A Study to Compare Tivozanib (AV-951) to Sorafenib in Subjects With Advanced Renal Cell Carcinoma

Advanced Renal Cell Carcinoma Clinical Trial

— TIVO-1  

Official title:

A Phase 3, Randomized, Controlled, Multi-Center, Open-Label Study to Compare Tivozanib (AV-951) to Sorafenib in Subjects With Advanced Renal Cell Carcinoma (TIVO-1)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01030783
• Other study ID #: AV-951-09-301
• Status: Completed
• Phase: Phase 3
• Start date: December 2009
• Est. completion date: June 2013

Study information

• Verified date: October 2019
• Source: AVEO Pharmaceuticals, Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This is an open-label, randomized, controlled, multi-national, multi-center, parallel-arm trial comparing tivozanib to sorafenib in subjects with advanced RCC. The study is designed to compare the PFS, OS, ORR, DR, safety and tolerability, and kidney specific symptoms/health outcome measurements of tivozanib and sorafenib.

Description:

This is an open-label, randomized, controlled, multi-national, multi-center, parallel-arm trial comparing tivozanib to sorafenib in subjects with advanced RCC. The study is designed to compare the PFS, OS, ORR, DR, safety and tolerability, and kidney specific symptoms/health outcome measurements of tivozanib and sorafenib.

Subjects will be randomized (1:1) to treatment with tivozanib or sorafenib and stratified by geographic region (North America/Western Europe, Central/Eastern Europe, or rest of the world); number of prior treatments (0 or 1); and number of metastatic sites/organs involved (1 or ≥ 2).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 517
• Est. completion date: June 2013
• Est. primary completion date: July 2012
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

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.

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.

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 hematologic abnormalities (as noted in the protocol).

5. Any serum chemistry abnormalities (as noted in the protocol).

6. Significant cardiovascular disease.

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.

12. Significant bleeding disorders within 6 months prior to administration of first dose of study drug.

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 pre-menopausal female subjects (and female partners of male subjects) must use adequate contraceptive measures, while on study and for 50 days after the last dose of study drug. Sexually active male subjects must use adequate contraceptive measures, while on study for at least 90 days after the last dose of drug. All fertile male and female subjects and their partners must agree to use a highly effective method of contraception (including their partner). 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.)

Related Conditions & MeSH terms

• Advanced Renal Cell Carcinoma
• Carcinoma
• Carcinoma, Renal Cell

Intervention

Drug:
• tivozanib (AV-951)
Tivozanib: 1.5 mg orally once daily. Subjects will receive 1.5 mg tivozanib once daily beginning on Day 1 for 3 weeks followed by 1 week off treatment. One cycle will be defined as 4 weeks of treatment. Cycles will be repeated every 4 weeks.
• Sorafenib
Sorafenib: 400 mg orally twice daily. Subjects will receive 400 mg (2 x 200 mg tablets) sorafenib twice daily continuously, beginning on Day 1. One cycle will be defined as 4 weeks of treatment. Cycles will be repeated every 4 weeks.

Locations

Country	Name	City	State
Argentina	Site 102	Sante Fe
Bulgaria	Site 403	Plovdiv
Bulgaria	Site 400	Sofia
Bulgaria	Site 404	Sofia
Bulgaria	Site 401	Varna
Bulgaria	Site 402	Veliko Tarnovo
Canada	Site 110	Montréal	Quebec
Chile	Site 121	La Reina	Santiago De Chile
Chile	Site 122	Santiago
Chile	Site 123	Temuco
Czechia	Site 411	Prague 8
France	Site 130	Marseille
France	Site 133	Saint Herblain Cedex
Hungary	Site 423	Budapest
Hungary	Site 421	Kaposvár
Hungary	Site 422	Pécs
Hungary	Site 424	Szombathely
India	Site 156	Ahmedabad	Gujarat
India	Site 154	Delhi
India	Site 157	Hyderabad	Andhra Pradesh
India	Site 155	Jaipur	Rajasthan
India	Site 191	Jaipur	Rajasthan
India	Site 150	Kolkata	West Bengal
India	Site 158	Lucknow	Uttar Pradesh
India	Site 151	Nashik	Maharashtra
India	Site 190	Patna	Bihar
India	Site 153	Pune	Maharashtra
India	Site 159	Pune	Maharashtra
India	Site 152	Vellore	Tamil Nadu
Italy	Site 160	Arezzo
Italy	Site 161	Pavia
Italy	Site 162	Roma
Poland	Site 432	Bialystok
Poland	Site 434	Bydgoszcz
Poland	Site 431	Gdansk
Poland	Site 435	Olsztyn
Poland	Site 433	Poznan
Poland	Site 430	Warsaw
Poland	Site 436	Warsaw
Romania	Site 444	Brasov
Romania	Site 440	Bucharest
Romania	Site 441	Bucharest
Romania	Site 443	Bucharest
Romania	Site 442	Timisoara
Russian Federation	Site 451	Chelyabinsk
Russian Federation	Site 455	Ekaterinburg
Russian Federation	Site 468	Ioshkar Ola
Russian Federation	Site 452	Kazan
Russian Federation	Site 453	Moscow
Russian Federation	Site 454	Moscow
Russian Federation	Site 458	Moscow
Russian Federation	Site 460	Moscow
Russian Federation	Site 461	Moscow
Russian Federation	Site 462	Moscow
Russian Federation	Site 450	Nizhny Novgorod
Russian Federation	Site 456	Obninsk
Russian Federation	Site 467	Omsk
Russian Federation	Site 463	Pyatigorsk
Russian Federation	Site 457	Rostov-on-Don
Russian Federation	Site 465	St. Petersburg
Russian Federation	Site 466	St. Petersburg
Russian Federation	Site 459	Ufa	Republic Of Bashkortostan
Russian Federation	Site 464	Yaroslavi
Serbia	Site 480	Belgrade
Serbia	Site 481	Belgrade
Serbia	Site 482	Belgrade
Serbia	Site 483	Nis
Serbia	Site 484	Sremska Kamenica
Ukraine	Site 491	Chernihiv
Ukraine	Site 492	Dniproperovsk
Ukraine	Site 498	Dnipropetrovsk
Ukraine	Site 493	Donetsk
Ukraine	Site 496	Donetsk
Ukraine	Site 490	Ivano-Frankivsk
Ukraine	Site 494	Kharkiv
Ukraine	Site 497	Uzhhorod
Ukraine	Site 495	Zaporizhia
United Kingdom	Site 170	Cambridge
United Kingdom	Site 173	Ipswich
United Kingdom	Site 172	Leicester
United States	Site 187	Dallas	Texas
United States	Site 180	Gainesville	Florida
United States	Site 185	Los Angeles	California
United States	Site 182	Minneapolis	Minnesota
United States	Site 186	New York	New York
United States	Site 184	Orlando	Florida

