Phase 1 trial of vorolanib (CM082) in combination with everolimus in patients with advanced clear-cell renal cell carcinoma.

Vorolanib (X-82, CM082) is a multi-target tyrosine kinase inhibitor. This study aimed to evaluate the tolerability, safety, pharmacokinetics and antitumor activities of vorolanib plus everolimus (an inhibitor of mammalian target of rapamycin).

Patients had histologically or cytologically confirmed advanced RCC and failed with standard therapy were eligible for this study. Dose-escalated combinations of vorolanib (100, 150 or 200 mg once daily) with everolimus (5 mg once daily) were administered on 28-day cycles until disease progression or unacceptable toxicity using a conventional 3 + 3 dose-escalation design.

22 patients (100 mg n = 4, 150 mg n = 3, 200 mg n = 15) were enrolled. Only one patient experienced dose-limiting toxicity (DLT, grade 4 thrombocytopenia) in the vorolanib 200 mg combination cohort, and the maximum tolerated dose (MTD) was not reached. The most common treatment-related adverse events were proteinuria (100%), leukopenia (77%), hypercholesterolaemia (77%), increased low-density lipoprotein (68%), hypertriglyceridaemia (64%), hyperglycaemia (59%), and fatigue (55%). Most treatment-related adverse events were grade 1 to 2, with grade 3 or higher toxicities mostly seen in the 200 mg cohort. Single dosing of vorolanib demonstrated dose-proportional increases in the Cmax and AUC, and observed short t1/2z ranging from 4.74±1.44 to 12.89±7.49 h. The pharmacokinetic parameters for everolimus were similar among all cohorts. Of 19 evaluable patients, the ORR and DCR was 32% (n = 6, 95% CI, 13-57%) and 100% (95% CI, 82-100%), respectively.

Combination therapy of vorolanib 200 mg plus everolimus 5 mg once daily is potentially effective with potential activity. Further evaluation of the combination in advanced RCC patients is ongoing (NCT03095040).

Betta Pharmaceutical Co., Ltd., Hangzhou, China.

EBioMedicine. 2020 Apr 23 [Epub ahead of print]

Xinan Sheng, Xieqiao Yan, Zhihong Chi, Chuanliang Cui, Lu Si, Bixia Tang, Siming Li, Lili Mao, Bin Lian, Xuan Wang, Xue Bai, Li Zhou, Yan Kong, Jie Dai, Lieming Ding, Li Mao, Jun Guo

Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Renal Cancer and Melanoma, Peking University Cancer Hospital & Institute, Beijing 100142, China., Betta Pharmaceutical Co., Ltd., Hangzhou 301106, China., Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Renal Cancer and Melanoma, Peking University Cancer Hospital & Institute, Beijing 100142, China. Electronic address: .

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