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

EBioMedicine. 2020 May:55:102755. doi: 10.1016/j.ebiom.2020.102755. Epub 2020 Apr 23.

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 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.

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).

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

Keywords: CM082; Combination therapy; Everolimus; Renal cell carcinoma; Vorolanib.

Publication types

  • Clinical Trial, Phase I

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Antineoplastic Combined Chemotherapy Protocols / administration & dosage*
  • Antineoplastic Combined Chemotherapy Protocols / adverse effects
  • Carcinoma, Renal Cell / drug therapy*
  • Carcinoma, Renal Cell / enzymology
  • Carcinoma, Renal Cell / mortality
  • Carcinoma, Renal Cell / pathology
  • Disease Progression
  • Drug Administration Schedule
  • Everolimus / administration & dosage*
  • Everolimus / adverse effects
  • Female
  • Humans
  • Hypercholesterolemia / enzymology
  • Hypercholesterolemia / etiology
  • Hypercholesterolemia / mortality
  • Hyperglycemia / enzymology
  • Hyperglycemia / etiology
  • Hyperglycemia / mortality
  • Indoles / administration & dosage*
  • Indoles / adverse effects
  • Kidney Neoplasms / drug therapy*
  • Kidney Neoplasms / enzymology
  • Kidney Neoplasms / mortality
  • Kidney Neoplasms / pathology
  • Leukopenia / enzymology
  • Leukopenia / etiology
  • Leukopenia / mortality
  • Male
  • Middle Aged
  • Protein Kinase Inhibitors / administration & dosage*
  • Protein Kinase Inhibitors / adverse effects
  • Proteinuria / enzymology
  • Proteinuria / etiology
  • Proteinuria / mortality
  • Pyrroles / administration & dosage*
  • Pyrroles / adverse effects
  • Pyrrolidines / administration & dosage*
  • Pyrrolidines / adverse effects
  • Survival Analysis

Substances

  • Indoles
  • Protein Kinase Inhibitors
  • Pyrroles
  • Pyrrolidines
  • Everolimus
  • vorolanib

Associated data

  • ClinicalTrials.gov/NCT03095040