A Study of Pazopanib With or Without Abexinostat in Patients With Locally Advanced or Metastatic Renal Cell Carcinoma (RENAVIV)

Sponsor

Xynomic Pharmaceuticals, Inc. (Industry)

Overall Status

Recruiting

CT.gov ID

NCT03592472

Collaborator

(none)

413

Enrollment

Locations

Arms

59.4

Anticipated Duration (Months)

10.9

Patients Per Site

0.2

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This is a randomized, Phase 3, double-blind, placebo-controlled study of pazopanib plus abexinostat versus pazopanib plus placebo in patients with locally advanced unresectable or metastatic renal cell carcinoma (RCC).

Condition or Disease	Intervention/Treatment	Phase
Renal Cell Carcinoma	Drug: Pazopanib Drug: Abexinostat Other: Placebo	Phase 3

Detailed Description

In this randomized, Phase 3, double-blind, placebo-controlled study, patients will be randomized 2:1 to receive either a combination of pazopanib plus abexinostat or pazopanib plus placebo. At the time of disease progression, patient treatment assignment will be unblinded, and those patients randomized to the pazopanib plus placebo treatment arm will have the option of crossing over to receive treatment with a combination of pazopanib plus abexinostat. After providing written informed consent, patients will be screened for study eligibility within 28 days before their first dose of study drug. After screening assessments, patients who are eligible for inclusion in the study will be randomized and receive their first dose of study drug on Cycle 1 Day 1 (C1D1), within 7 days of randomization. A treatment cycle is 28 days in length. Patients may continue to receive study drug until any of the following events: the development of IRC-verified radiographic progression as assessed by RECIST version 1.1, clinical disease progression, unacceptable toxicity, another discontinuation criterion is met, withdrawal of consent, or closure of the study by the sponsor. No maximum duration of therapy has been set.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

413 participants

Allocation:

Randomized

Intervention Model:

Crossover Assignment

Masking:

Double (Participant, Investigator)

Masking Description:

This is a double-blind study. The sponsor, investigators, study coordinators, and the patients will be blinded to the study drug (abexinostat/placebo).

Primary Purpose:

Treatment

Official Title:

A Randomized, Phase 3, Double-blind, Placebo-controlled Study of Pazopanib With or Without Abexinostat in Patients With Locally Advanced or Metastatic Renal Cell Carcinoma(RENAVIV)

Actual Study Start Date :

Jul 17, 2018

Anticipated Primary Completion Date :

Jun 30, 2023

Anticipated Study Completion Date :

Jun 30, 2023

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Pazopanib plus abexinostat Randomized patients will receive a combination of pazopanib plus abexinostat. The patients will receive pazopanib by mouth (p.o.) daily on Days 1 to 28 of each treatment cycle and will receive abexinostat p.o twice daily (BID) on Days 1 to 4, 8 to 11, and 15 to 18 of every 28-day cycle, 2 doses 4 hours apart. Patients will be instructed to take their once- daily oral dose of pazopanib and BID oral dose of abexinostat at the same time each day.	Drug: Pazopanib All patients will receive pazopanib at a starting dose of 800 mg by mouth (p.o.) daily on Days 1 to 28 of each treatment cycle. Patients should be instructed to take their once- daily oral dose of pazopanib at the same time each morning. Each dose of pazopanib should be taken with an 8 oz/240 mL glass of water either 1 hour before or 2 hours after a meal. Patients should be instructed to swallow the tablets whole and not chew them. Other Names: Votrient® Drug: Abexinostat The starting dose and schedule of abexinostat will be 80 mg p.o. BID on Days 1 to 4, 8 to 11, and 15 to 18 of every 28-day cycle, 2 doses 4 hours apart. Each dose of abexinostat should be taken with an 8 oz/240 mL glass of water at least half an hour before meals or more than 2 hours after a meal and must be 4 hours apart. Patients should be instructed to swallow the tablets whole and not chew them. Other Names: PCI-24781
Placebo Comparator: Pazopanib plus placebo Randomized patients will receive a combination of pazopanib plus abexinostat matching placebo. The patients will receive pazopanib by mouth (p.o.) daily on Days 1 to 28 of each treatment cycle and will receive abexinostat matching placebo p.o BID on Days 1 to 4, 8 to 11, and 15 to 18 of every 28-day cycle, 2 doses 4 hours apart. Patients will be instructed to take their once- daily oral dose of pazopanib and BID oral dose of placebo at the same time each day.	Drug: Pazopanib All patients will receive pazopanib at a starting dose of 800 mg by mouth (p.o.) daily on Days 1 to 28 of each treatment cycle. Patients should be instructed to take their once- daily oral dose of pazopanib at the same time each morning. Each dose of pazopanib should be taken with an 8 oz/240 mL glass of water either 1 hour before or 2 hours after a meal. Patients should be instructed to swallow the tablets whole and not chew them. Other Names: Votrient® Other: Placebo The starting dose and schedule of abexinostat matching placebo will be 80 mg p.o. BID on Days 1 to 4, 8 to 11, and 15 to 18 of every 28-day cycle, 2 doses 4 hours apart. Each dose of placebo should be taken with an 8 oz/240 mL glass of water at least half an hour before meals or more than 2 hours after a meal and must be 4 hours apart. Patients should be instructed to swallow the tablets whole and not chew them.

