bevacizumab/temsirolimus is effective in patients with advanced renal carcinoma progressing after anti-VEGF treatment

• Drug: Bevacizumab
  Bevacizumab 10mg/kg intravenous every 2 weeks until disease progression, unacceptable toxicity or consent withdrawal.
• Drug: Temsirolimus
  Temsirolimus 25mg intravenous once weekly until disease progression, unacceptable toxicity or consent withdrawal.

Inclusion Criteria:

• Adult patients (18th year of age completed)
• Signed and dated written informed consent form prior to any procedures related to this protocol.
• Histologically confirmed advanced clear cell renal cancer.
• Measurable disease.
• Failure of first line anti-VEGF treatment.
• Performance status 0-2, according to Eastern Cooperative Oncology Group (ECOG) .

• Satisfactory hematological parameters:

  • White blood cell count > 4000 mm3.
  • Platelet count 100000/mm3.
  • Neutrophil blood cell count > 1200/ mm3 .
  • Hemoglobin > 9,0 g/dL (can be achieved with red blood cell transfusion).

• Satisfactory biochemical parameters:

  • Serum creatinine < 2 x Upper Limit of Normal(ULN)
  • Aspartate Aminotransferase (AST)<2,5 x ULN
  • Alanine Transaminase (ALT)< 2,5 x ULN.
  • Bilirubin <2 x ULN
• (For female patients) Absence of pregnancy (negative pregnancy test for women of reproductive age before enrollment).
• (For female patients) Non-lactating women.
• Use of efficient contraceptive measures (women and men) to prevent possible pregnancy of female patient or female partner of a male patient during treatment and until 6 months after the end of treatment.

Exclusion Criteria:

• Prior treatment with mTOR inhibitor.
• Major surgery (including open biopsy) or insufficient recovery or existence of major trauma within 4 weeks before enrollment.
• Uncontrolled hypertension.
• Active infection requiring systemic treatment within 4 weeks prior to enrollment.
• Minor surgery (for instance, catheter placement) within 2 days before enrollment.
• Scheduled major surgery within the treatment period.
• Medical history in the last 6 months prior to enrollment of significant cardiovascular disease, diabetes, cardiac infarction, unstable angina, uncontrolled arrhythmia or significant heart failure.
• Indications of uncontrolled metastases or disease progression in CNS lesions (the suspicion of uncontrolled metastases or disease progression should be eliminated by imaging techniques within 14 days prior to enrollment).
• Medical history in the last 5 years prior to enrollment of any other malignancies (excluding the basal or squamous skin cell carcinoma or in situ carcinoma of the cervix).
• History of non-healing wound including active gastric ulcer.
• History of fistula in the last 6 months prior to enrollment.
• History of gastrointestinal perforations.
• Patient incapacity (for psychiatric or social reasons) to conform with the protocol.
• History of hemorrhagic predisposition.
• History of hypersensitivity to the medications under investigation.
• Significant proteinurea.
• Prior immunotherapy within 4 weeks prior to enrollment.
• Prior radiation treatment within 2 weeks prior to enrollment.
• Concomitant medication with inducers or strong inhibitors of the coenzyme CYP3A4 (see Appendix 5 for an indicative list of active compounds).
• Concurrent participation in other interventional clinical trials with investigational medicinal products.
• History of chronic interstitial lung disease.