Study to Compare Tivozanib in Combination With Nivolumab to Tivozanib Monotherapy in Subjects With Renal Cell Carcinoma

Sponsor

AVEO Pharmaceuticals, Inc. (Industry)

Overall Status

Recruiting

CT.gov ID

NCT04987203

Collaborator

Parexel (Industry), Bristol-Myers Squibb (Industry)

326

Enrollment

166

Locations

Arms

46.7

Anticipated Duration (Months)

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This study will be comparing tivozanib in combination with nivolumab to tivozanib alone in subjects with advanced Renal Cell Carcinoma (RCC) who have had 1 or 2 prior lines of therapy, one of which was an Immune Checkpoint Inhibitor (ICI).

Condition or Disease	Intervention/Treatment	Phase
Renal Cell Carcinoma	Drug: Tivozanib Drug: Nivolumab	Phase 3

Detailed Description

This will be an open-label, randomized, controlled, multicenter, multi-national, parallel-arm study. The study is designed to compare the progression free survival (PFS), overall survival (OS), Objective response rate (ORR), duration of response (DoR), and safety of tivozanib and the combination of tivozanib with nivolumab.

Approximately 326 subjects with refractory advanced RCC at approximately 190 sites will be randomized in a 1:1 ratio to treatment with tivozanib plus nivolumab (163 subjects) or tivozanib (163 subjects). Subjects will be randomly assigned to a treatment.

Subjects will receive 1.34 mg/day (monotherapy arm) or 0.89mg/day (combination arm) of tivozanib once daily (QD) for 3 weeks followed by 1 week off study drug. One cycle will be defined as 4 weeks: 3 weeks on treatment and 1 week off treatment. Subjects who receive nivolumab will be infused with 1 treatment of nivolumab at specified dose on specified days of each Cycle.

Subjects with documented stable disease or an objective response may continue to receive both tivozanib and nivolumab therapy at the same dose and schedule until progression as long as the tolerability is acceptable. Nivolumab will be discontinued in all subjects after 2 years. A Safety Follow-up Visit will be performed 30 days (± 7 days) after the last dose of study drug.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

326 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

TiNivo-2: A Phase 3, Randomized, Controlled, Multicenter, Open-label Study to Compare Tivozanib in Combination With Nivolumab to Tivozanib Monotherapy in Subjects With Renal Cell Carcinoma Who Have Progressed Following One or Two Lines of Therapy Where One Line Has an Immune Checkpoint Inhibitor

Actual Study Start Date :

Sep 9, 2021

Anticipated Primary Completion Date :

Aug 1, 2024

Anticipated Study Completion Date :

Aug 1, 2025

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Tivozanib in Combination with Nivolumab Subjects with advanced RCC will receive 0.89 mg of tivozanib once daily (QD) for 3 weeks followed by 1 week off study drug and nivolumab every 4 weeks on Day 1 of each Cycle, until disease progression or unacceptable toxicities occur, other withdrawal criteria are met, or completion of 2 years of treatment [for nivolumab] whichever occurs first.	Drug: Tivozanib Tivozanib will be administered orally. Drug: Nivolumab Nivolumab will be administered via intravenous infusion.
Experimental: Tivozanib Subjects with advanced RCC will receive 1.34 mg of tivozanib once daily (QD) for 3 weeks followed by 1 week off study drug until disease progression or unacceptable toxicities occur, or other withdrawal criteria are met.	Drug: Tivozanib Tivozanib will be administered orally.

Arm

Intervention/Treatment

Experimental: Tivozanib in Combination with Nivolumab

Subjects with advanced RCC will receive 0.89 mg of tivozanib once daily (QD) for 3 weeks followed by 1 week off study drug and nivolumab every 4 weeks on Day 1 of each Cycle, until disease progression or unacceptable toxicities occur, other withdrawal criteria are met, or completion of 2 years of treatment [for nivolumab] whichever occurs first.

Drug: Tivozanib

Tivozanib will be administered orally.

Drug: Nivolumab

Nivolumab will be administered via intravenous infusion.

