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

Abstract

Background: 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). Methods: 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. Findings: 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 C max and AUC, and observed short t 1/2z 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, 13À57%) and 100% (95% CI, 82À100%), respectively. Interpretation: 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).

Discovery and Anticancer Activity of Novel 1,3,4-Thiadiazole- and Aziridine-Based Indolin-2-ones via In Silico Design Followed by Supramolecular Green Synthesis

“…Famitinib and Tafetinib also act against c-KIT in patients with advanced solid cancer . Vorolanib was also found to inhibit c-KIT with an excellent IC 50 value …”

“…16 Vorolanib was also found to inhibit c-KIT with an excellent IC 50 value. 17 Compounds bearing the 1,3,4-thiadiazole framework with excellent in vitro activities against a range of tumor cells with diverse modes of action, including angiogenesis, tumor infiltration, and cell-cycle events, have been reported in the literature. 18 The thiadiazole's heteroatoms can establish interactions, such as hydrogen bonding, with important kinases involved in cancer.…”

Phase 1b trial of anti-VEGF/PDGFR vorolanib combined with immune checkpoint inhibitors in patients with advanced solid tumors

“…Its short half-life of approximately 4–8 h by clinical pharmacokinetic data and limited tissue accumulation allows for continuous dosing [ 28 , 29 ]. Vorolanib has been investigated in other phase 1/2 trials as monotherapy or in combination with other agents, including chemotherapy with other pathway inhibitors, at doses of 50–800 mg [ 30 ]. In these studies, the maximum tolerated dose (MTD) was not reached at 800 mg, but absorption plateaued at 400 to 800 mg daily dosing.…”

Vorolanib and everolimus: Lenvatinib and everolimus part deux, or something new?

“…In a Phase I dose-finding study, Sheng et al assess the safety, tolerability, and efficacy of vorolanib when used in conjunction with everolimus for the treatment of mRCC patients who have progressed through at least one previous line of TKI therapy [1]. Vorolanib is novel, highly potent vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor (PDGFR) TKI with activity against Flt3 and c-Kit that does not exhibit an inhibitory effect on RET or AMPK.…”

“…A staple following first-line therapy for over a decade, everolimus is an inhibitor of mammalian target of rapamycin (mTOR), which is a component of an intracellular signaling pathway regulating cell growth and proliferation, and metabolism [2]. In the target dose cohort, vorolanib plus everolimus was generally well tolerated and all 14 of 22 patients who experienced grade 3 or higher treatment-related toxicity were effectively managed with dose adjustments or supportive medication [1].…”