An Extension Treatment Protocol for Subjects Who Have Participated in a Study of Tivozanib Versus Sorafenib in Kidney Carcinoma (Protocol AV-951-09-301).

Advanced Renal Cell Carcinoma Clinical Trial

Official title:

An Extension Treatment Protocol for Subjects Who Have Participated in a Phase 3 Study of Tivozanib vs. Sorafenib in Renal Cell Carcinoma (Protocol AV-951-09-301).

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01076010
• Other study ID #: AV-951-09-902
• Secondary ID: 2009-015987-32
• Status: Completed
• Phase: Phase 3
• Start date: March 2010
• Est. completion date: July 2014

Study information

• Verified date: September 2020
• Source: AVEO Pharmaceuticals, Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Open-label, multi-center extension treatment protocol to allow access to tivozanib and sorafenib for subjects who have participated on the AV-951-09-301 protocol. Eligible subjects who were randomized to receive sorafenib on AV-951-09-301 and had documented progression of disease will receive a tivozanib dose of 1.5 mg/day. Eligible subjects who were randomized to tivozanib or sorafenib in AV-951-09-301, and displayed clinical benefit and acceptable tolerability to treatment, will continue to receive tivozanib or sorafenib at the same dose and schedule as in AV-951-09-301.

Description:

This is an extension treatment protocol to allow access to tivozanib or sorafenib for subjects enrolled on AV-951-09-301(parent protocol). Subjects who failed sorafenib on the parent protocol will be offered tivozanib. Subjects who were randomized to tivozanib, and demonstrated clinical benefit and acceptable tolerability will be offered long-term access to tivozanib. Subjects who were randomized to sorafenib, and demonstrated clinical benefit and acceptable tolerability will be offered long-term access to sorafenib. Subjects who continue receiving sorafenib on this protocol and progress will be allowed to cross-over to tivozanib.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 277
• Est. completion date: July 2014
• Est. primary completion date: July 2014
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

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 or sorafenib on protocol AV-951-09-301.

2. Eastern Cooperative Oncology Group performance status = 2 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

Exclusion Criteria:

1. Newly identified central nervous system (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 for allowed steroid maintenance therapy.

2. Duration since last dose on Protocol AV-951-09-301:

1. For subjects continuing tivozanib or sorafenib (subjects who demonstrated clinical benefit and acceptable tolerability during treatment with tivozanib or sorafenib on protocol AV-951-09-301): more than 2 weeks since last dose of tivozanib or sorafenib.

2. For subjects initiating tivozanib (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

• Absolute neutrophil count < 1500 per mm3

• Platelet count < 75,000 per mm3

• Prothrombin time or Partial thromboplastin time >1.5 × upper limit of normal (ULN)

5. Any of the following serum chemistry abnormalities:

• Total bilirubin > 1.5 × ULN (or > 2.5 × ULN for subjects with Gilbert's syndrome)

• Aspartate aminotransferase or alanine aminotransferase > 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) Intrauterine device 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).

Related Conditions & MeSH terms

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

Intervention

Drug:
• Tivozanib
Tivozanib capsules, administered orally, on a dosing schedule of 3 weeks of treatment (beginning on Day 1) followed by 1 week off treatment. One cycle was defined as 4 weeks of treatment.
• Sorafenib
Sorafenib tablets, 400 mg twice daily, administered orally for 4 weeks (1 cycle = 4 weeks). One cycle was defined as 4 weeks of treatment. Cycles were repeated every 4 weeks.