Experimental: Tivozanib

Subjects with advanced RCC will receive 1.34 mg of tivozanib once daily (QD) for 3 weeks followed by 1 week off study drug until disease progression or unacceptable toxicities occur, or other withdrawal criteria are met.

Drug: Tivozanib

Tivozanib will be administered orally.

Outcome Measures

Primary Outcome Measures

Progression free survival [until progressive disease [PD] (Approximately 30 months)]
Comparison of the PFS of tivozanib in combination with nivolumab to tivozanib in subjects with RCC who have progressed following 1 or 2 lines of therapy. PFS is defined as the time from randomization to first documentation of objective tumor progression (progressive disease [PD], radiological) according to Response Evaluation Criteria In Solid Tumors (RECIST), or death due to any reasons whichever comes first.

Secondary Outcome Measures

Overall Survival [From Screening (Days -28 to -1) until death (Approximately 42 months)]
Comparsion of the OS of subjects randomized to treatment with tivozanib in combination with nivolumab compared to tivozanib. OS is defined as the time from the date of randomization to date of death due to any cause.
Objective Response Rate [From Screening (Days -28 to -1) until PD (Approximately 30 months)]
Comparison of ORR of subjects randomized to treatment with tivozanib in combination with nivolumab compared to tivozanib. ORR is defined as the proportion of subjects with confirmed complete response or confirmed partial response according to RECIST relative to the total population of randomized subjects.
Duration of Response [From Screening (Days -28 to -1) until PD or death (Approximately 30 months)]
Comparison of DoR of subjects randomized to treatment with tivozanib in combination with nivolumab compared to tivozanib. DoR is defined as the time from the first documentation of objective tumor response to the first documentation of objective tumor progression or to death due to any cause.
Number of subjects with serious and non-serious adverse events [From Screening (Day -28 to Day -1) to Follow-up visit (30 days after last dose of study drug ± 7 days)]
Assessment of the safety and tolerability of tivozanib in combination with nivolumab compared to tivozanib.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 130 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Radiographic disease progression during or following at least 6 weeks of treatment with ICI for locally advanced or metastatic RCC with a clear cell component either in first- or second-line treatment.
Subjects must have recovered from the adverse events of prior therapy or returned to baseline.
Histologically or cytologically confirmed RCC with a clear cell component.
Measurable disease per RECIST criteria Version 1.1.
Eastern Cooperative Oncology Group performance status of 0 or 1.
All participants must follow protocol defined contraceptive measures.

Exclusion Criteria:

