| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 9.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10050513 |
| E.1.2 | Term | Metastatic renal cell carcinoma |
|
| 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 |
The primary objective is to:
Compare the PFS of patients with mRCC receiving AG-013736 (axitinib) vs sorafenib
following failure of prior systemic first-line regimen containing one or more of the
following : sunitinib, bevacizumab + IFN α, temsirolimus or cytokine(s). |
|
| E.2.2 | Secondary objectives of the trial |
The secondary objectives are to:
• Compare the OS of patients in each arm;
• Compare the ORR of patients in each arm;
• Evaluate the safety and tolerability of AG-013736;
• Estimate the DR of patients in each arm;
• Compare the kidney specific symptoms, and health status of patients in each arm as measured by the FKSI, and EQ-5D. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Subjects must meet all of the following inclusion criteria to be eligible for enrollment into the trial:
1. Histologically confirmed metastatic renal cell cancer with a component of clear cell
histology.
2. Evidence of unidimensionally measurable disease (ie, ≥1 malignant tumor mass that can be accurately measured in at least 1 dimension ≥ 20 mm with conventional computerized tomography [CT] scan or Magnetic Resonance Imaging [MRI], or ≥10 mm with spiral CT scan using a 5 mm or smaller contiguous reconstructionalgorithm). Bone lesions, ascites, peritoneal carcinomatosis or miliary lesions, pleural or pericardial effusions, lymphangitis of the skin or lung, cystic lesions, or irradiated lesions are not considered measurable.
3. Must have failed (experienced disease progression as defined below) one prior systemic first-line regimen for metastatic renal cell cancer. The prior regimen must have contained one or more of the following: sunitinib, bevacizumab + IFN α, temsirolimus, or cytokine(s).
• Disease progression will be defined by RECIST documented by 2 sets of CT/MRI
(or sets of chest x-rays, bone scans, or x-rays of bone lesion) performed any time
within period of 4 weeks prior to the first dose of prior therapy to 4 months after
the last dose of prior treatment showing objective evidence of disease progression.
These pre-study scans or x-rays documenting disease progression must be
confirmed by the Principal Investigator prior to enrollment in the study (after
patient enrollment, pre-study scans or x-rays must be submitted to independent
third-party imaging core laboratory for retrospective review). Patients who
discontinue first-line therapy without evidence of disease progression whilst on
first-line therapy must subsequently have documented evidence (eg, CT/MRI
scan) of disease progression within 4 months after the last dose of their previous
regimen.
4. Adequate organ function as defined by the following criteria:
• absolute neutrophil count (ANC) ≥1500 cells/mm3;
• platelets ≥75,000 cells/mm3.
• Hemoglobin ≥9.0 g/d.
• AST and ALT ≤2.5 x upper limit of normal (ULN), unless there are liver
metastases in which case AST and ALT ≤5.0 x ULN;
• Total bilirubin ≤1.5 x ULN;
• Serum creatinine ≤1.5 x ULN or calculated creatinine clearance ≥60 mL/min;
• Urinary protein <2+ by urine dipstick. If dipstick is ≥2+ then a 24-hour urine
collection can be done and the patient may enter only if urinary protein is <2 g per
24 hours.
5. Male or female, age ≥18 years.
6. ECOG performance status of 0 or 1.
7. Life expectancy of ≥12 weeks.
8. At least 2 weeks since the end of prior systemic treatment (4 weeks for bevacizumab + IFN α), radiotherapy, or surgical procedure with resolution of all treatment-related toxicity to NCI CTCAE Version 3.0 grade ≤1 or back to baseline except for alopecia.
9. No evidence of preexisting uncontrolled hypertension as documented by 2 baseline blood pressure readings taken at least 1 hour apart. The baseline systolic blood pressure readings must be ≤140 mm Hg, and the baseline diastolic blood pressure readings must be ≤90 mm Hg. Patients whose hypertension is controlled by antihypertensive therapies are eligible.