Locations

Country	Name	City	State
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 122	Santiago
Chile	Site 123	Temuco
Czechia	Site 411	Prague 8
France	Site 133	Saint Herblain Cedex
Hungary	Site 423	Budapest
Hungary	Site 421	Kaposvár
Hungary	Site 422	Pécs
India	Site 156	Ahmedabad	Gujarat
India	Site 154	Delhi
India	Site 191	Jaipur	Rajasthan
India	Site 150	Kolkata	West Bengal
India	Site 158	Lucknow	Uttar Pradesh
India	Site 151	Nashik	Maharashtra
India	Site 153	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 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	Yaroslavl
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	Dniproperovsk
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 172	Leicester
United States	Site 187	Dallas	Texas
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,  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	Number of Days Subjects Received Treatment in Each Treatment Arm	Number of days subjects received treatment who were from Protocol AV-951-09-301 who either continued on tivozanib in this trial (subjects with first-line experience on tivozanib treatment), who crossed over from sorafenib to tivozanib in this trial (crossover subjects) participated in, and who continued on sorafenib in this trial (subjects with first-line experience on sorafenib treatment). Subjects could be discontinued due to unacceptable toxicities or clinical or documented PD	From enrollment to until all subjects discontinue (due to documented progressive disease [PD] or unacceptable toxicities) or until 3 years after the first subject was enrolled in Protocol AV-951-09-902
Primary	Number of Cycles Subjects Received Treatment in Each Treatment Arm	Number of cycles subjects received who were from Protocol AV-951-09-301 who either continued on tivozanib in this trial (subjects with first-line experience on tivozanib treatment), who crossed over from sorafenib to tivozanib in this trial (crossover subjects) participated in, and who continued on sorafenib in this trial (subjects with first-line experience on sorafenib treatment). Subjects could be discontinued due to unacceptable toxicities or clinical or documented PD	From enrollment to until all subjects discontinue (due to documented PD or unacceptable toxicities) or until 3 years after the first subject was enrolled in Protocol AV-951-09-902
Primary	Total Dose Administered to Subjects in Each Treatment Arm (mg)	The total dose administered to subjects who were from Protocol AV-951-09-301 who either continued on tivozanib in this trial (subjects with first-line experience on tivozanib treatment), who crossed over from sorafenib to tivozanib in this trial (crossover subjects) participated in, and who continued on sorafenib in this trial (subjects with first-line experience on sorafenib treatment). Subjects could be discontinued due to unacceptable toxicities or clinical or documented PD	From enrollment to until all subjects discontinue (due to documented PD or unacceptable toxicities) or until 3 years after the first subject was enrolled in Protocol AV-951-09-902
Primary	Average Daily Dose Administered to Subjects in Each Treatment Arm	The average daily dose administered to subjects who were from Protocol AV-951-09-301 who either continued on tivozanib in this trial (subjects with first-line experience on tivozanib treatment), who crossed over from sorafenib to tivozanib in this trial (crossover subjects) participated in, and who continued on sorafenib in this trial (subjects with first-line experience on sorafenib treatment). Subjects could be discontinued due to unacceptable toxicities or clinical or documented PD	From enrollment to until all subjects discontinue (due to documented PD or unacceptable toxicities) or until 3 years after the first subject was enrolled in Protocol AV-951-09-902
Primary	Relative Dose Intensity (RDI) of Treatment Administered to Subjects in Each Treatment Arm	RDI is defined as 100% times the actual dose intensity divided by the intended dose intensity. The RDI of subjects who were from Protocol AV-951-09-301 who either continued on tivozanib in this trial (subjects with first-line experience on tivozanib treatment), who crossed over from sorafenib to tivozanib in this trial (crossover subjects) participated in, and who continued on sorafenib in this trial (subjects with first-line experience on sorafenib treatment). Subjects could be discontinued due to unacceptable toxicities or clinical or documented PD	From enrollment to until all subjects discontinue (due to documented PD or unacceptable toxicities) or until 3 years after the first subject was enrolled in Protocol AV-951-09-902
Primary	Number of Subjects With Adverse Events	Number of subjects with Treatment-Related Adverse Events (AEs) as assessed by Common Terminology Criteria for Adverse Events v3.0	From enrollment assessed up to 3 years of treatment or until follow-up (up to 30 days end-of-trial visit after treatment discontinuation), whichever occurs earlier
Secondary	Number of Subjects With Objective Response Rate (ORR) Who Continued Treatment With Tivozanib or Sorafenib and Who Received Tivozanib After Failure of Sorafenib	ORR is defined as the proportion of subjects with confirmed complete response (CR) or confirmed partial response (PR) according to RECIST (Version 1.0), relative to the total population of dosed subjects. CR is disappearance of all target and non-target lesions and normalization of tumor marker levels. At least a 30% decrease in the sum of the loading dose (LD) of target lesions, taking as reference the baseline sum LD. To allow long-term access to sorafenib for subjects who participated in Protocol AV-951-09-301 (NCT01030783), and demonstrated clinical benefit and acceptable tolerability to sorafenib.	From Day 1 to the end of treatment (EOT) Visit, approximately every 8 weeks
Secondary	Duration of Response (DR)	DR was defined as the time from the first documentation of objective tumor response (confirmed CR or confirmed PR) according to RECIST (Version 1.0) to the first documentation of objective tumor progression or to death due to any reason. DR was calculated for the subgroup of subjects with a confirmed objective tumor response (PR or CR). CR is Disappearance of all target and non-target lesions and normalization of tumor marker levels. PR is At least a 30% decrease in the sum of the LD of target lesions, taking as reference the baseline sum LD. Number of subjects with disease progression or death and censored endpoints were summarized and statistical analysis were performed for duration of response.	From the first documentation of objective tumor response to the first documentation of objective tumor progression, assessed up to treatment discontinuation or to death due to any reason or maximum up to 3 years, whichever occurs earlier
Secondary	Progression-free Survival (PFS)	PFS was defined as the date of first dose of study drug to the first documentation of objective tumor progression or death due to any reason, whichever occurred first. For the crossover subjects and subjects with first-line experience on tivozanib treatment, the timeframe for PFS assessment started from the date of first dose of tivozanib in the AV-951-09-902 study. For subjects with first-line experience on sorafenib treatment, the timeframe for PFS assessment started from the date of first dose of sorafenib in the AV-951-09-902. Number of subjects with disease progression or death was summarized and statistical analysis were performed for PFS.	From the date of first dose of study drug (tivozanib or sorafenib) in the AV-951-09-902 study to the first documentation of objective tumor progression or death due to any reason or maximum up to 3 years, whichever occurred first
Secondary	Overall Survival (OS)	OS was defined as the time from the first dose of study drug (tivozanib or sorafenib) date on this study to date of death due to any cause. Number of subjects died or alive was summarized and statistical analysis were performed for OS.	From the date of first dose of study drug (tivozanib or sorafenib) in the AV-951-09-902 study to death due to any reason or maximum up to 3 years, whichever occurred first

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