More than 2 prior lines of therapy in the advanced or metastatic setting.
History of life-threatening toxicity related to prior immune therapy.
Active, known, or suspected autoimmune disease as well as those that required discontinuation of prior immuno-oncological (IO) therapy due to immune mediated AEs.
Uncontrolled hypertension.
More than 1 prior line of therapy with a checkpoint inhibitor in the metastatic setting.
Subjects on immune suppressive therapy for organ transplant or subjects with a history of genetic or acquired immune suppression disease such as human immunodeficiency virus (HIV) [Patients with HIV who have CD4+ T-cell counts >350 cells/µL, without a history of acquired immune deficiency syndrome (AIDS)-defining opportunistic infections, and are on established antiretroviral therapy which does not include a cytochrome P450 (CYP)3A4 inducer, for at least 4 weeks and have an HIV viral load less than 400 copies/mL, are eligible].
History of clinically significant interstitial lung disease or current non-infectious pneumonitis.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Genesis Cancer and Blood Institute	Hot Springs	Arkansas	United States	71913
2	Providence Medical Foundation	Fullerton	California	United States	92835
3	University of California San Diego	La Jolla	California	United States	92037
4	Kaiser Permanente Riverside Medical Center	Riverside	California	United States	92505
5	Mount Sinai Comprehensive Canc	Miami Beach	Florida	United States	33140
6	NorthShore University HealthSystem	Evanston	Illinois	United States	60201
7	University of Kentucky UK Markey Cancer Center	Lexington	Kentucky	United States	40536
8	Tulane Cancer Center Clinic - Oncology	New Orleans	Louisiana	United States	70112
9	University of Maryland Medical Center-Greenebaum Cancer Ctr	Baltimore	Maryland	United States	21201
10	John Hopkins Medicine - Hematology/oncology	Baltimore	Maryland	United States	21287
11	Dana-Farber Cancer Institute - Medicine	Boston	Massachusetts	United States	02215
12	Henry Ford Hospital	Detroit	Michigan	United States	48202
13	St. Vincent Frontier Cancer Center	Billings	Montana	United States	59102-6746
14	Nebraska Cancer Center	Omaha	Nebraska	United States	68130
15	Oncology Hematology West PC dba Nebraska Cancer Specialists	Omaha	Nebraska	United States	68130
16	US Oncology - Comprehensive Cancer Centers of Nevada (CCCN)	Las Vegas	Nevada	United States	89169
17	Memorial Sloan Kettering Cancer Center - Basking Ridge - Oncology	Basking Ridge	New Jersey	United States	07920
18	Memorial Sloan Kettering Cancer Center - Monmouth - Oncology	Middletown	New Jersey	United States	07748-3052
19	Memorial Sloan Kettering Cancer Center - Oncology - Bergen	Montvale	New Jersey	United States	07645
20	University of New Mexico - Comprehensive Cancer Center	Albuquerque	New Mexico	United States	87131-0001
21	Memorial Sloan Kettering Cancer Center - Commack	Commack	New York	United States	11725
22	Memorial Sloan Kettering Cancer Center - Westchester	Harrison	New York	United States	10604
23	Memorial Sloan Kettering Cancer Center (MSKCC) - Memorial Hospital	New York	New York	United States	10065
24	Stony Brook University Cancer Clinical Trials	Stony Brook	New York	United States	11794
25	Memorial Sloan Kettering Cancer Center - Nassau	Uniondale	New York	United States	11553
26	Cleveland Clinic	Cleveland	Ohio	United States	44195-0001
27	Fox Chase Cancer Center - Medical Oncology	Philadelphia	Pennsylvania	United States	19111-2497
