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 | 14.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10067946 |
E.1.2 | Term | Renal cell carcinoma |
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 allow access to tivozanib hydrochloride for subjects who participated in Protocol AV-951-09-301 and AV-951-09-902 and failed sorafenib treatment on either protocol.
· To allow long-term access to tivozanib hydrochloride for subjects who participated in Protocol AV-951-09-301 and demonstrated clinical benefit and acceptable tolerability to tivozanib hydrochloride
· To allow long-term access to sorafenib for subjects who participated in Protocol AV-951-09-301 and demonstrated clinical benefit and acceptable tolerability to sorafenib
·To assess long-term safety in subjects who continue treatment with tivozanib hydrochloride |
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E.2.2 | Secondary objectives of the trial |
· To determine the objective response rate (ORR), duration of response (DR), and progression-free survival (PFS) of subjects who continue treatment with tivozanib hydrochloride or sorafenib
· To determine the ORR, DR, and PFS of subjects who receive tivozanib hydrochloride after failure of sorafenib
· To determine overall survival (OS) of subjects who continue treatment with tivozanib hydrochloride or sorafenib |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Subjects who have discontinued treatment in the AV-951-09-301 protocol and have been undergoing tumor assessment and/or survival follow-up will not need to meet the eligibility criteria (defined below) for their long term follow-up in the current study
1. The subject must have participated on Protocol AV-951-09-301, and must meet either of the following bulleted criteria:
- Demonstrated disease progression per RECIST during treatment with sorafenib, OR
- Demonstrated clinical benefit [complete response (CR), partial response (PR), or stable disease (SD) per RECIST] and acceptable tolerability after treatment with tivozanib hydrochloride or sorafenib on protocol AV-951-09-301
2. ECOG performance status ≤ 2 (see Appendix C) and life expectancy ≥ 3 months.
3. If female and of childbearing potential, documentation of negative pregnancy test prior to enrollment.
4. Ability to give written informed consent |
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E.4 | Principal exclusion criteria |
1. Newly identified CNS malignancies or documented progression of CNS metastases; subjects will be allowed only if the CNS metastases have been adequately treated with radiotherapy or surgery. For subjects receiving steroid therapy please refer to Section 6.3 for allowed steroid maintenance therapy
2. Duration since last dose on Protocol AV-951-09-301:
For subjects continuing tivozanib hydrochloride or sorafenib (subjects who demonstrated clinical benefit and acceptable tolerability during treatment with tivozanib hydrochloride or sorafenib on protocol AV-951-09-301): more than 2 weeks since last dose of tivozanib hydrochloride or sorafenib
For subjects initiating tivozanib hydrochloride (ie demonstrated disease progression during treatment with sorafenib): more than 4 weeks since last dose of sorafenib. Subjects demonstrating disease progression due to CNS metastasis will be allowed up to 8 weeks since last dose of sorafenib in order to complete treatment for CNS metastasis
3. Inadequate recovery from any prior surgical procedure or major surgical procedure within 4 weeks prior to administration of first dose of study drug
4. Any of the following hematologic abnormalities:
· Hemoglobin < 9.0 g/dL
· ANC < 1500 per mm
· Platelet count < 75,000 per mm3
· PT or PTT >1.5 × ULN
3. Any of the following serum chemistry abnormalities:
· Total bilirubin > 1.5 × ULN (or > 2.5 × ULN for subjects with Gilbert’s syndrome)
· AST or ALT > 2.5 × ULN (or > 5 × ULN for subjects with liver metastasis)
· Alkaline phosphatase > 2.5 × ULN (or > 5 × ULN for subjects with liver or bone metastasis)
· Creatinine > 2.0 × ULN
· Proteinuria > 3+ by urinalysis or urine dipstick
6. If female, pregnant or lactating
7. Sexually active pre-menopausal female subjects (and female partners of male subjects) must use adequate contraceptive measures, while on 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 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. Effective birth control includes (a) IUD plus one barrier method; or (b) 2 barrier methods. Effective barrier methods are male or female condoms, diaphragms, and spermicides
(creams or gels that contain a chemical to kill sperm). (Note: Oral, implantable, or injectable contraceptives may be affected by cytochrome P450 interactions, and are not considered effective for this study.)
8. 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 24 hours apart.
9. Unhealed wounds (including active peptic ulcers)
10. Serious/active infection or infection requiring parenteral antibiotics
11. Life-threatening illness or organ system dysfunction compromising safety evaluation
12. Psychiatric disorder, altered mental status precluding informed consent or necessary testing
13. Inability to comply with protocol requirements
14. Treatment with another anti-cancer therapy or participation in another interventional protocol (excluding AV-951-09-301) |
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E.5 End points |
E.5.1 | Primary end point(s) |
•provide access to tivozanib hydrochloride for subjects who participated in AV-951-09-301 and AV-951-09-902 and failed sorafenib treatment on either protocol
•provide access to tivozanib hydrochloride for subjects who participated in AV-951-09-301 and demonstrated clinical benefit and acceptable tolerability to tivozanib hydrochloride
•provide access to sorafenib subjects who participated in AV-951-09-301 and demonstrated clinical benefit and acceptable tolerability to sorafenib
•to assess long term safety in subjects who continue treatment with tivozanib hydrochloride |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
- to determine the ORR, DR and PFS on patients who continue treatment with Tivozanib Hydrochloride or Sorafenib, or who initiate treatment with Tivozanib Hydrochloride after failure on Sorafenib
- and to determine OS of subjects who continue treatment with Tivozanib Hydrochloride or Sorafenib |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
ORR and DR as well as PFS are measured every two cycles (2 months) by CT scans. OS is assesed every 2 months following treatment discontinuation. |
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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 | 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 | Yes |
E.8.1.7.1 | Other trial design description |
Subjects who demonstrate DP on sorafenib may start tivozanib hydrochloride treatment |
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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 | 7 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 41 |
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 |
Bulgaria |
Canada |
Chile |
Czech Republic |
France |
Hungary |
India |
Italy |
Poland |
Romania |
Russian Federation |
Serbia |
Ukraine |
United Kingdom |
United States |
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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 study will continue until all subjects completed their survival follow-up. All subjects will be followed until death. |
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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 | 4 |
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 | 4 |
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 |