| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Metastatic renal cell carcinoma |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| 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 | 21.1 |
| 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 |
| The objective of this study is to evaluate the effect of cabozantinib compared with everolimus on progression-free survival (PFS) and overall survival (OS) in subjects with advanced renal cell cancer that has progressed after prior VEGFR tyrosine kinase inhibitor therapy. |
|
| E.2.2 | Secondary objectives of the trial |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Documented histological or cytological diagnosis of renal cell cancer with a clear-cell component.
2. Measurable disease per RECIST 1.1 as determined by the investigator.
3. Must have received at least one VEGFR-targeting TKI (eg, sorafenib, sunitinib, axitinib, pazopanib or tivozanib). Prior treatment with other anticancer therapies including cytokines (eg, interleukin-2, interferon-alfa), monoclonal antibodies, (eg, bevacizumab), and cytotoxic chemotherapy is allowed (except Exclusion Criterion #1).
4. For the most recently received VEGFR-targeting TKI the following criteria must apply:
a. Must have radiographically progressed during treatment, or been treated for at least 4 weeks and radiographically progressed within 6 months after the last dose. Radiographic progression is defined as unequivocal progression of existing tumor lesions or developing new tumor lesions as assessed by the investigator on CT or MRI scans.
b. The last dose must have been within 6 months before the date of randomization.
5. Recovery to baseline or ≤ Grade 1 CTCAE v.4.0 from toxicities related to any prior treatments, unless AE(s) are clinically nonsignificant and/or stable on supportive therapy.
6. Age eighteen years or older on the day of consent.
7. Karnofsky Performance Status (KPS) score of ≥ 70%.
8. Adequate organ and marrow function, based upon all of the following laboratory criteria within 10 days before randomization:
a. Absolute neutrophil count (ANC) ≥ 1500/mm3 (≥ 1.5 GI/L).
b. Platelets ≥ 100,000/mm3 (≥ 100 GI/L).
c. Hemoglobin ≥ 9 g/dL (≥ 90 g/L).
d. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < 3.0 × upper limit of normal.
e. Total bilirubin ≤ 1.5 × the upper limit of normal. For subjects with Gilbert’s disease ≤ 3 mg/dL (≤ 51.3 μmol/L).
f. Fasting serum triglycerides ≤ 2.5 × upper limit of normal AND total cholesterol ≤ 300 mg/dL (≤ 7.75 mmol/L). Lipid-lowering medication is allowed.
g. HbA1c ≤ 8%. For subjects with a condition (eg, hemoglobin variant) that affects the interpretation of HBA1c results, a fasting glucose ≤ 160mg/dL (≤8.9 mmol/L).
h. Serum creatinine ≤ 2.0 × upper limit of normal or calculated creatinine clearance ≥ 30 mL/min (≥ 0.5 mL/sec) using the Cockroft-Gault equation.
i. Urine protein-to-creatinine ratio (UPCR) ≤ 1 mg/mg (≤ 113.2 mg/mmol) creatinine or 24-hour urine protein < 1 g.
9. Capable of understanding and complying with the protocol requirements and must have signed the informed consent document.
10. Sexually active fertile subjects and their partners must agree to use medically accepted methods of contraception (eg, barrier methods, including male condom, female condom, or diaphragm with spermicidal gel) during the course of the study and for 4 months after the last dose of study treatment.
11. Female subjects of childbearing potential must not be pregnant at screening. Females of childbearing potential are defined as premenopausal females capable of becoming pregnant (ie, females who have had any evidence of menses in the past 12 months, with the exception of those who had prior hysterectomy). However, women who have been amenorrheic for 12 or more months are still considered to be of childbearing potential if the amenorrhea is possibly due to prior chemotherapy, antiestrogens, low body weight, ovarian suppression or other reasons. |
|
| E.4 | Principal exclusion criteria |
1. Prior treatment with everolimus, or any other specific or selective TORC1/PI3K/AKT inhibitor, or cabozantinib.
2. Receipt of any type of small molecule kinase inhibitor within 2 weeks before randomization.
3. Receipt of any type of anticancer antibody within 4 weeks before randomization.
4. Radiation therapy for bone metastasis within 2 weeks, any other external radiation therapy within 4 weeks before randomization. Systemic treatment with radionuclides within 6 weeks before randomization. Subjects with clinically relevant ongoing complications from prior radiation therapy are not eligible.
5. Known brain metastases or cranial epidural disease unless adequately treated with radiotherapy and/or surgery and stable for at least 3 months before randomization. Eligible subjects must be neurologically asymptomatic and without corticosteroid treatment at the time of randomization.
6. Concomitant anticoagulation at therapeutic doses with oral anticoagulants or platelet inhibitors. Note: Low-dose aspirin for cardioprotection (per local applicable guidelines), low-dose warfarin (< 1 mg/day), and low dose, low molecular weight heparins (LMWH) are permitted. Anticoagulation with therapeutic doses of LMWH is allowed in subjects without radiographic evidence of brain metastasis, who are on a stable dose of LMWH for at least 12 weeks before randomization, and who have had no complications from a thromboembolic event or the anticoagulation regimen.
7. Chronic treatment with corticosteroids or other immunosuppressive agents (with the exception of inhaled or topical corticosteroids or corticosteroids with a daily dosage equivalent ≤ 10 mg prednisone if given for disorders other than renal cell cancer). Subjects with brain metastases requiring systemic corticosteroid are not eligible.