28	UH Cleveland Medical Center	Columbia	South Carolina	United States	29210
29	Baptist Cancer Center	Memphis	Tennessee	United States	38120
30	Vanderbilt-Ingram Cancer Center	Nashville	Tennessee	United States	37232
31	Inova Schar Cancer Institute - Medical Oncology	Fairfax	Virginia	United States	22031
32	University Of Washington - Medical Center	Seattle	Washington	United States	98109
33	Northwest Medical Specialties PLLC	Tacoma	Washington	United States	98405-5016
34	Centro Oncológico Korben	Buenos Aires	Ciudad Autónoma De Buenos Aire	Argentina	C1280AEB
35	Clínica Viedma	Viedma	Río Negro	Argentina	R8500JYJ
36	Centro Oncologico de Rosario	Rosario	Santa Fe	Argentina	S2000KZE
37	Centro para la Atención Integral del paciente Oncológico	San Miguel de Tucumán	Tucumán	Argentina	T4000GTB
38	Instituto Fleming	Buenos Aires		Argentina	C1426ANZ
39	Clínica Universitaria Reina Fabiola - Oncology	Córdoba		Argentina	X5004FHP
40	Hospital Privado de Comunidad	Mar Del Plata		Argentina	B7602
41	Liverpool Hospital Cancer Therapy Centre	Liverpool	New South Wales	Australia	2170
42	Northern Cancer Institute	St. Leonards	New South Wales	Australia	2065
43	Mater Misericordiae Limited	Brisbane	Queensland	Australia	4101
44	Townsville Hospital and Health Service (THHS) HREC/RGO	Douglas	Queensland	Australia	4814
45	Princess Alexandra Hospital	Woolloongabba	Queensland	Australia	4102
46	Flinders Medical Centre	Bedford Park	South Australia	Australia
47	Cabrini Health - Cabrini Institute	East Melbourne	Victoria	Australia	8006
48	St Vincent's Hospital Melbourne	Fitzroy	Victoria	Australia	3065
49	Sunshine Hospital	Geelong	Victoria	Australia	3220
50	Institut Jules Bordet - Oncologie Médicale	Anderlecht	Brussels Capital Region	Belgium	1070
51	Jessa Ziekenhuis - Campus Virga Jesse - Medische Oncologie	Hasselt	Limburg	Belgium	3500
52	UZ Gent - Medische Oncologie	Gent	Oost-Vlaanderen	Belgium	9000
53	AZ Sint-Jan Brugge - Oostende AV - Campus Sint-Jan - Oncology	Brugge	West-Vlaanderen	Belgium	8000
54	ZNA Middelheim	Antwerpen		Belgium	2020
55	CHU Brugmann - Victor Horta	Bruxelles		Belgium	1020
56	AZ Groeninge - Campus Kennedylaan	Kortrijk		Belgium	8500
57	Instituto Brasileiro de Controle do Cancer - ibcc	São Paulo		Brazil	03102-002
58	Tom Baker Cancer Centre	Calgary	Alberta	Canada	T2N 4N2
59	BC Cancer - Vancouver Centre	Vancouver	British Columbia	Canada	V5Z 4E6
60	Sunnybrook Research Institute, sunnybrook Health Sciences Ct	Toronto	Ontario	Canada	M4N 3M5
61	University Health Network - Princess Margaret Cancer Centre	Toronto	Ontario	Canada	M5G 2M9
62	Meditek Ltda.	Santiago de Chile	Región Metropolitana De Santiago	Chile	8420383
63	Centro de Estudios Clínicos SAGA SpA	Santiago	Región Metropolitana De Santia	Chile
64	ACEREY Centro de Investigación Clínica Oncológica	Viña del mar	Valparaíso	Chile	2520612
65	Centro de Investigaciones Clinicas Viña del Mar	Viña Del Mar	Valparaíso	Chile	254-0364
66	University Hospital Brno	Brno	Brno-město	Czechia	625 00
67	NH Hospital a.s.	Horovice		Czechia	268 31
68	FN Hradec Kralove	Hradec Kralove		Czechia	500 05
69	Fakultni nemocnice Olomouc	Olomouc		Czechia	779 00
70	FN Kralovske Vinohrady	Praha 10		Czechia	100 34
71	Fakultni Thomayerova nemocnice	Praha 4		Czechia	140 59
72	Institut de cancérologie de Strasbourg Europe - ICANS	Strasbourg	Alsace	France	67200
73	Institut Paoli Calmettes - HÃ´pital de jour	Marseille	Bouches-du-Rhône	France	13273
