Abstract CT171: Phase I/II study to evaluate the safety and preliminary activity of nivolumab in combination with vorolanib in patients with refractory thoracic tumors
Authors: Whisenant Jennifer G. , Beckerman Katy , Borghaei Hossein , Owonikoko Taofeek , Patel Jyoti , Shyr Yu , Harrow Kimberly , Liang Chris , Holzhausen Allison , Wakelee Heather , Horn Leora 
Published: August 2019

Abstract
Background: Nivolumab monotherapy results in limited responses (19-25%) in thoracic tumors, therefore the potential exists to design combination strategies to improve tumor response. Evidence exists to suggest that antiangiogenic agents have the potential to stimulate the immune system. Several pilot trials combined inhibitors of PD-1/PD-L1 and VEGFR in renal cell carcinoma, and the combinations outperformed either single agent. However, none of the combinations were well tolerated at full doses of the drugs. Therefore, it is desirable to explore immunotherapy and antiangiogenic agent combinations that have lower toxicity. Vorolanib is structurally similar to the antiangiogenic agent sunitinib but was designed to improve the safety profile without compromising efficacy. Preclinically, vorolanib had comparable anti-tumor activity to sunitinib, and toxicokinetic analyses suggested a very high safety window.
Methods: NCT03583086 is a multi-institutional, phase I/II study of nivolumab and vorolanib in patients with thoracic tumors who failed at least one prior line of chemotherapy. The primary objective of phase I is to determine the maximum tolerated dose. Dose escalation uses a standard 3+3 design with three dose levels of vorolanib (200, 300, and 400 mg once-daily) and 240 mg nivolumab every two weeks. Phase II evaluates efficacy of the combination among five cohorts: immunotherapy naïve non-small cell lung cancer (NSCLC), NSCLC patients that have progressed (primary refractory and acquired resistance) on immunotherapy, thymic carcinoma, and small cell lung cancer (SCLC) patients with progression on prior platinum-based chemotherapy. Primary refractory is defined as radiographic progression of disease within 12 weeks after initiation of checkpoint therapy; acquired resistance includes achieving radiographic partial or complete response, or stable disease for at least 12 weeks followed by radiographic disease progression. Enrollment to phase II will use a Simon two-stage design for each cohort. Exploratory objectives will be performed to quantify changes in the innate and adaptive immune responses after treatment. Mass cytometry will be used to monitor serial changes in multiple immune markers on individual circulating cells in the blood. Changes in each marker will be correlated with response using the Lasso-based elastic net method. Single cell gene expression analysis from peripheral blood samples collected prior to and at the end of treatment will be performed and correlated with response to combination therapy in order to improve our understanding of the biology behind systemic changes to this treatment. Enrollment to phase I is ongoing; 7 patients have been enrolled, including 3 in dose cohort 1 and 4 in dose cohort 2. Thus far, a dose-limiting toxicity of elevated liver function tests possibly related to nivolumab and vorolanib was observed in one patient enrolled in dose cohort 2.
Citation Format: Jennifer G. Whisenant, Katy Beckerman, Hossein Borghaei, Taofeek Owonikoko, Jyoti Patel, Yu Shyr, Kimberly Harrow, Chris Liang, Allison Holzhausen, Heather Wakelee, Leora Horn. Phase I/II study to evaluate the safety and preliminary activity of nivolumab in combination with vorolanib in patients with refractory thoracic tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT171.