| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Advanced / metastatic renal cell carcinoma |
|
| E.1.1.1 | Medical condition in easily understood language |
| Advanced / metastatic renal cancer |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 19.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10038410 |
| E.1.2 | Term | Renal cell carcinoma recurrent |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 19.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10050513 |
| E.1.2 | Term | Metastatic renal cell carcinoma |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To evaluate if progression -free survival from randomization to progression or death during second -line therapy (total PFS) of sorafenib followed by pazopanib ist non-inferior compared to pazopanib followed by sorafenib |
|
| E.2.2 | Secondary objectives of the trial |
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 (FACT-F, FKSI-10)
7. Safety and tolerability
|
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Explorative biomarker programms:
1. Circulating Tumor Cells
2. Single Nucleotide Polymorphisms
3. Serum Protein Signatures
4. C-reactive protein as prognostic marker
|
|
| E.3 | Principal 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/μl
- Platelet count 100,000/μl
- 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 |
|
| E.4 | Principal 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
a. Co-administration of pazopanib with medicines that increase gastric pH should
be avoided.
- Proton-pump inhibitor (PPI), H2-receptor antagonist, 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
c. Hypoglycemic therapy including insulin: Transient decreases in serum glucose may require an adjustment in the dose of
hypoglycemic and/or insulin therapy.
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. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| To evaluate if progression -free survival from randomization to progression or death during second -line therapy (total PFS) of sorafenib followed by pazopanib ist non-inferior compared to pazopanib followed by sorafenib |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
No interim analyses are planned.
The final analyses will take place once all patients have terminated trial therapy. This is planned for Q4 2016. |
|
| E.5.2 | Secondary end point(s) |
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 (FACT-F, FKSI-10)
7. Safety and tolerability
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
No interim analyses are planned.
The final analyses will take place once all patients have terminated trial therapy. This is planned for Q4 2016. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
Explorative biomarker programms:
1. Circulating Tumor Cells
2. Single Nucleotide Polymorphisms
3. Serum Protein Signatures
4. C-reactive protein as prognostic marker
|
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
| Sequential application of two study medications (Sorafenib->Pazopanib vs. Pazopanib->Sorafenib) |
|
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 11 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 85 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
Data collection will be stopped after the end of safety follow-up (LPLV – 31st October 2016) and clean data for the patients exist. After that the trial is terminated.
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 5 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 5 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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