74	Hopital Saint-Andre - Service d'Oncologie Medicale	Bordeaux	Gironde	France	33075
75	Hopital Foch	Suresnes	Hauts-de-Seine	France	92151
76	CHU Michallon - Hopital Nord - Cancérologie Et Hématologie	Grenoble	Isère	France	38043
77	Hôpital privé Le Bois	Lille	Nord	France	59000
78	Centre Hospitalier de Poitiers	Poitiers	Poitou-Charentes	France	86021
79	Hospices Civils de Lyon (HCL) - Centre Hospitalier Lyon-Sud	Pierre-Bénite	Rhône-Alpes	France	69495
80	Centre Leon Berard - departement d'oncologie medicale	Lyon	Rhône	France	69373
81	Clinique Victor Hugo - Hematologie	Le Mans	Sarthe	France	72000
82	CHD Vendee La Roche sur Yon - Gastro-Entérologie	La Roche-sur-Yon		France	85925
83	Centre de Lutte Contre le Cancer (CLCC)	Nice		France	06189
84	ICO - Site Rene Gauducheau - Oncologie Medicale	St Herblain		France	44805
85	Hopital Trousseau - medical oncology	Tours		France	37044
86	Institut de Cancérologie de Lorraine	Vandœuvre-lès-Nancy		France	54511
87	Centre de Lutte Contre le Cancer (CLCC) - Gustave Roussy (Institut de Cancerologie Gustave-Roussy)	Villejuif	Île-de-France	France	94805
88	Universitätsklinikum Heidelberg	Heidelberg	Baden-Württemberg	Germany	69120
89	University Hospital Tuebingen	Tübingen	Baden-Württemberg	Germany	72076
90	Universitätsklinikum Erlangen - Urologische und Kinderurologische Universitätsklinik (Erlangen)	Erlangen	Bayern	Germany	91054
91	Medizinische Hochschule Hannover	Hannover	Niedersachsen	Germany	30625
92	Evangelisches Klinikum Bethel gGmbH	Bielefeld	Nordrhein-Westfalen	Germany	33611
93	Universitaetsklinikum Duesseldorf AöR	Düsseldorf	Nordrhein-Westfalen	Germany	40225
94	Universitätsmedizin Mainz - III. Medizinische Klinik und Poliklinik	Mainz	Rheinland-Pfalz	Germany
95	Praxis Eckert	Lutherstadt Eisleben	Sachsen-Anhalt	Germany	06295
96	Universitätsklinikum Carl Gustav Carus	Dresden	Sachsen	Germany	01307
97	University Hospital Hamburg- Eppendorf	Hamburg		Germany	20246
98	P.O. Ss. Annunziata	Chieti Scalo	Chieti	Italy	66013
99	IRST	Meldola (Fc)	Forli	Italy	47014
100	Centro Riferimento Oncologico di Aviano	Aviano	Pordenone	Italy	cB2 0QQ
101	Ospedale S.Donato, AUSL 8 di Arezzo	Arezzo		Italy	52100
102	Ospedale Cannizzaro, AO per l'Emergenza Cannizzaro	Catania		Italy	95126
103	Azienda Mater Domini	Catanzaro		Italy	88100
104	PO di Cremona, ASST di Cremona - Oncologia medica	Cremona		Italy
105	AOUC Azienda Ospedaliero-Universitaria Careggi	Firenze		Italy	50134
106	European Institute of Oncology	Milano		Italy	20141
107	AOU Policlinico di Modena - Attività Integrata di Oncologi	Modena		Italy	41124
108	IRCCS Fondazione "Giovanni Pas	Napoli		Italy	80131
109	IRCCS Policlinico San Matteo	Pavia		Italy	27100
110	SO S.Chiara, AOU Pisana - Oncologia 2	Pisa		Italy	56126
111	Fondazione Policlinico Universitario Agostino Gemelli	Roma		Italy	'00168
112	AO S.Camillo-Forlanini	Roma		Italy	00152
113	Azienda Ospedaliera Santa Maria di Terni	Terni		Italy	05100
114	iCan Oncology Center Centro Medico AVE	Monterrey	Nuevo León	Mexico	64710
115	Oaxaca Site Management Organization S.C. (OSMO) - Investigacion Clinica - Pharmacy	México	Oaxaca	Mexico	68000
116	Cuidados Oncologicos	Santiago De Querétaro	Querétaro	Mexico
117	Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán	Tlalpan		Mexico	14080
118	Szpital Specjalistyczny im. L. Rydygiera w Krakowie	Kraków	Malopolskie	Poland	31-826
119	Europejskie Centrum Zdrowia Otwock, Szpital im. F. Chopina	Otwock	Mazowieckie	Poland	05-400
120	Specjalistyczny Szpital Onkologiczny NU-MED	Tomaszów Mazowiecki	Mazowieckie	Poland	97-200
