| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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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 | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10050076 |
| E.1.2 | Term | Metastatic renal carcinoma |
| E.1.2 | System Organ Class | 100000004864 |
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| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
To compare the progression-free survival (PFS) of tivozanib in combination with nivolumab to tivozanib in subjects with renal cell carcinoma (RCC) who have progressed following 1 or 2 lines of therapy which includes an immune checkpoint inhibitor (ICI) assessed by a blinded independent radiological review (IRR).
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| E.2.2 | Secondary objectives of the trial |
a) To compare the overall survival (OS) of subjects randomized to treatment with tivozanib in combination with nivolumab compared to tivozanib;
b) To compare the overall response rate (ORR) and duration of response (DoR) of subjects randomized to treatment with tivozanib in combination with nivolumab compared to tivozanib assessed by a blinded IRR;
c) To assess the safety and tolerability of tivozanib in combination with nivolumab compared to tivozanib. |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. ≥ 18 years of age.
2. Radiographic disease progression during or following at least 6 weeks of treatment with ICI for locally advanced or metastatic RCC with a clear cell component either in first- or second-line treatment. Subjects must have progressed no longer than 6 months prior to randomization. An ICI is defined by anti-PD-L1 or anti-PD1 antibody including atezolizumab, avelumab, pembrolizumab, or nivolumab. Only subjects who have 1 prior line including 1 PD-1 or PD-L1 will be allowed.
a. Postoperative or adjuvant systemic therapy can be counted as a prior ICI therapy as long as recurrence is detected within 6 months of completion of treatment, in which case it will be counted as a prior therapy for metastatic disease. One or 2 prior therapies for metastatic disease are permissible but one of the treatments must have been an ICI.
b. Subjects must be off all systemic anti-cancer therapy or radiotherapy for at least 2 weeks prior to Cycle 1 Day 1.
3. Subjects must have recovered from the AEs of prior therapy to grade ≤ 1 or baseline. Controlled AEs such as hypothyroidism are permitted.
4. Histologically or cytologically confirmed RCC with a clear cell component.
5. Measurable disease per the Response Evaluation Criteria in Solid Tumors (RECIST) criteria Version 1.1.
6. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
7. Life expectancy ≥ 3 months.
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.
10. Women of childbearing potential (WOCBP) must meet and/or agree to all of the contraception described in the Protocol, Inclusion Criteria section.
11. Men who are sexually active with WOCBP must meet and/or agree to all of the contraception described in the Protocol, Inclusion Criteria section. |
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| E.4 | Principal exclusion criteria |
1. Subjects who received:
a. A single agent TKI in the first line setting followed by a single agent ICI in the second line setting.
b. More than 2 prior lines of therapy in the advanced or metastatic setting.
2. History of allergy or hypersensitivity to study drug or components.
3. History of life-threatening toxicity related to prior immune therapy (e.g. anti-CTLA-4 or anti-PD-1/PD-L1 treatment or any other antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint pathways) except those that are unlikely to re-occur with standard countermeasures (e.g., hypothyroidism).
4. Active autoimmune disease as well as those that required discontinuation of prior immunooncological (IO) therapy due to immune mediated AEs. Exceptions for participants with type I diabetes mellitus, hypothyroidism, and other endocrine disorders only requiring hormone replacement, skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or conditions not expected to recur.
5. Uncontrolled hypertension: systolic blood pressure > 150 mmHg or diastolic blood pressure > 100 mmHg on 2 or more antihypertensive medications, documented on 2 consecutive measurements taken at least 2 hours apart. Anti-hypertensives must not have been increased for 14 days prior to the first dose of study drug.
6. Condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalent) within 14 days of treatment initiation or other immunosuppressive medications within 30 days of randomization. Inhaled or topical steroids, and adrenal replacement steroid doses < 10 mg daily prednisone equivalent, are permitted in the absence of active autoimmune disease.
