Faculty Collaboration Database

Phase I Dose-Escalation Study of the Multikinase Inhibitor Lenvatinib in Patients with Advanced Solid Tumors and in an Expanded Cohort of Patients with Melanoma. Clin Cancer Res 2015 Nov 01;21(21):4801-10

Date

07/15/2015

Pubmed ID

26169970

Pubmed Central ID

PMC4840931

DOI

10.1158/1078-0432.CCR-14-3063

Scopus ID

2-s2.0-84947233902 (requires institutional sign-in at Scopus site)   61 Citations

Abstract

PURPOSE: This "3+3" phase I study evaluated the safety, biologic, and clinical activity of lenvatinib, an oral multikinase inhibitor, in patients with solid tumors.

EXPERIMENTAL DESIGN: Ascending doses of lenvatinib were administered per os twice daily in 28-day cycles. Safety and response were assessed for all patients. Angiogenic and apoptotic factors were tested as possible biomarkers in an expanded melanoma cohort.

RESULTS: Seventy-seven patients were treated in 3 cohorts: 18 with intermittent twice-daily dosing (7 days on, 7 days off) of 0.1-3.2 mg; 33 with twice-daily dosing of 3.2-12 mg; and 26 with twice-daily dosing of 10 mg (expanded melanoma cohort). Maximum tolerated dose was established at 10 mg per os twice daily. Prominent drug-related toxicities included hypertension (43%), fatigue (42%), proteinuria (39%), and nausea (25%); dose-limiting toxicities included hypertension, fatigue, and proteinuria. Twelve patients (15.6%) achieved partial response (PR, n = 9) or unconfirmed PR (uPR, n = 3), and 19 (24.7%) achieved stable disease (SD) ≥23 weeks. Total PR/uPR/SD ≥23 weeks was 40.3% (n = 31). Responses (PR/uPR) by disease were as follows: melanoma, 5 of 29 patients (includes 1 patient with NRAS mutation); thyroid, 3 of 6 patients; pancreatic, 1 of 2 patients; lung, 1 of 1 patients; renal, 1 of 1 patients; endometrial, 1 of 4 patients; and ovarian, 1 of 5 patients. AUC(0-24) and C(max) increased dose proportionally. In multivariate Cox proportional hazard model analyses, increased baseline systolic blood pressure and decreased angiopoietin-1 ratio (2 hours:baseline) were associated with longer progression-free survival (PFS) in the expanded melanoma cohort (P = 0.041 and P = 0.03, respectively).

CONCLUSIONS: The toxicity profile, pharmacokinetics, and antitumor activity of lenvatinib are encouraging. Decreases in the angiopoietin-1 ratio correlated with longer PFS in melanoma patients.

Author List

Hong DS, Kurzrock R, Wheler JJ, Naing A, Falchook GS, Fu S, Kim KB, Davies MA, Nguyen LM, George GC, Xu L, Shumaker R, Ren M, Mink J, Bedell C, Andresen C, Sachdev P, O'Brien JP, Nemunaitis J

Author

Razelle Kurzrock MD Center Associate Director, Professor in the Medicine department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Administration, Oral
Adult
Aged
Aged, 80 and over
Angiogenesis Inhibitors
Antineoplastic Agents
Cohort Studies
DNA Mutational Analysis
Female
Follow-Up Studies
Humans
Kaplan-Meier Estimate
Male
Maximum Tolerated Dose
Melanoma
Middle Aged
Mutation
Neoplasm Staging
Neoplasms
Phenylurea Compounds
Protein Kinase Inhibitors
Quinolines
Treatment Outcome