121	Szpital Specjalist. w Brzozowie,Podkarpacki Ośrodek Onkologi	Brzozow	Podkarpackie	Poland	36-200
122	Nzoz Mrukmed Lekarz Beata Madej-Mruk I Partner Sp. P.	Rzeszow	Podkarpackie	Poland	35-021
123	COPERNICUS Podmiot Leczn. Sp z o.o.,Wojew. Centrum Onkologii	Gdańsk	Pomorskie	Poland	80-219
124	Szpital Kliniczny Przemienienia Panskiego UM w Poznaniu	Poznan	Wielkopolskie	Poland	60-569
125	Wojewodzki Szpital Specjalistyczny	Biala Podlaska		Poland	21-500
126	Centralny Szpital Kliniczny Ministerstwa Spraw Wewnetrznych	Warszawa		Poland	02-507
127	Narodowy Instytut Onkologii im. Marii Skłodowskiej-Curie - Państwowy Instytut Badawczy	Warszawa		Poland	02-781
128	Uniwersytecki Szpital Kliniczny im. Jana Mikulicza-Radeckiego we Wroclawiu	Wroclaw		Poland	50-556
129	H. Prof. Doutor Fernando Fonseca	Amadora	Lisboa	Portugal	2720-276
130	Instituto Portugues de Oncologia Francisco Gentil	Coimbra		Portugal	3000-075
131	Hospital Particular do Algarve - Gambelas-Faro	Faro		Portugal	8005-226
132	Hospital da Luz	Lisboa		Portugal	1500-650
133	H. de Santa Maria. Centro Hospitalar Lisboa Norte - Oncologia	Lisboa		Portugal	1649-035
134	H. Santo Antonio. Centro Hospitalar do Porto	Porto		Portugal	4099-001
135	Instituto Português Oncologia Francisco Gentil do Porto	Porto		Portugal	4200-072
136	Centro Hospitalar Universitário de São João (CHUSJ)	Porto		Portugal	4200-319
137	H.G.U. de Elche	Elche	Alicante	Spain	03203
138	Hospital Universitario Son Espases	Palma de Mallorca	Baleares	Spain	07010
139	Hospital Universitari Parc Tau	Sabadell	Barcelona	Spain	8208
140	Hospital Universitario Y Politécnico La Fe	Valencia	Valenciana, Comunidad	Spain	46026
141	Institut Català d'Oncologia-Hospital Universitari Germans Trias i Pujol	Badalona		Spain	8916
142	Hospital de La Santa Creu i Sant Pau	Barcelona		Spain	08025
143	Hospital Universitario Vall d'	Barcelona		Spain	08035
144	Institut Catalá d´Oncología (I.C.O.)	Barcelona		Spain	08908
145	Hospital Del Mar	Barcelona		Spain	8003
146	ICO-Hospital Universitari de G	Girona		Spain	17007
147	Hospital Universitario Ramón y Cajal	Madrid		Spain	28034
148	Hospital Clínico San Carlos	Madrid		Spain	28040
149	Hospital U. 12 Octubre	Madrid		Spain	28041
150	Hospital Universitario La Paz	Madrid		Spain	28046
151	C.H.U. de Orense	Orense		Spain	32005
152	Hospital Universitario Virgen	Sevilla		Spain	41009
153	Fundación Instituto Valenciano	Valencia		Spain	46009
154	Addenbrooke's Hospital - Oncology	Cambridge	Cambridgeshire	United Kingdom	CB2 0QQ
155	Mount Vernon Cancer Centre	Northwood	England	United Kingdom	HA6 2JW
156	Beatson West of Scotland Cancer Centre - Oncology	Glasgow	Glasgow City	United Kingdom	G12 0YN
157	Royal Blackburn Hospital - Oncology	Preston	Lancashire	United Kingdom	PR2 9HT
158	Royal Free London NHS Foundation Trust	London	London, City Of	United Kingdom	NW3 2QG
159	Imperial College Healthcare NHS Trust - Hammersmith Hospital	London	London, City Of	United Kingdom	W6 8RF
160	Royal Marsden - Sutton	Sutton	Surrey	United Kingdom	SM2 5PT
161	Royal Marsden Hospital	Sutton	Surrey	United Kingdom	SM2 5PT
162	Singleton Hospital	Swansea	Swansea [Abertawe Gb-ata]	United Kingdom	SA2 8QA
163	Royal Derby Hospital	Derby		United Kingdom	DE22 3NE
164	Leeds Teaching Hospitals NHS Trust	Leeds		United Kingdom	LS9 7TF
165	The Christie NHS Foundation Trust - Medical Oncology	Manchester		United Kingdom	M20 4BX
166	New Cross Hospital	Wolverhampton		United Kingdom	WV10 0QP