Primary:To evaluate if progression-free survival from randomization to progression or death during second-line therapy (total PFS) of sorafenib followed by pazopanib is non-inferior compared to pazopanib followed by sorafenib.Secondary:1. Time from…
ID
Source
Brief title
Condition
- Renal and urinary tract neoplasms malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Total Progression Free Survival
Secondary outcome
1. Time from randomization 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. Health-related Quality of Life (FACIT-F, FKSI-10)
7. Veiligheid en verdraagbaarheid
Background summary
Renal cell carcinoma (RCC) is the most common cancer of the kidney and accounts
for 2 % of all cancers. Up to 30% of patients with RCC present with metastatic
disease. When distant metastases are present, disease-free survival is poor.
Surgical resection is the mainstay of treatment. Even in patients with
disseminated tumor, surgical resection of tumor mass may have a positive impact
on survival. RCC is highly resistant to chemotherapy.
Approximately 50 % of patients with RCC develop metastatic disease. The median
survival of these patients is approximately 1 year, and survival at 2 years is
10 % or less in most studies. Metastatic RCC is resistant to chemotherapy.
Spontaneous regressions have been reported in some patients.
Interleukin-2 (IL-2) and interferon alpha-2a (IFN -2a) have shown tumor
response. However, i. v. IL-2 induces severe side effects. Only 20 % of the
patients benefit from high-dose IL-2 and/or IFN -2a.
Median overall survival (OS) following progression after cytokine therapy is
approximately 10 to13 months, and no effective treatment was available until a
few years ago for patients whose disease progresses after an initial response
or who did not respond to cytokine therapy.
A growing understanding of the underlying biology of RCC has identified
vascular endothelial growth factor (VEGF), platelet-derived growth factor
(PDGF), mTOR (mammalian target of rapamycin), and a number of other
hypoxia-inducible proteins as logical therapeutic targets. In fact, while
IFN(interferon)-based immunotherapy and high-dose immunotherapy with
intravenous interleukin-2 represented the standard of care until the past few
years, agents such as sorafenib, sunitinib, pazopanib, bevacizumab (in
combination with IFN), emsirolimus, and everolimus now dominate the treatment
in mRCC.
Sorafenib and pazopanib are both effective and promising treatments for
advanced RCC. Both drugs are registered for this indication. No prospective
comparative data in advanced RCC (or other indications) have been published. As
sequential therapy is now the standard of treatment for advanced RCC it is
important to evaluate in clinical trials what the value of different sequential
strategies is. As there are no data yet on the sequential use of sorafenib
followed by pazopanib or vice versa, this sequence, however, will most
certainly be used in daily practice, it is required to examine efficacy and
safety of this sequential approach in a clinical trial in a randomized setting.
Study objective
Primary:
To evaluate if progression-free survival from randomization to progression or
death during second-line therapy (total PFS) of sorafenib followed by pazopanib
is non-inferior compared to pazopanib followed by sorafenib.
Secondary:
1. Time from randomization 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. Health-related Quality of Life (FACIT-F, FKSI-10)
7. Veiligheid en verdraagbaarheid
Study design
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 pazopanib and in the
control arm pazopanib until progression followed by sorafenib.
Sorafenib-patients will switch to pazopanib and vice versa, with a
treatment-free period of at least seven and up to maximum 28 days after
confirmed first-line treatment failure, in order to avoid additive toxicity. In
general, the first-line treatment should be continued until progression (RECIST
1.1). However, if patients do not tolerate the first-line medication (sorafenib
or pazopanib) because of toxicity, they may cross-over to the secondline
therapy (pazopanib 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, onlyafter non-hematological 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 cross-over, 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 four weeks duration. Patients will undergo a CT/MRI scan after
every second cycle (i.e. after 8 weeks each), which will be evaluated according
to RECIST 1.1 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 383 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.
Intervention
Arm 1:
Sorafenib 400 mg bid orally until progression or intolerable toxicity, followed
by pazopanib 800 mg once daily orally until progression or intolerable toxicity
Arm 2:
Pazopanib 800 mg once daily orally until progression or intolerable toxicity,
followed by Sorafenib 400 mg bid orally until progression or intolerable
toxicity
During first- and second-line, treatment visits are scheduled in weeks 0, 2, 4,
8, 12, and every 4 weeks thereafter, with tumor assessments and
electrocardiogram after every second cycle (every 8 weeks).
