E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Advanced Renal Cell Carcinoma |
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E.1.1.1 | Medical condition in easily understood language |
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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 | 14.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10038407 |
E.1.2 | Term | Renal cell cancer |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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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 compare the progression-free survival (PFS) of subjects with advanced renal cell cancer (RCC) randomized to treatment with tivozanib or sorafenib |
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E.2.2 | Secondary objectives of the trial |
To compare the overall survival (OS) of subjects randomized to treatment with tivozanib or sorafenib
To compare objective response rate (ORR) and duration of response (DR) of subjects randomized to treatment with tivozanib or sorafenib
To compare the safety and tolerability of tivozanib and sorafenib
To compare kidney-specific symptoms and health outcome measurements in subjects randomized to treatment with tivozanib or sorafenib
To evaluate the pharmacokinetics (PK) of tivozanib
Tertiary Objective is: “To study biomarkers in blood and archived tissue samples, and their correlations with clinical activity and/or treatment related toxicity in subjects randomized to tivozanib or sorafenib” |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. ≥ 18-years of age.
2. Subjects with recurrent or metastatic RCC.
3. Subjects must have undergone prior nephrectomy (complete or partial) for excision of the primary tumor.
4. Histologically or cytologically confirmed RCC with a clear cell component (subjects with pure papillary cell tumor or other non-clear cell histologies, including collecting duct, medullary, chromophobe, mixed tumor containing predominantly sarcomatoid cells, and unclassified RCC are excluded).
5. Measurable disease per the RECIST criteria Version 1.0 (see Appendix A). Measurable disease must be verified by an independent radiologist prior to randomization.
6. Treatment naïve subjects or subjects who have received no more than one prior systemic treatment (immunotherapy, including interferon-alfa or interleukin-2 based therapy, chemotherapy, hormonal therapy or an investigational agent) for metastatic RCC. Postoperative or adjuvant systemic therapy will not be counted as a prior therapy unless recurrence is detected within 6 months of completion of treatment, in which case it will be counted as a prior therapy for metastatic disease.
7. ECOG performance status of 0 or 1, and life expectancy ≥ 3 months (see Appendix B).
8. If female and of childbearing potential, documentation of negative pregnancy test prior to enrollment.
9. Ability to give written informed consent and comply with protocol requirements. |
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E.4 | Principal exclusion criteria |
1. Any prior VEGF-directed therapy including VEGF antibody (eg, bevacizumab), VEGF receptor tyrosine kinase inhibitor (eg, sunitinib, sorafenib, axitinib, pazopanib, etc.), VEGF trap (eg, aflibercept), or any other agent or investigational agent targeting the VEGF pathway.
2. Any prior therapy with an agent targeting the mTOR pathway (eg, temsirolimus, everolimus, etc)
3. Primary CNS malignancies or CNS metastases; subjects with previously treated brain metastasis will be allowed if the brain metastasis have been stable without steroid treatment for at least 3 months following prior treatment (radiotherapy or surgery).
4. Any listed hematologic abnormalities, ≥ Grade 2
5. Any listed serum chemistry abnormalities, ≥ Grade 2
6. Significant cardiovascular disease, ≥ Grade 2
7. Non-healing wound, bone fracture, or skin ulcer.
8. Active peptic ulcer disease, inflammatory bowel disease, ulcerative colitis, or other gastrointestinal condition with increased risk of perforation; history of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 4 weeks prior to administration of first dose of study drug
9. Serious/active infection or infection requiring parenteral antibiotics.
10. Inadequate recovery from any prior surgical procedure or major surgical procedure within 4 weeks prior to administration of first dose of study drug.
11. Significant thromboembolic or vascular disorders within 6 months prior to administration of first dose of study drug, including but not limited to: Deep vein thrombosis Pulmonary embolism Cerebrovascular accident (CVA) or transient ischemic attach (TIA) Peripheral arterial ischemia > Grade 2 Coronary or peripheral artery bypass graft.
12. Significant bleeding disorders within 6 months prior to administration of first dose of study drug, including but not limited to. Hematemesis, hematochezia, melena or other gastrointestinal bleeding Grade 2 Hemoptysis or other pulmonary bleeding Grade 2 Hematuria or other genitourinary bleeding Grade 2
13. Currently active second primary malignancy, including hematologic malignancies (leukemia, lymphoma, multiple myeloma, etc.), other than non-melanoma skin cancers, non-metastatic prostate cancer, in situ cervical cancer and ductal or lobular carcinoma in situ of the breast. Subjects are not considered to have a currently active
malignancy if they have completed anti-cancer therapy and have been disease free for >2 years.
14. Pregnant or lactating females.
15. History of genetic or acquired immune suppression disease such as HIV; subjects on immune suppressive therapy for organ transplant.
16. Life-threatening illness or organ system dysfunction compromising safety evaluation.
17. Requirement for hemodialysis or peritoneal dialysis.
18. Inability to swallow pills, malabsorption syndrome or gastrointestinal disease that severely affects the absorption of tivozanib or sorafenib, major resection of the stomach or small bowel, or gastric bypass procedure.
19. Psychiatric disorder or altered mental status precluding informed consent or necessary testing.
20: Sexually active premenopausal female subjects (and female partners of male subjects) must use adequate contraceptive measures while on the study and for at least 50 days after the last dose of study drug. Sexually active male subjects must use adequate contraceptive measures while on the study and for at least 90 days after the last dose of study drug. All fertile male and female subjects and their partners must agree to use a highly effective method of contraception.
21. Participation in another interventional study |
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E.5 End points |
E.5.1 | Primary end point(s) |
To compare the progression-free survival (PFS) of subjects with advanced renal cell cancer (RCC) randomized to treatment with tivozanib or sorafenib |
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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 | Yes |
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.8.2.4 | 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 | 4 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 40 |
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 |
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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
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Treatment duration is estimated to last approximately 12 months with a follow-up period of 30 days. Overall duration of subject participation is approx 26 months.
Subjects with documented stable disease or an objective response may continue to receive therapy at the same dose and schedule for up to 2 years from the first dose as long as tolerability is acceptable. |
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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 | 0 |
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 | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |