A Study to Compare Tivozanib (AV-951) to Sorafenib in Subjects With Advanced Renal Cell Carcinoma (TIVO-1)

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)

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.

Study Overview

• Status: Completed
• Conditions: Advanced Renal Cell Carcinoma
• Intervention / Treatment: Drug: tivozanib (AV-951); Drug: 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).

• Study Type: Interventional
• Enrollment (Actual): 517
• Phase: Phase 3

Contacts and Locations

Study Locations

• Argentina
  • Sante Fe, Argentina, 3077
    • Site 102
• Bulgaria
  • Plovdiv, Bulgaria, 4004
    • Site 403
  • Sofia, Bulgaria, 1431
    • Site 404
  • Sofia, Bulgaria, 1756
    • Site 400
  • Varna, Bulgaria, 9002
    • Site 401
  • Veliko Tarnovo, Bulgaria, 5000
    • Site 402
• Canada
  • Quebec
    • Montréal, Quebec, Canada, H2X 1N8
      • Site 110
• Chile
  • Santiago, Chile, 8320000
    • Site 122
  • Temuco, Chile, 4810469
    • Site 123
  • Santiago De Chile
    • La Reina, Santiago De Chile, Chile, 7510009
      • Site 121
• Czechia
  • Prague 8, Czechia, 180 81
    • Site 411
• France
  • Marseille, France, 13009
    • Site 130
  • Saint Herblain Cedex, France, 44805
    • Site 133
• Hungary
  • Budapest, Hungary, H-1108
    • Site 423
  • Kaposvár, Hungary, H-7400
    • Site 421
  • Pécs, Hungary, H-7624
    • Site 422
  • Szombathely, Hungary, H-9700
    • Site 424
• India
  • Delhi, India, 110085
    • Site 154
  • Andhra Pradesh
    • Hyderabad, Andhra Pradesh, India, 500004
      • Site 157
  • Bihar
    • Patna, Bihar, India, 801505
      • Site 190
  • Gujarat
    • Ahmedabad, Gujarat, India, 380015
      • Site 156
  • Maharashtra
    • Nashik, Maharashtra, India, 422005
      • Site 151
    • Pune, Maharashtra, India, 411004
      • Site 153
    • Pune, Maharashtra, India, 411005
      • Site 159
  • Rajasthan
    • Jaipur, Rajasthan, India, 302004
      • Site 191
    • Jaipur, Rajasthan, India, 302013
      • Site 155
  • Tamil Nadu
    • Vellore, Tamil Nadu, India, 632004
      • Site 152
  • Uttar Pradesh
    • Lucknow, Uttar Pradesh, India, 226003
      • Site 158
  • West Bengal
    • Kolkata, West Bengal, India, 700054
      • Site 150
• Italy
  • Arezzo, Italy, 52100
    • Site 160
  • Pavia, Italy, 27100
    • Site 161
  • Roma, Italy, 00152
    • Site 162
• Poland
  • Bialystok, Poland, 15-027
    • Site 432
  • Bydgoszcz, Poland, 85-168
    • Site 434
  • Gdansk, Poland, 80-952
    • Site 431
  • Olsztyn, Poland, 10-228
    • Site 435
  • Poznan, Poland, 61-878
    • Site 433
  • Warsaw, Poland, 02-781
    • Site 430
  • Warsaw, Poland, 04-141
    • Site 436
• Romania
  • Brasov, Romania, 500085
    • Site 444
  • Bucharest, Romania, 022328
    • Site 441
  • Bucharest, Romania, 041345
    • Site 440
  • Bucharest, Romania, 050659
    • Site 443
  • Timisoara, Romania, 300239
    • Site 442
• Russian Federation
  • Chelyabinsk, Russian Federation, 454087
    • Site 451
  • Ekaterinburg, Russian Federation, 620102
    • Site 455
  • Ioshkar Ola, Russian Federation, 424037
    • Site 468
  • Kazan, Russian Federation, 420029
    • Site 452
  • Moscow, Russian Federation, 105077
    • Site 454
  • Moscow, Russian Federation, 115478
    • Site 453
  • Moscow, Russian Federation, 115478
    • Site 458
  • Moscow, Russian Federation, 115478
    • Site 460
  • Moscow, Russian Federation, 115478
    • Site 461
  • Moscow, Russian Federation, 125284
    • Site 462
  • Nizhny Novgorod, Russian Federation, 603109
    • Site 450
  • Obninsk, Russian Federation, 249036
    • Site 456
  • Omsk, Russian Federation, 644013
    • Site 467
  • Pyatigorsk, Russian Federation, 357500
    • Site 463
  • Rostov-on-Don, Russian Federation, 344022
    • Site 457
  • St. Petersburg, Russian Federation, 193312
    • Site 466
  • St. Petersburg, Russian Federation, 198255
    • Site 465
  • Yaroslavi, Russian Federation, 150054
    • Site 464
  • Republic Of Bashkortostan
    • Ufa, Republic Of Bashkortostan, Russian Federation, 450054
      • Site 459
• Serbia
  • Belgrade, Serbia, 11000
    • Site 480
  • Belgrade, Serbia, 11000
    • Site 481
  • Belgrade, Serbia, 11000
    • Site 482
  • Nis, Serbia, 18000
    • Site 483
  • Sremska Kamenica, Serbia, 21204
    • Site 484
• Ukraine
  • Chernihiv, Ukraine, 14029
    • Site 491
  • Dniproperovsk, Ukraine, 49102
    • Site 492
  • Dnipropetrovsk, Ukraine, 49005
    • Site 498
  • Donetsk, Ukraine, 83092
    • Site 493
  • Donetsk, Ukraine, 83092
    • Site 496
  • Ivano-Frankivsk, Ukraine, 76000
    • Site 490
  • Kharkiv, Ukraine, 61037
    • Site 494
  • Uzhhorod, Ukraine, 88014
    • Site 497
  • Zaporizhia, Ukraine, 69600
    • Site 495
• United Kingdom
  • Cambridge, United Kingdom, CB2 0QQ
    • Site 170
  • Ipswich, United Kingdom, IP4 5WW
    • Site 173
  • Leicester, United Kingdom, LE1 5WW
    • Site 172
• United States
  • California
    • Los Angeles, California, United States, 90095
      • Site 185
  • Florida
    • Gainesville, Florida, United States, 32625
      • Site 180
    • Orlando, Florida, United States, 32806
      • Site 184
  • Minnesota
    • Minneapolis, Minnesota, United States, 55455
      • Site 182
  • New York
    • New York, New York, United States, 10065
      • Site 186
  • Texas
    • Dallas, Texas, United States, 75246
      • Site 187

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: tivozanib (AV-951)	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.
Active Comparator: sorafenib	Drug: 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
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
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
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
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
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
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

Collaborators and Investigators

• Sponsor: AVEO Pharmaceuticals, Inc.
• Investigators: Principal Investigator: Robert J. Motzer, MD, Memorial Sloan Kettering Cancer Center

Publications and helpful links

Helpful Links

• Related Info

Study record dates

Study Major Dates

• Study Start: December 1, 2009
• Primary Completion (Actual): July 1, 2012
• Study Completion (Actual): June 1, 2013

Study Registration Dates

• First Submitted: December 9, 2009
• First Submitted That Met QC Criteria: December 10, 2009
• First Posted (Estimate): December 11, 2009

Study Record Updates

• Last Update Posted (Actual): October 28, 2019
• Last Update Submitted That Met QC Criteria: October 7, 2019
• Last Verified: October 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Urologic Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Kidney Diseases; Urologic Diseases; Adenocarcinoma; Neoplasms, Glandular and Epithelial; Kidney Neoplasms; Carcinoma, Renal Cell; Carcinoma; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Protein Kinase Inhibitors; Sorafenib
• Other Study ID Numbers: AV-951-09-301