Arm

Intervention/Treatment

Experimental: Pazopanib plus abexinostat

Randomized patients will receive a combination of pazopanib plus abexinostat. The patients will receive pazopanib by mouth (p.o.) daily on Days 1 to 28 of each treatment cycle and will receive abexinostat p.o twice daily (BID) on Days 1 to 4, 8 to 11, and 15 to 18 of every 28-day cycle, 2 doses 4 hours apart. Patients will be instructed to take their once- daily oral dose of pazopanib and BID oral dose of abexinostat at the same time each day.

Drug: Pazopanib

All patients will receive pazopanib at a starting dose of 800 mg by mouth (p.o.) daily on Days 1 to 28 of each treatment cycle. Patients should be instructed to take their once- daily oral dose of pazopanib at the same time each morning. Each dose of pazopanib should be taken with an 8 oz/240 mL glass of water either 1 hour before or 2 hours after a meal. Patients should be instructed to swallow the tablets whole and not chew them.

Other Names:

Votrient®

Drug: Abexinostat

The starting dose and schedule of abexinostat will be 80 mg p.o. BID on Days 1 to 4, 8 to 11, and 15 to 18 of every 28-day cycle, 2 doses 4 hours apart. Each dose of abexinostat should be taken with an 8 oz/240 mL glass of water at least half an hour before meals or more than 2 hours after a meal and must be 4 hours apart. Patients should be instructed to swallow the tablets whole and not chew them.

Other Names:

PCI-24781

Placebo Comparator: Pazopanib plus placebo

Randomized patients will receive a combination of pazopanib plus abexinostat matching placebo. The patients will receive pazopanib by mouth (p.o.) daily on Days 1 to 28 of each treatment cycle and will receive abexinostat matching placebo p.o BID on Days 1 to 4, 8 to 11, and 15 to 18 of every 28-day cycle, 2 doses 4 hours apart. Patients will be instructed to take their once- daily oral dose of pazopanib and BID oral dose of placebo at the same time each day.

Drug: Pazopanib

Other Names:

Votrient®

Other: Placebo

The starting dose and schedule of abexinostat matching placebo will be 80 mg p.o. BID on Days 1 to 4, 8 to 11, and 15 to 18 of every 28-day cycle, 2 doses 4 hours apart. Each dose of placebo should be taken with an 8 oz/240 mL glass of water at least half an hour before meals or more than 2 hours after a meal and must be 4 hours apart. Patients should be instructed to swallow the tablets whole and not chew them.

Outcome Measures

Primary Outcome Measures

Progression-free survival (PFS) [From randomization date to date of first documentation of progression OR death (up to approximately 4 years).]
To compare the PFS between treatment arms. PFS is defined as the time (month) interval between date of randomization and date of radiographic disease progression or death for those without prior evidence of progression, as assessed by blinded Independent Review Committee (IRC) according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.

