Clinical trial NCT01030783: A Study to Compare Tivozanib (AV-951) to Sorafenib in Subjects With Advanced Renal Cell Carcinoma
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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Advanced Renal Cell Carcinoma
Lead sponsor: AVEO Pharmaceuticals, Inc.
Sponsor class: INDUSTRY
First posted: 2009-12-11
Enrollment: 517
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.

Detailed 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).

Eligibility criteria: 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.)

Primary outcomes:
measure: Progression-free Survival (PFS) of Subjects With Advanced Renal Cell Cancer (RCC) Randomized to Treatment With Tivozanib or Sorafenib
timeFrame: 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 outcomes:
measure: Overall Survival (OS) of Subjects Randomized to Treatment With Tivozanib or Sorafenib
timeFrame: Date of randomization to date of death
measure: Objective Response Rate (ORR) of Subjects Randomized to Treatment With Tivozanib or Sorafenib
timeFrame: Every 8 weeks from date of randomization until disease progression
measure: Duration of Response (DR) of Subjects Randomized to Treatment With Tivozanib or Sorafenib
timeFrame: Assessed every 8 weeks from date of randomization until date of progression
measure: Safety and Tolerability of Tivozanib and Sorafenib
timeFrame: From start of treatment therapy to completion of treatment therapy, an average of 11 months
measure: To Compare Kidney-specific Symptoms and Health Outcome Measurements in Subjects Randomized to Treatment With Tivozanib or Sorafenib
timeFrame: At Day 1 of each 28 day cycle throughout the course of the study, for an average of 11 months per subject
measure: Pharmacokinetics (Serum Concentrations) of Tivozanib
timeFrame: 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
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: Site 185
state: California
city: Gainesville
country: United States
facility: Site 180
state: Florida
city: Orlando
country: United States
facility: Site 184
state: Florida
city: Minneapolis
country: United States
facility: Site 182
state: Minnesota
city: New York
country: United States
facility: Site 186
state: New York
city: Dallas
country: United States
facility: Site 187
state: Texas
city: Sante Fe
country: Argentina
facility: Site 102
city: Plovdiv
country: Bulgaria
facility: Site 403
city: Sofia
country: Bulgaria
facility: Site 404
city: Sofia
country: Bulgaria
facility: Site 400
city: Varna
country: Bulgaria
facility: Site 401
city: Veliko Tarnovo
country: Bulgaria
facility: Site 402
city: Montréal
country: Canada
facility: Site 110
state: Quebec
city: La Reina
country: Chile
facility: Site 121
state: Santiago De Chile
city: Santiago
country: Chile
facility: Site 122
city: Temuco
country: Chile
facility: Site 123
city: Prague 8
country: Czechia
facility: Site 411
city: Marseille
country: France
facility: Site 130
city: Saint Herblain Cedex
country: France
facility: Site 133
city: Budapest
country: Hungary
facility: Site 423
city: Kaposvár
country: Hungary
facility: Site 421
city: Pécs
country: Hungary
facility: Site 422
city: Szombathely
country: Hungary
facility: Site 424
city: Hyderabad
country: India
facility: Site 157
state: Andhra Pradesh
city: Patna
country: India
facility: Site 190
state: Bihar
city: Ahmedabad
country: India
facility: Site 156
state: Gujarat
city: Nashik
country: India
facility: Site 151
state: Maharashtra
city: Pune
country: India
facility: Site 153
state: Maharashtra
city: Pune
country: India
facility: Site 159
state: Maharashtra
city: Jaipur
country: India
facility: Site 191
state: Rajasthan
city: Jaipur
country: India
facility: Site 155
state: Rajasthan
city: Vellore
country: India
facility: Site 152
state: Tamil Nadu
city: Lucknow
country: India
facility: Site 158
state: Uttar Pradesh
city: Kolkata
country: India
facility: Site 150
state: West Bengal
city: Delhi
country: India
facility: Site 154
city: Arezzo
country: Italy
facility: Site 160
city: Pavia
country: Italy
facility: Site 161
city: Roma
country: Italy
facility: Site 162
city: Bialystok
country: Poland
facility: Site 432
city: Bydgoszcz
country: Poland
facility: Site 434
city: Gdansk
country: Poland
facility: Site 431
city: Olsztyn
country: Poland
facility: Site 435
city: Poznan
country: Poland
facility: Site 433
city: Warsaw
country: Poland
facility: Site 430
city: Warsaw
country: Poland
facility: Site 436
city: Brasov
country: Romania
facility: Site 444
city: Bucharest
country: Romania
facility: Site 441
city: Bucharest
country: Romania
facility: Site 440
city: Bucharest
country: Romania
facility: Site 443
city: Timisoara
country: Romania
facility: Site 442
city: Ufa
country: Russian Federation
facility: Site 459
state: Republic Of Bashkortostan
city: Chelyabinsk
country: Russian Federation
facility: Site 451
city: Ekaterinburg
country: Russian Federation
facility: Site 455
city: Ioshkar Ola
country: Russian Federation
facility: Site 468
city: Kazan
country: Russian Federation
facility: Site 452
city: Moscow
country: Russian Federation
facility: Site 454
city: Moscow
country: Russian Federation
facility: Site 453
city: Moscow
country: Russian Federation
facility: Site 458
city: Moscow
country: Russian Federation
facility: Site 460
city: Moscow
country: Russian Federation
facility: Site 461
city: Moscow
country: Russian Federation
facility: Site 462
city: Nizhny Novgorod
country: Russian Federation
facility: Site 450
city: Obninsk
country: Russian Federation
facility: Site 456
city: Omsk
country: Russian Federation
facility: Site 467
city: Pyatigorsk
country: Russian Federation
facility: Site 463
city: Rostov-on-Don
country: Russian Federation
facility: Site 457
city: St. Petersburg
country: Russian Federation
facility: Site 466
city: St. Petersburg
country: Russian Federation
facility: Site 465
city: Yaroslavi
country: Russian Federation
facility: Site 464
city: Belgrade
country: Serbia
facility: Site 480
city: Belgrade
country: Serbia
facility: Site 481
city: Belgrade
country: Serbia
facility: Site 482
city: Nis
country: Serbia
facility: Site 483
city: Sremska Kamenica
country: Serbia
facility: Site 484
city: Chernihiv
country: Ukraine
facility: Site 491
city: Dniproperovsk
country: Ukraine
facility: Site 492
city: Dnipropetrovsk
country: Ukraine
facility: Site 498
city: Donetsk
country: Ukraine
facility: Site 493
city: Donetsk
country: Ukraine
facility: Site 496
city: Ivano-Frankivsk
country: Ukraine
facility: Site 490
city: Kharkiv
country: Ukraine
facility: Site 494
city: Uzhhorod
country: Ukraine
facility: Site 497
city: Zaporizhia
country: Ukraine
facility: Site 495
city: Cambridge
country: United Kingdom
facility: Site 170
city: Ipswich
country: United Kingdom
facility: Site 173
city: Leicester
country: United Kingdom
facility: Site 172
Study officials:
affiliation: Memorial Sloan Kettering Cancer Center
name: Robert J. Motzer, MD
role: PRINCIPAL_INVESTIGATOR
References: