Everolimus in Patients With Metastatic Renal Cell Carcinoma Following Progression on Prior Bevacizumab Treatment
Condition: Metastatic Renal Cell Carcinoma
MeSH terms: Carcinoma; Carcinoma, Renal Cell
Study type: Interventional
Phase: Phase 4

Summary: 
      An estimated 10,000 metastatic renal cell carcinoma (RCC) patients receive first-line therapy
      in the Russian Federation. Bevacizumab (Avastin) in combination with interferon-alpha (IFN)
      is a recommended first-line treatment for metastatic RCC according to clinical
      recommendations of Russian Ministry of Health from 15.07.2010. Two randomized phase III
      trials (AVOREN, CALGB) showed that 50% of patients will progress on bevacizumab plus IFN
      within 8.5 - 10.2 months and will need sequential therapy.

      Everolimus (Afinitor) is a single agent which was evaluated and demonstrated efficacy in
      randomized phase III study (RECORD-1) in metastatic RCC patients after failure of targeted
      therapy. However, in this trial everolimus was compared with placebo for the treatment of
      patients whose disease had progressed on treatment with sunitinib or sorafenib (n=227). Only
      9% (n=24) of patients received bevacizumab. Thus, efficacy data of everolimus in patients
      with disease progression on first-line bevacizumab is limited.

      Evaluating the effectiveness of everolimus in metastatic RCC patients with failure on
      bevacizumab with/without interferon alpha has a scientific and practical sense, and it is
      important for Russian Federation.
    

Detailed description: 
      17563 new cases of renal cancer and 83790 associated deaths have recorded in the Russian
      Federation in 2008. Renal cell carcinoma (RCC) is responsible for 4,3% of all malignancies,
      with increased risk of disease after the age of 60 years. Renal cell carcinoma accounts for
      90% renal neoplasms, and in 85% of renal cell carcinoma cases light-cell morphology is
      diagnosed. Papillary, chromophobic cancer and cancer of the kidney collecting tubules.

      30% patients with localized renal cell carcinoma are found to progress after surgical
      treatment. In the other 30% renal cell carcinoma is established at the dissemination stage.
      Therefore approximately 60% of renal cell carcinoma patients are estimated to have
      metastases.

      According to estimations by Kidney Cancer Research Bureau, currently first line treatment is
      indicated to approximately 10,000 patients with metastatic renal cell carcinoma in Russia
      annually.

      Until recently opportunities for systemic treatment in metastatic renal cell carcinoma were
      limited to administration of cytokines and clinical research investigating novel medications.
      Various combinations and doses of interleukin-2 (IL-2) and interferon-alpha (IFN) have been
      investigated in randomized studies in metastatic renal cell carcinoma. Immunotherapy was
      found to have only limited efficacy (overall response rate 15-16%, survival of 12 months).
      Therefore target medicines, specifically - tyrosine kinase inhibitors and mTOR inhibitors,
      are under development as first and subsequent lines of treatment.

      According to standards of medical care established by the Ministry of Health and Social
      Development of the Russian Federation as of July 15, 2010, combination of bevacizumab
      (Avastin™) and interferon is recommended as first line treatment. According to two randomized
      phase III trials (AVOREN, CALGB) more than half of patients are expected to require further
      treatment for disease progression in 8,5-10,2 months. Everolimus (Afinitor) is the only
      medicine that has been investigated in a phase III multicenter study (RECORD-1) as second and
      subsequent lines of treatment for metastatic renal cell carcinoma resistant to targeted
      agents. However, most patients (n=277) had received sunitinib or sorafenib prior to
      enrolment; only some of them (24 patients (9%) had received bevacizumab. Therefore currently
      convincing evidence of everolimus efficacy after progression on prior treatment with
      bevacizumab or bevacizumab + IFN is lacking.

      Hence it is deemed reasonable and practically relevant to investigate everolimus efficacy in
      patients with metastatic renal cell carcinoma previously treated on bevacizumab-containing
      regimens, in the Russian Federation.

      Efficacy endpoints

      Primary:

      Primary endpoint is the proportion of progression-free patients for 2 months (based on
      results of a phase III study)

      Secondary:

      Median progression-free survival and overall survival from the time of enrolment Response
      rate, according to RECIST 1.1 Treatment safety and tolerability according to NCI-CTCAE v.4.0
      Patients quality of life, according to EORTC QLQ-C30 questionnaire
    

Intervention name(s): Everolimus
Intervention type(s): Drug
Intervention description(s): All patients with metastatic renal cell carcinoma progressing on prior treatment with bevacizumab ± interferon enrolled into this study will receive everolimus in the dose of 10 mg daily until the disease progression or unacceptable toxicity.
Intervention MeSH terms: Everolimus
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: renal cell carcinoma; kidney cancer; bevacizumab failure; everolimus