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A Phase III Randomized Sequential Open-Label Study to Evaluate the Efficacy and Safety of Sorafenib Followed by Sunitinib Versus Sunitinib Followed by Sorafenib in the Treatment of First-Line Advanced / Metastatic Renal Cell Carcinoma

Phase 3
18 Years
85 Years
Open (Enrolling)
Renal Cell Carcinoma

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Trial Information

A Phase III Randomized Sequential Open-Label Study to Evaluate the Efficacy and Safety of Sorafenib Followed by Sunitinib Versus Sunitinib Followed by Sorafenib in the Treatment of First-Line Advanced / Metastatic Renal Cell Carcinoma

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 231 disease
progressions under second-line therapy 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.

Inclusion Criteria:

1. Patients with metastatic / advanced RCC (all histologies), who are not suitable for
cytokine therapy and for whom study medication constitutes first-line therapy

2. Age >= 18 ans <= 85years

3. ECOG Performance Status of 0 or 1

4. MSKCC prognostic score, low or intermediate

5. Life expectancy of at least 12 weeks.

6. Subjects with at least one uni-dimensional (for RECIST) measurable lesion. Lesions
must be measured by CT/MRI-scan.

7. Adequate bone marrow, liver and renal function as assessed by the following
laboratory requirements to be conducted within 7 days prior to start of therapy:

- Hemoglobin >= 9.0 g/dl

- Absolute neutrophil count (ANC) >= 1,500/mm³

- Platelet count >= 100,000/μl

- Total bilirubin <= 1.5 times the upper limit of normal

- ALT and AST <= 2.5 x upper limit of normal (<= 5 x upper limit of normal for
patients with liver involvement of their cancer)

- Alkaline phosphatase < 4 x upper limit of normal

- PT-INR/PT < 1.5 x upper limit of normal [Patients who are being therapeutically
anticoagulated with an agent such as coumadin or heparin will be allowed to
participate provided that no prior evidence of underlying abnormality in these
parameters exists.]

- Serum creatinine <= 2 x upper limit of normal.

8. Written Informed Consent

Exclusion Criteria:

1. History of cardiac disease: congestive heart failure >NYHA class 2 or with LVEF at
baseline echocardiography < 50%; active CAD (MI more than 6 months prior to study
entry is allowed); cardiac arrhythmias requiring anti-arrhythmic therapy (beta
blockers or digoxin are permitted) or uncontrolled hypertension (defined as blood
pressure >= 160 mmHg systolic and/or >= 90 mmHG diastolic on medication).

2. History of HIV infection or chronic hepatitis B or C

3. Active clinically serious infections (> grade 2 NCI-CTC version 3.0)

4. Symptomatic metastatic brain or meningeal tumors (unless the patient is > 6 months
from definitive therapy, has a negative imaging study within 4 weeks of study entry
and is clinically stable with respect to the tumor at the time of study entry)

5. Patients with seizure disorder requiring medication (such as steroids or

6. History of organ allograft

7. Patients with evidence or history of bleeding diathesis

8. untreated hypothyrosis

9. Patients undergoing renal dialysis

10. Previous or concurrent cancer that is distinct in primary site or histology from the
cancer being evaluated in this study EXCEPT cervical carcinoma in situ, treated basal
cell carcinoma, superficial bladder tumors [Ta, Tis & T1] or any cancer curatively
treated > 3 years prior to study entry.

11. Pregnant or breast-feeding patients. Women of childbearing potential must have a
negative pregnancy test performed within 7 days of the start of treatment. Both men
and women enrolled in this trial must use adequate barrier birth control measures
during the course of the trial and 3 months after the completion of trial.

12. Substance abuse, medical, psychological or social conditions that may interfere with
the patient's participation in the study or evaluation of the study results

13. Any condition that is unstable or could jeopardize the safety of the patient and
their compliance in the study

14. Patients unable to swallow oral medications

15. Known allergy to sunitinib or sorafenib or one of its constituents

Excluded therapies and medications, previous and concomitant:

1. Anticancer chemotherapy or immunotherapy during the study or within 4 weeks of study

2. Radiotherapy during study or within 3 weeks of start of study drug. (Palliative
radiotherapy will be allowed). Major surgery within 4 weeks of start of study

3. Autologous bone marrow transplant or stem cell rescue within 4 months of study

4. Use of biologic response modifiers, such as G-CSF, within 3 week of study entry.

[G-CSF and other hematopoietic growth factors may be used in the management of acute
toxicity such as febrile neutropenia when clinically indicated or at the discretion
of the investigator; however they may not be substituted for a required dose
reduction.] [Patients taking chronic erythropoietin are permitted provided no dose
adjustment is undertaken within 2 months prior to the study or during the study]

5. Investigational drug therapy outside of this trial during or within 4 weeks of study

6. Prior exposure to the study drug.

7. Any St. John's wort containing remedy

Type of Study:


Study Design:

Allocation: Randomized, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

total Progression Free Survival

Outcome Time Frame:

Last patient last visit (LPLV) to June 2013

Safety Issue:



Germany: Federal Institute for Drugs and Medical Devices

Study ID:




Start Date:

January 2009

Completion Date:

November 2013

Related Keywords:

  • Renal Cell Carcinoma
  • Renal Cell Carcinoma
  • Sunitinib
  • Sorafenib
  • Sequential
  • Carcinoma
  • Carcinoma, Renal Cell