8. The subject has uncontrolled, significant intercurrent or recent illness including, but not limited to, the following conditions:
a. Cardiovascular disorders:
i. Congestive heart failure New York Heart Association class 3 or 4, unstable angina pectoris, serious cardiac arrhythmias.
ii. Uncontrolled hypertension defined as sustained BP > 150 mm Hg systolic or > 100 mm Hg diastolic despite optimal antihypertensive treatment.
iii. Stroke (including TIA), myocardial infarction, or other ischemic event, or
thromboembolic event (eg, deep venous thrombosis, pulmonary embolism) within 6 months before randomization.
b. Gastrointestinal (GI) disorders including those associated with a high risk of perforation or fistula formation:
i. Tumors invading the GI-tract, active peptic ulcer disease, inflammatory bowel disease, diverticulitis, cholecystitis, symptomatic cholangitis or appendicitis, acute pancreatitis or acute obstruction of the pancreatic or biliary duct, or gastric outlet obstruction.
ii. Abdominal fistula, gastrointestinal perforation, bowel obstruction, or intraabdominal abscess within 6 months before randomization. Note: Complete healing of an intra-abdominal abscess must be confirmed before randomization.
c. Clinically significant hematuria, hematemesis, or hemoptysis of > 0.5 teaspoon (2.5 ml) of red blood, or other history of significant bleeding (eg, pulmonary hemorrhage) within 3 months before randomization.
d. Cavitating pulmonary lesion(s) or known endobronchial disease manifestation.
e. Lesions invading major pulmonary blood vessels.
f. Other clinically significant disorders such as:
i. Active infection requiring systemic treatment, infection with human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome
(AIDS)-related illness, or chronic hepatitis B or C infection.
ii. Serious non-healing wound/ulcer/bone fracture.
iii. Malabsorption syndrome.
iv. Uncompensated/symptomatic hypothyroidism.
v. Moderate to severe hepatic impairment (Child-Pugh B or C).
vi. Requirement for hemodialysis or peritoneal dialysis.
vii. History of solid organ transplantation.
9. Major surgery (eg, GI surgery, removal or biopsy of brain metastasis) within 2 months before randomization. Complete wound healing from major surgery must have occurred 1 month before randomization and from minor surgery (eg, simple excision, tooth extraction) at least 10 days before randomization. Subjects with clinically relevant ongoing complications from prior surgery are not eligible.
10. Corrected QT interval calculated by the Fridericia formula (QTcF) > 500 msec within 10 days before randomization. Three ECGs must be performed. If the average of these three consecutive results for QTcF is ≤ 500 msec, the subject meets eligibility in this regard.
11. Pregnant or lactating females.
12. Inability to swallow tablets or capsules.
13. Previously identified allergy or hypersensitivity to components of the study treatment formulations.
14. Diagnosis of another malignancy within 2 years before randomization, except for superficial skin cancers, or localized, low grade tumors deemed cured and not treated with systemic therapy. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Progression-Free Survival, per RECIST 1.1, per independent radiology committee (IRC) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| At screening and every 8 weeks (± 5 days) after randomization throughout the first 12 months on study. Upon completion of 12 months on study, these assessments will be performed every 12 weeks (± 7 days) . For subjects who discontinue study treatment before radiographic disease progression or within 8 weeks after radiographic disease progression, final assessment is to be performed 8 weeks after radiographic disease progression. For subjects who continue to receive study drug for more than 8 weeks after radiographic disease progression, assessments are to continue per the protocol defined schedule until study treatment is permanently discontinued. |
|
| E.5.2 | Secondary end point(s) |
• Overall Survival
• Objective Response Rate (ORR), per RECIST 1.1, per IRC
Additional endpoints:
• Duration of radiographic response
• Changes in bone scans
• Safety and tolerability
• Characterization of the pharmacokinetics of cabozantinib
• Change in kidney-cancer related symptoms as assessed by the Functional Assessment of Cancer Therapy-Kidney Cancer Symptom Index (FKSI-19)
• Change in mobility, self-care, usual activities, pain/discomfort, and anxiety/depression, and global health as assessed by the EuroQol Health questionnaire instrument (EQ-5D-5L)
• Proportion of subjects with post-randomization skeletal-related events (SREs)
• Relationship of baseline and changes in plasma biomarkers, serum bone markers, serum calcium, and circulating tumor cells (CTCs) with treatment and/or clinical outcome
• Health care resource utilization |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| At scheduled visits and every 8 weeks (± 7 days) after the post-treatment follow-up visit. Subjects will be followed until death or sponsor decision to no longer collect these data. |
|
| 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 | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | No |
| 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.8.2.4 | 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 | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 88 |
| 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 | No |
| 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 |
| Argentina |
| Australia |
| Austria |
| Belgium |
| Brazil |
| Canada |
| Chile |
| Czech Republic |
| Denmark |
| Finland |
| France |
| Germany |
| Hungary |
| Ireland |
| Italy |
| Korea, Republic of |
| Netherlands |
| Poland |
| Portugal |
| Russian Federation |
| Slovakia |
| Spain |
| Sweden |
| Taiwan |
| Turkey |
| United Kingdom |
| United States |
|
| 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 | 3 |
| E.8.9.1 | In the Member State concerned months | 9 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 9 |
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