7. Serious or uncontrolled medical disorder.
8. Treatment with any live or attenuated vaccine within 30 days of start of treatment.
9. Prior radiation therapy within 2 weeks prior to randomization of start of study treatment. Subjects should have recovered (i.e., Grade ≤ 1 or at baseline) from radiation-related toxicities.
10. Investigational agents for the treatment of RCC. Subjects can be on a prior clinical trial if the specific agent is known (i.e., if any blind is broken).
11. Prior treatment with tivozanib.
12. More than 1 prior line of therapy with a checkpoint inhibitor in the metastatic setting.
13. Known central nervous system (CNS) metastases other than stable, treated brain metastases. Subjects with previously treated brain metastasis will be allowed if the brain metastasis has been stable by neuroimaging for at least 2 months following prior treatment (radiotherapy or surgery), and subjects are off all steroid treatment.
14. Any of the hematologic abnormalities mentioned in the protocol.
15. Any of the serum chemistry abnormalities mentioned in the protocol.
16. Significant cardiovascular disease.
17. 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.
18. Serious/active infection or infection requiring parenteral antibiotics.
19. Inadequate recovery from any prior surgical procedure or major surgical procedure within 4 weeks prior to administration of first dose of study drug.
20. Significant thromboembolic or vascular disorders within 6 months prior to administration of first dose of study drug.
21. Significant bleeding disorders within 1 month prior to administration of first dose of study drug.
22. Currently active second primary malignancy, including hematologic malignancies (leukemia, lymphoma, multiple myeloma, etc.), other than non melanoma skin cancers, non-muscle-invasive urothelial cancer, non-metastatic prostate cancer, in situ cervical cancer and ductal or lobular carcinoma in situ of the breast and some slow progressing hematologic malignancies (i.e., CLL). Subjects are not considered to have a currently active malignancy if they have completed anti-cancer therapy and have been disease free for > 1 year.
23. Pregnant or lactating females.
24. Subjects on immune suppressive therapy for organ transplant or subjects with a history of genetic or acquired immune suppression disease such as human immunodeficiency virus (HIV), except patients with HIV who have CD4+ T-cell counts > 350 cells/μL, without a history of acquired immune deficiency syndrome (AIDS).
25. Life-threatening illness or organ system dysfunction compromising safety evaluation.
26. Requirement for hemodialysis or peritoneal dialysis.
27. Inability to swallow pills, malabsorption syndrome or gastrointestinal disease that severely affects the absorption of tivozanib, major resection of the stomach or small bowel, or gastric bypass procedure. Other protocol defined exclusion criteria may apply.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint of the trial is PFS (progression free survival): defined as the time from randomization to first documentation of objective tumor progression (progressive disease [PD], radiological) according to RECIST (Version 1.1) or death due to any reasons whichever comes first. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Analysis of the primary endpoint will occur after 191 PFS events have occurred (>=18 months after the last subject is accrued). |
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| E.5.2 | Secondary end point(s) |
• OS (overall survival): Overall survival is defined as the time from the date of randomization to date of death due to any cause.
• ORR (overall response rate): defined as the proportion of subjects with confirmed CR or confirmed PR according to RECIST relative to the total population of randomized subjects.
• DoR (duration of response): defined as the time from the first documentation of objective tumor response to the first documentation of objective tumor progression or to death due to any cause.
• Safety and tolerability parameters: study drug exposure, AEs, laboratory parameters, vital signs, medical history, concomitant medications, and Pes (physical exams). |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| The secondary endpoints are evaluated at the time of final PFS analysis. |
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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 | 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 | 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 | 11 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 133 |
| 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 |
| Brazil |
| Canada |
| Chile |
| Mexico |
| United States |
| Belgium |
| Czechia |
| France |
| Germany |
| Hungary |
| Italy |
| Poland |
| Portugal |
| Spain |
| United Kingdom |
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| 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
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| The End of Trial is defined as either the date of the last visit of the last subject to complete the study, or the date of receipt of the last data point from the last subject that is required for primary or secondary analysis, as specified in the protocol and/or the statistical analysis plan, whichever is the later date. |
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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 | 9 |
| 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 | 9 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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