NCT03136627

Phase 1/2 Study of Tivozanib in Combination With Nivolumab in Subjects With RCC

A Phase 1b/2, Open-Label, Multi-Center Study of Tivozanib in Combination With Nivolumab in Subjects With Metastatic Renal Cell Carcinoma

• Status: Completed
• Phase: Phase 1 / Phase 2
• Study type: Interventional
• Enrollment: 28 (actual)
• Sponsor: AVEO Pharmaceuticals, Inc. · Industry
• Sex: All
• Age: 18 Years
• Healthy volunteers: Not accepted

Summary

This study will evaluate the safety, tolerability, dose-limiting toxicities, MTD, and preliminary anti-tumor activity of tivozanib in combination with nivolumab in subjects with metastatic renal cell cancer. This will use a standard '3+3' dose-escalation trial design. A cohort of 3 subjects will be enrolled at each dose level. If 1 of 3 subjects experiences a DLT during Cycle 1, that dose level will be expanded to 6 subjects. If 0 of 3 or ≤ 1 of 6 subjects experience a DLT during Cycle 1, escalation to the next dose will occur. If ≥ 2 of 6 subjects experience a DLT during Cycle 1, dose escalation will stop and the prior dose will be considered the MTD. This is a validated trial design for Phase 1 trials. Following completion of the dose-escalation cohorts and determination of MTD, an expansion cohort of up to 20 subjects may be enrolled at MTD to further evaluate safety, tolerability, and preliminary anti-tumor activity of tivozanib in combination with nivolumab in the same target population.

Detailed description

Tivozanib hydrochloride (tivozanib; previously known as AV-951 and as KRN951) has the chemical name (N-{2-Chloro-4-\[(6,7-dimethoxy-4-quinolyl)oxy\]phenyl}-N'-(5-methyl-3-isoxazolyl)urea hydrochloride monohydrate. Tivozanib is a novel and potent vascular endothelial growth factor (VEGF) receptor tyrosine kinase inhibitor (VEGFR TKI) that has demonstrated significant anti-tumor effects in pre clinical experiments \[1\]. Tivozanib inhibits phosphorylation of VEGF receptors (VEGFR) -1, -2 and -3 at picomolar concentrations (IC50 of 0.21, 0.16 and 0.24 nM respectively), and inhibits c-Kit and platelet derived growth factor receptor (PDGFR) at 10-times higher concentrations (IC50 of 1.63 and 1.72 nM respectively). Based on its biochemical profile, tivozanib appears to be one of the most potent and selective VEGF tyrosine kinase inhibitor in clinical development. Other agents used for treatment of renal cell carcinoma (RCC) such as sunitinib and sorafenib inhibit multiple tyrosine kinases in addition to the VEGF receptor tyrosine kinase, leading to off-target toxicities such as fatigue, hand-foot syndrome, stomatitis, and neutropenia. The adverse event (AE) profile of tivozanib demonstrates that it is a selective VEGF tyrosine kinase inhibitor, with reduced off-target toxicities. Nivolumab is a fully human IgG4 programmed death 1 (PD-1) immune checkpoint inhibitor antibody that selectively blocks the interaction between PD-1, which is expressed on activated T cells, and PD-1 ligand 1 (PD-L1) and 2 (PD-L2) which are expressed on immune cells and tumor cells. Interaction between PD-1 and PD-L1 or PD-L2 normally results in the inhibition of the cellular immune response. Nivolumab has shown activity in renal cell carcinoma. \[2\] This study is designed to test the hypothesis that tivozanib can be combined with nivolumab for the treatment of patients with renal cell carcinoma. The purpose of the study is to determine the maximum dose of tivozanib that can be safely combined with nivolumab, and to evaluate the safety profile and tolerability of this combination. Given the different mechanisms of action and a lack of overlapping toxicities this combination may provide an alternative therapy to patients with renal cell carcinoma.

Conditions

• Carcinoma, Renal Cell

Interventions

Type	Name	Description
DRUG	Tivozanib	Tivozanib (AV-951): Phase 1b study and Phase 2a study: Subjects will receive 1 dose of tivozanib daily for 21 days followed by a 7 day rest period (1 cycle = 4 weeks).
DRUG	Nivolumab	Nivolumab: Phase 1b study and Phase 2a study: All subjects will receive IV nivolumab 240 mg every 2 weeks administered over 1 hour.

Timeline

• Start date: 2017-03-22
• Primary completion: 2017-12-21
• Completion: 2021-06-18
• First posted: 2017-05-02
• Last updated: 2021-12-06

Locations

4 sites across 1 country: France