Study burden and risks
Study assessments will be performed at screening, CxD1, C1D15, C1D3, CxD28
(only the even numbered cycles), stop first line therapy. Treatment duration
will continue until disease progression, unacceptable toxicity, patient
withdrawal of consent, death, or discontinuation from the study for any other
reason, whereupon all patients will complete the End of Treatment visit ± 7
days after last study medication. FU will take place every 3 months
Please refer to the Flowchart of the protocol.
Risks:
*Toxicity due to the use of the studymedication.
*Reaction to the use of contrast fluid (used for CT/MRI scans
*Possible side effects of blood sampling (bruises, bleeding, bloodclots,
infection)
*Exposure to radiation with X-rays
Ismaninger Str. 22
München 81675
DE
Ismaninger Str. 22
München 81675
DE
Listed location countries
Age
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
treatment. For cytokine-unsuitability at least one of the following criteria must be
fulfilled*:
* Age 66 to 88 years
* Non-clear cell histology RCC
* Intermediate risk according to MSKCC score
* ECOG * 1 and> 1 organ metastasis + < 24 months between diagnosis and
establishing indication for interleukin-2-therapy
* ECOG * 1 and *unable to carry on normal activity or do active work*
(Karnofsky Index 70%)
* Creatinine * 1x ULN and < 2x ULN
* Total bilirubin * 1x ULN and < 1.5x ULN
* Present autoimmune disease
* Patients who might require steroids
* Hypersensitivity against cytokines
* Severe organic disease, not interfering with other in-/exclusion criteria of the
Switch-2 study
* Non-symptomatic brain metastases
* Severe lung disease (e.g. PAH, COPD) with Pa O2 < 60 mmHg on rest
2. Age * 18 and * 85 years
3. Karnofsky Index * 70% (see appendix *15.1 Performance Status (ECOG,
Karnofsky)*)
4. MSKCC prognostic score (2004), low or intermediate (see appendix *15.2
Motzer Scoring*)
5. Life expectancy of at least 12 weeks
6. Subjects with at least one uni-dimensional (for RECIST 1.1, see appendix *15.3
RECIST 1.1) 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/*l
* Platelet count * 100,000/*l
* Total bilirubin < 1.5x the upper limit of normal (Note: Subjects with Gilbert*s
Syndrome are eligible if their total bilirubin is <3.0 X ULN and direct bilirubin
is * 35%.)
* ALAT and ASAT < 2.5x upper limit of normal (Note: concomitant elevations in
bilirubin and ASAT/ALAT above 1.0x upper limit of normal are not permitted).
* Alkaline phosphatase < 4x upper limit of normal
* PT-INR/aPTT < 1.2x 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 their INR is stable and within the
recommended range for the desired level of anticoagulation and no prior
evidence of underlying abnormality in these parameters exists.]
* Serum creatinine < 2 x upper limit of normal
8. Written Informed Consent
_____________________________________________________________________
*Based on references:
o Kirchner H., H. Heinzer, J. Roigas und F. Overkamp: Differentialtherapie beim
metastasierenden Nierenzellkarzinom. Der Onkologe 2008; 14: 191-197;
o SmPC of interleukin-2
o SmPC of interferon alfa -2a
Exclusion criteria
1. History of cardiac disease: congestive heart failure >NYHA class 2 or with LVEF at
baseline echocardiography < 50% (echocardiography is optional); 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)
2. Uncontrolled hypertension (defined as blood pressure * 150 mmHg systolic and/or
* 90 mmHg diastolic on medication).
3. History of HIV infection or chronic hepatitis B or C
4. Active clinically serious infections (> grade 2 NCI-CTC version 4.03)
5. 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)
6. Patients with seizure disorder requiring medication (such as steroids or antiepileptics)
7. Patients with evidence or history of bleeding diathesis
8. History of organ allograft
9. Major surgery within 4 weeks of start of study
10. Autologous bone marrow transplant or stem cell rescue within 4 months before
study start.