Secondary Outcome Measures

PFS by investigator assessment according to RECIST version 1.1. [From randomization date to date of first documentation of progression OR death (up to approximately 4 years).]
To compare the PFS between treatment arms by investigator assessment. PFS is defined as the time (month) interval between date of randomization and date of radiographic disease progression or death for those without prior evidence of progression, as assessed by IRC according to RECIST version 1.1.
Overall survival (OS) [From progression or end of study, every 3 months follow up until death, patient withdrawal from study follow-up, or study closure, whichever occurs first (up to approximately 4 years).]
OS is defined as the interval between date of randomization and date of death. The main objective was to compare the OS between treatment arms by investigator assessment.
Adverse events by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5 [From Day 1 until end of treatment visit (up to approximately 4 years).]
To characterize the safety profile of pazopanib in combination with abexinostat.
Objective response rate (ORR) [Screening, Cycle 3 Day 1 (C3D1), Cycle 5 Day 1 (C5D1), Cycle 7 Day 1 (C7D1), and on Day 1 of every third cycle (each cycle is 28 days in length) thereafter until end-of-treatment visit (up to approximately 4 years).]
ORR is defined as the proportion of patients with objective evidence of CR or PR by RECIST version 1.1. The main objective was to compare the ORR between treatment arms by investigator assessment.
Duration of response (DOR) [Screening, Cycle 3 Day 1 (C3D1), C5D1, C7D1, and on Day 1 of every third cycle (each cycle is 28 days in length) thereafter until end-of-treatment visit (up to approximately 4 years).]
DOR is defined as the time from the first documentation of response (CR or PR) to the first documentation of objective tumor progression or death due to any cause by RECIST version 1.1. The main objective was to compare the DOR between treatment arms by investigator assessment.
ORR by RECIST version 1.1 in cross-over patient population [Screening, Cycle 3 Day 1 (C3D1), C5D1, C7D1, and on Day 1 of every third cycle (each cycle is 28 days in length) thereafter until end-of-treatment visit (up to approximately 4 years).]
To describe the ORR in patients who cross over to receive pazopanib plus abexinostat at the time of disease progression on pazopanib monotherapy by investigator assessment.
DOR by RECIST version 1.1 in cross-over patient population [Screening, Cycle 3 Day 1 (C3D1), C5D1, C7D1, and on Day 1 of every third cycle (each cycle is 28 days in length) thereafter until end-of-treatment visit (up to approximately 4 years).]
To describe the DOR in patients who cross over to receive pazopanib plus abexinostat at the time of disease progression on pazopanib monotherapy by investigator assessment.
Mean change from Baseline in Functional Assessment of Cancer Therapy Kidney System Index (FKSI-19) scores [First day of treatment Cycle1, Cycle 2, Cycle 6 (each cycle is 28 days in length) until end-of-treatment visit (up to approximately 4 years).]
To assess the impact of pazopanib with or without abexinostat on disease-related symptoms and health-related quality of life (QoL) by investigator assessment. QoL will be assessed by measuring change from baseline in FKSI-19. The FKSI-19 assesses disease-related symptoms experienced in the past 7 days. Patients are asked to respond to 12 questions ("I have a lack of energy," "I feel pain," for example) by using a 5-point scale (0=not at all, 1=a little bit, 2=somewhat, 3=quite a bit, 4=very much; possible total score of 0 to 48).
Mean change from Baseline in Functional Assessment of Chronic Illness Therapy (FACIT-F) scores [First day of treatment Cycle1, Cycle 2, Cycle 6 (each cycle is 28 days in length) and at end-of-treatment visit (up to approximately 4 years).]
To assess the impact of pazopanib with or without abexinostat on disease-related symptoms and QoL by investigator assessment. QoL will be assessed by measuring change from baseline in FACIT-F. The FACIT-F scale measures QoL experienced in the past seven days. The measurement consisted of 5 domains (physical well-being, social/family well-being, emotional well-being, functional well-being, and additional concerns) assessed on a 5-point scale (0=not at all; 1=a little bit; 2=somewhat; 3=quite a bit; 4=very much).

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

To be enrolled in the study, patients will be required to meet all of the following criteria:

Patients aged ≥ 18 years at time of study entry.
Patients have histologically confirmed RCC with clear cell component.
Patients have locally advanced and unresectable or metastatic disease.
Measurable disease as assessed only by the investigator (not verified by IRC) according to RECIST version 1.1.
Patients must not have had any prior vascular endothelial growth factor (VEGF) tyrosine kinase inhibitor treatment in either (neo)adjuvant or locally advanced/metastatic setting. Up to 1 line of prior cytokine or immune checkpoint inhibitor treatment is allowed in either the (neo)adjuvant or metastatic setting provided screening scans indicate progressive disease (PD) during or following completion of treatment.
Patients have Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
Patients have adequate baseline organ function.
Patients have adequate baseline hematologic function
Patient must be at least 2 weeks from last systemic treatment or dose of radiation prior to date of randomization.

Exclusion Criteria:

Patients who meet any of the following criteria at Screening will not be enrolled in the study:

Has persistent clinically significant toxicities (Grade ≥ 2; per NCI CTCAE version 5 from previous anticancer therapy (excluding alopecia which is permitted and excluding Grades 2 and 3 laboratory abnormalities if they are not associated with symptoms, are not considered clinically significant by the investigator, and can be managed with available medical therapies).
Has untreated central nervous system (CNS) metastases. Patients with treated CNS metastases are eligible provided imaging demonstrates no new or progressive metastases obtained at least 4 weeks following completion of treatment. CNS imaging during Screening is not required unless clinically indicated.
Has an additional malignancy requiring treatment within the past 3 years. Patients with the following concomitant neoplastic diagnoses are eligible: non-melanoma skin cancer, carcinoma in situ, and non-muscle invasive urothelial carcinoma.
Poorly controlled hypertension, defined as systolic blood pressure ≥ 160 or diastolic blood pressure ≥ 100 mmHg. Use of anti-hypertensives and rescreening is permitted.
A new pulmonary embolism or deep venous thrombosis diagnosed within 3 months prior to randomization.
Has a QTcF interval > 480 msec.
New York Heart Association Class III or IV congestive heart failure.
Use of prohibited medication within 7 days or 5 half-lives, whichever is shorter, prior to first dose of study drug.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University Of UA Cancer Center(UACC)/DH-SJHMC	Phoenix	Arizona	United States	85004
2	University of California Davis Comprehensive Cancer Center	Sacramento	California	United States	95817
3	UCSF Helen Diller Family Comphrensive Cancer Center - Hemato	San Francisco	California	United States	94158
4	Norton Cancer Institute, Norton Healthcare Pavilion	Louisville	Kentucky	United States	40202
5	Ochsner Clinic Foundation	New Orleans	Louisiana	United States	70121
6	GU Research Network/Urology Cancer Center	Omaha	Nebraska	United States	68130
7	Nebraska Cancer Specialists	Omaha	Nebraska	United States	68130
8	Northwell Health/Monter Cancer Center	Lake Success	New York	United States	11042
9	Mainstreet Physicans Care	Rochester	New York	United States	14642
10	Precision Cancer Research/Dayton Physicians Network - Treatment	Kettering	Ohio	United States	45409
11	Oregon Health and Science University	Portland	Oregon	United States	97239
12	St. Luke's Hospital	Easton	Pennsylvania	United States	18045
13	HOPE Cancer Center of East Texas	Tyler	Texas	United States	75701
14	Medical Oncology Associates, PS (dba Summit Cancer Centers)	Spokane	Washington	United States	99208
15	Beijing Cancer Hospital	Beijing		China	100142
16	Zhongshan Hospital Affiliated to Fudan University	Shanghai		China	200032
17	Fondazione del Piemonte per l'Oncologia_Istituto di Candiolo, IRCCS_ Oncologia Medica	Candiolo		Italy	10060
18	A.O. Cannizzaro_UOS Oncologia Medica	Catania		Italy	95126
19	IRCCS Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) UO Oncologia Medica	Meldola (FC)		Italy	47014
20	Istituto Europeo di Oncologia_Unità Oncologia Medica Urogenitale e Cervico Facciale	Milano		Italy	20141
21	Istituto Nazionale dei Tumori-Fondazione Pascale- SC Oncologia Medica	Napoli		Italy	80131
22	Azienda Ospedaliero-Universitaria Maggiore della Carità Novara_SC Oncologia Medica	Novara		Italy	28100
23	Istituti Clinici Scientifici Maugeri Spa-SB_ UO Oncologia Medica	Pavia		Italy	27100
24	Azienda Ospedaliero Universitaria Pisana_ UO Oncologia Medica Universitaria	Pisa		Italy	56126
25	Fondazione Policlinico Universitario A. Gemelli, U.O.C. Oncologia Medica	Roma		Italy	'00168
26	National Cancer Center - Center For Prostate Cancer	Goyang-si		Korea, Republic of	10408
27	CHA Bundang Medical Center, CHA University	Seongnam-si		Korea, Republic of	13496
28	Severance Hospital, Yonsei University Health System - Medical Oncology	Seoul		Korea, Republic of	03722
29	Asan Medical Center - University of Ulsan College of Medicin	Seoul		Korea, Republic of	05505
30	Samsung Medical Center - Hematology-Oncology	Seoul		Korea, Republic of	06351
31	Szpital Specjalistyczny w Brzozowie Podkarpacki Osrodek Onkologiczny	Brzozow		Poland	36-200
32	Szpitale Pomorskie Sp. z o.o. Oddział Onkologii i Radioterapii	Gdynia		Poland	81-519
33	Szpital Specjalistyczny im. Ludwika Rydygiera w Krakowie Sp. z o.o. Oddział Onkologii Klinicznej z Pododdziałem Dziennym	Krakow		Poland	31-826
34	Clinical Research Center Sp. z o.o., Medic-R Sp. K.	Poznan		Poland	60-848
35	H.G.U. de Elche	Elche		Spain	03203
36	Hospital Universitario Fundación Jiménez Díaz	Madrid		Spain	28040
37	Hospital Universitario 12 de Octubre	Madrid		Spain	28041
38	H.U. Virgen de la Victoria	Málaga		Spain	29010