Sequential Study to Treat Renal Cell Carcinoma
Condition: Renal Cell Carcinoma
MeSH terms: Carcinoma; Carcinoma, Renal Cell
Study type: Interventional
Phase: Phase 3

Summary: 
      Primary:

      To evaluate if progression-free survival from first treatment to progression or death during
      second-line therapy (total PFS) of sorafenib followed by sunitinib is superior compared to
      sunitinib followed by sorafenib.

      Secondary:

        1. Time from first treatment to progression during second-line therapy (total TTP)

        2. Time to first-line treatment failure (progression, death, discontinuation due to
           toxicity) descriptively in each arm

        3. PFS in first-line and second-line treatment, descriptively

        4. Overall survival, descriptively (data cut-off same as for primary endpoint)

        5. Disease Control Rate (DCR); Response rates in first-line and in second-line (CR, PR, SD
           according to RECIST criteria)

        6. Cardiotoxicity analysis by means of echocardiography and NT-pro BNP with an interim
           analysis after 100 patients of each arm have completed the study

        7. Safety and tolerability
    

Detailed description: 
      The results of three sequential retrospective studies (Sablin et al, ASCO 2007; Dham et al,
      ASCO 2007; and Tamaskar et al, 2008) support the sequential administration of sorafenib and
      sunitinib even though these two drugs have an overlap of targets. These results suggest the
      lack of cross resistance between sorafenib and sunitinib. This study is a sequential,
      randomized, open-label (1:1), multicenter phase III study starting in first-line of
      metastatic / advanced RCC using in the experimental arm sorafenib until progression followed
      by sunitinib and in the control arm sunitinib until progression followed by sorafenib.
      Sorafenib-patients will switch to sunitinib and vice versa, with a treatment-free period of
      at least one and up to maximum four weeks after confirmed first-line treatment failure, in
      order to avoid additive toxicity. In general, the first-line treatment should be continued
      until progression (RECIST). However, if patients do not tolerate the first-line medication
      (sorafenib or sunitinib) because of toxicity, they may cross-over to the second-line therapy
      (sunitinib or sorafenib) despite the lack of progression, if an appropriate attempt according
      to a specific dose reduction / interruption scheme has been made to cope with the toxicity
      and try to resume first line therapy, if deemed appropriate with a reduced dose. In case of
      discontinuation of first-line treatment because of toxicity, patients will be enrolled for
      the second-line treatment, only after nonhematological toxicity has resolved to grade ≤1 and
      hematological toxicity to grade ≤2. As an exception, patients who refuse to be treated
      further with the first-line regimen due to intolerability despite having no progression may
      be crossed over to the second-line treatment, if they consent and are in general compliance.
      Any crossover, also without progression, requires a CT scan, which is in this case also
      considered the baseline scan for the second-line treatment. One cycle is of six weeks
      duration. Patients will undergo a CT/MRI scan after every second cycle (i.e. after 12 weeks
      each), which will be evaluated according to RECIST criteria. There will be no continuation of
      the same study medication beyond progression in both first- or second-line therapy. After the
      study reached its primary endpoint cut off, i.e. after 194 endpoint events have occurred,
      clean data for these patients exist and a statistical analysis has been performed data
      collection will be stopped. After that the trial is terminated and a close out visit will be
      performed. Remaining patients will be treated outside the study and will be censored in the
      analysis.
    

Intervention name(s): Sunitinib (Sutent); Sorafenib (Nexavar)
Intervention type(s): Drug; Drug
Intervention description(s): Sunitinib 50 mg once daily 4 weeks on, 2 weeks off, and after discontinuation (due to PD or toxicity), followed by sorafenib 400 mg BID; Sorafenib 400 mg BID, followed by Sunitinib 50 mg once daily 4 weeks on, 2 weeks off, and after discontinuation (due to PD or toxicity)
Intervention MeSH terms: Sorafenib; Sunitinib
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Renal Cell Carcinoma; Sunitinib; Sorafenib; Sequential