10. Women of childbearing potential must have a negative serum or urine pregnancy test within 3 days prior to treatment.
11. Signed and dated informed consent document indicating that the patient (or legally acceptable representative) has been informed of all pertinent aspects of the trial prior to enrollment.
12. Willingness and ability to comply with scheduled visits, treatment plans (including
willingness to take either AG-013736 or sorafenib according to randomization),
laboratory tests, and other study procedures, including completion of patient-reported outcome measures (FKSI and EQ-5D questionnaires). |
|
| E.4 | Principal exclusion criteria |
Subjects presenting with any of the following will not be included in the trial:
1. Prior treatment of mRCC with more than one systemic first-line regimen.
2. Patients treated with any neoadjuvant or adjuvant systemic therapy.
3. Major surgery <4 weeks or radiation therapy <2 weeks of starting the study treatment.
Prior palliative radiotherapy to metastatic lesion(s) is permitted, provided there is at least one measurable lesion that has not been irradiated.
4. Gastrointestinal abnormalities including:
• inability to take oral medication;
• requirement for intravenous alimentation;
• prior surgical procedures affecting absorption including total gastric resection;
• treatment for active peptic ulcer disease in the past 6 months;
• active gastrointestinal bleeding, unrelated to cancer, as evidenced by
hematemesis, hematochezia or melena in the past 3 months without evidence of
resolution documented by endoscopy or colonoscopy;
• malabsorption syndromes.
5. Current use or anticipated need for treatment with drugs that are known potent CYP3A4 inhibitors (ie, grapefruit juice, verapamil, ketoconazole, miconazole, itraconazole, erythromycin, telithromycin, clarithromycin, indinavir, saquinavir, ritonavir, nelfinavir, lopinavir, atazanavir, amprenavir, fosamprenavir and delavirdine).
6. Current use or anticipated need for treatment with drugs that are known CYP3A4 or CYP1A2 inducers (ie, carbamazepine, dexamethasone, felbamate, omeprazole,
phenobarbital, phenytoin, amobarbital, nevirapine, primidone, rifabutin, rifampin, and St.John’s wort).
7. Requirement of anticoagulant therapy with oral vitamin K antagonists. Low-dose
anticoagulants for maintenance of patency of central venous access devise or prevention of deep venous thrombosis is allowed. Therapeutic use of low molecular weight heparin is allowed.
8. Active seizure disorder or evidence of brain metastases, spinal cord compression, or carcinomatous meningitis.
9. A serious uncontrolled medical disorder or active infection that would impair their ability to receive study treatment.
10. Any of the following within the 12 months prior to study drug administration:
myocardial infarction, severe/unstable angina, coronary/peripheral artery bypass graft, symptomatic congestive heart failure, cerebrovascular accident or transient ischemic attack and 6 months for deep vein thrombosis or pulmonary embolism.
11. Known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS)-related illness.
12. History of a malignancy (other than renal cell cancer) except those treated with curative intent for skin cancer (other than melanoma), in situ breast or in situ cervical cancer, or those treated with curative intent for any other cancer with no evidence of disease for 2 years.
13. Dementia or significantly altered mental status that would prohibit the understanding or rendering of informed consent and compliance with the requirements of this protocol.
14. Female patients who are pregnant or lactating, or men and women of reproductive potential not willing or not able to employ an effective method of birth
control/contraception to prevent pregnancy during treatment and for 6 months after
discontinuing study treatment The definition of effective contraception should be in
agreement with local regulation and based on the judgment of the principal investigator or a designated associate.
15. Other severe acute or chronic medical or psychiatric condition, or laboratory abnormality that may increase the risk associated with study participation or study drug administration, or may interfere with the interpretation of study results, and in the judgment of the investigator would make the patient inappropriate for entry into this Study. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| PFS will be the primary endpoint. |
|
| 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 | No |
| 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 | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| 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) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| Information not present in EudraCT |
| 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 | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 56 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| 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
| |
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 1 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 1 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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