11. Any significant condition that increases the risk for bleeding, including, but not
limited to active peptic ulcer disease, inflammatory bowel disease, known
intraluminal or endobronchial metastatic lesions and/or lesions infiltrating major
pulmonary vessels with risk of bleeding, presence of non-healing wound or trauma
within 4 weeks prior to first dose of investigational drug
12. History of cerebrovascular accident including transient ischemic attack (TIA),
pulmonary embolism or untreated deep vein thrombosis (DVT) within the past 6
months (Note: Subjects with recent DVT who have been treated with therapeutic
anti-coagulating agents for at least 6 weeks are eligible)
13. Corrected QT Interval (QTc) > 480 msecs
14. Untreated hypothyroidism
15. Patients undergoing renal dialysis
16. 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
17. 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 (with a Pearl Index < 1) during the course of the trial and 3 months after
the completion of trial.
18. Substance abuse, medical, psychological or social conditions that may interfere
with the patient*s participation in the study or evaluation of the study results
19. Any condition that is unstable or could jeopardize the safety of the patient and their
compliance in the study
20. Patients unable to swallow oral medications
21. Clinically significant gastrointestinal abnormalities that may affect absorption of
investigational product
22. Known allergy to Votrient® or Nexavar®(i.e. to active substance or one of the
constituents)
23. Prior exposure to study drugs.
24. Investigational drug therapy within 4 weeks of study entry.
25. Use of biologic response modifiers, such as G-CSF and other hematopoietic
growth factors, within 3 weeks of study entry.
26. Radiotherapy within 3 weeks of start of study drug and planned radiotherapy
during the study
27. Concomitant medication: Any condition at the discretion of the investigator that
precludes compliance with concomitant therapy restrictions described below:
Non-permitted medication:
a. Other anticancer chemo-, cytokine- or targeted therapy for RCC, as well as
other investigational drug therapy.
b. Any St. John*s wort containing remedy
For further details also refer to chapters 7.1.3 / 7.2.3.
To be used with caution:
a. Co-administration of pazopanib with medicines that increase gastric pH should
be avoided.
* Proton-pump inhibitor (PPI): If the concomitant use of a proton-pump
inhibitor (PPI) is medically necessary, it is recommended that the dose of
pazopanib be taken without food once daily in the evening concomitantly
with the PPI.
* H2-receptor antagonist: If the concomitant administration of an H2-receptor
antagonist is medically necessary, pazopanib should be taken without food
at least 2 hours before or at least 10 hours after a dose of an H2-receptor
antagonist.
* Short-acting antacids: Pazopanib should be administered at least 1 hour
before or 2 hours after administration of short-acting antacids.
b. Anticoagulants: Pazopanib should be used with caution in subjects with
increased risk of severe bleeding or who are receiving concomitant
anticoagulant therapy (e.g., warfarin or its derivatives, low molecular weight
heparin, unfractionated heparin). Subjects taking concomitant anticoagulant
therapy should be monitored regularly for changes in relevant coagulation
parameters as clinically indicated, as well as for any clinical bleeding episodes.
c. Hypoglycemic therapy including insulin: Transient decreases in serum glucose
(mainly Grade 1 and 2, rarely Grade 3) have been observed in clinical studies
with pazopanib. Such changes may require an adjustment in the dose of
hypoglycemic and/or insulin therapy. Subjects should be advised to report
symptoms of hypoglycemia (e.g., confusion, visual disturbances, palpitations,
sweating). Serum glucose should be tested during treatment with pazopanib as
outlined in the protocol and as clinically indicated.
d. Simvastatin: Concomitant use of pazopanib and simvastatin increases the risk
of ALT elevations and should be undertaken with caution and close monitoring.
e. Strong CYP3A4 inhibitors* (e.g. grapefruit juice, star fruit or star fruit juice,
Seville orange, antibiotics, protease inhibitors, antifungals, antidepressants)
should be avoided during pazopanib treatment.
f. CYP3A4 inducers* should be avoided during pazopanib treatment, unless use of
the drug is essential and no substitute is available.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2011-004396-36-NL |
| ClinicalTrials.gov | NCT00732914 |
| CCMO | NL40447.094.12 |