Sponsors (1)

Lead Sponsor	Collaborator
AVEO Pharmaceuticals, Inc.

Countries where clinical trial is conducted

United States,  Argentina,  Bulgaria,  Canada,  Chile,  Czechia,  France,  Hungary,  India,  Italy,  Poland,  Romania,  Russian Federation,  Serbia,  Ukraine,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Progression-free Survival (PFS) of Subjects With Advanced Renal Cell Cancer (RCC) Randomized to Treatment With Tivozanib or Sorafenib	Progression-Free Survival (PFS) is defined as the time from randomization to first documentation of objective tumor progression (progressive disease) or death due to any reasons whichever comes first. Disease progression per RECIST 1.0 criteria is defined as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.	From date of randomization until the date of first documented progression or date of death from any cause, whichever came first. Disease progression was assessed every 8 weeks.
Secondary	Overall Survival (OS) of Subjects Randomized to Treatment With Tivozanib or Sorafenib	Overall survival (OS) is defined as the time from the date of randomization to date of death due to any cause. In the absence of confirmation of death, survival time will be censored at the last date the subject is known to be alive. Subjects lacking data beyond randomization will have their survival times censored on the date of randomization.	Date of randomization to date of death
Secondary	Objective Response Rate (ORR) of Subjects Randomized to Treatment With Tivozanib or Sorafenib	Objective response rate (ORR) is defined as the percentage of subjects who have at least a 30% reduction in the sum of diameters per RECIST (Version 1.0).	Every 8 weeks from date of randomization until disease progression
Secondary	Duration of Response (DR) of Subjects Randomized to Treatment With Tivozanib or Sorafenib	Duration of response (DR) is defined as the time from the first documentation of objective tumor response to the first documentation of tumor progression per RECIST 1.0 or to death due to any cause.	Assessed every 8 weeks from date of randomization until date of progression
Secondary	Safety and Tolerability of Tivozanib and Sorafenib	Dose reductions and interruptions were allowed for subjects taking tivozanib or sorafenib. Any modification of study drug administration, and the reason for such action, was clearly noted on the subject's eCRF.	From start of treatment therapy to completion of treatment therapy, an average of 11 months
Secondary	To Compare Kidney-specific Symptoms and Health Outcome Measurements in Subjects Randomized to Treatment With Tivozanib or Sorafenib	The Disease Related Symptom Scale of the Functional Assessment of Cancer Therapy - Advanced Kidney Cancer Symptom Index (FKSI-DRS) measured kidney specific symptoms on a 0-36 scale, with lower scores corresponding to worse overall QOL and higher scores corresponding to better overall QOL. The Functional Assessment of Cancer Therapy-General (FACT-G) measured general wellbeing scored on a 0-108 scale, with lower scores corresponding to worse overall QOL and higher scores corresponding to better overall QOL. The European Quality of Life-5 Dimensions (EQ-5D) measured patient health related quality of life scored on a 0-1 scale, with 0 being worse health state and 1 being perfect health state. The European Quality of Life-5 Dimensions Visual Analog Scales (EQ-5D VAS) measured patient health related quality of life on a visual analog scale from 0 to 100, with 0 being the worst and 100 being the best. These scales were self-administered by patients at the start of the visit.	At Day 1 of each 28 day cycle throughout the course of the study, for an average of 11 months per subject
Secondary	Pharmacokinetics (Serum Concentrations) of Tivozanib	Samples for tivozanib serum concentrations will be collected at the following time points: Cycle 1, Day 1 (prior to dosing), Cycle 1, Day 15 (prior to dosing), Cycle 2, Day 1 (prior to dosing), and Cycle 2, Day 22-28. The serum concentrations of tivozanib were tabulated for individual subjects and summarized by nominal time using standard descriptive statistics (concentrations presented in ng/mL).	Cycle 1, Day 1 (prior to dosing), Cycle 1, Day 15 (prior to dosing), Cycle 2, Day 1 (prior to dosing), and Cycle 2, Day 22-28

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