Reference Detail

Ref Type Journal Article
PMID (26169970)
Authors 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
Title 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.
Journal Clinical cancer research : an official journal of the American Association for Cancer Research
Vol 21
Issue 21
Date 2015 Nov 01
URL
Abstract Text This "3+3" phase I study evaluated the safety, biologic, and clinical activity of lenvatinib, an oral multikinase inhibitor, in patients with solid tumors.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.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).The toxicity profile, pharmacokinetics, and antitumor activity of lenvatinib are encouraging. Decreases in the angiopoietin-1 ratio correlated with longer PFS in melanoma patients.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
BRAF mut NRAS wild-type melanoma sensitive Lenvatinib Phase I Actionable In a Phase I clinical trial, Lenvima (lenvatinib) treatment resulted in stable disease in 100% (5/5) of melanoma patients harboring BRAF mutations and wild-type NRAS (PMID: 26169970). 26169970
BRAF wild-type NRAS wild-type melanoma sensitive Lenvatinib Phase I Actionable In a Phase I clinical trial, Lenvima (lenvatinib) treatment resulted in stable disease in 44% (4/9) and partial response in 22% (2/9) of melanoma patients carrying wild-type BRAF and NRAS (PMID: 26169970). 26169970
Unknown unknown lung non-small cell carcinoma not applicable Lenvatinib Phase I Actionable In a Phase I clinical trial, Lenvima (lenvatinib) demonstrated anti-tumor activity in patients with several advanced solid tumor types, including patients with non-small cell lung cancer (PMID: 26169970). 26169970
BRAF wild-type NRAS mutant melanoma sensitive Lenvatinib Phase I Actionable In a Phase I clinical trial, Lenvima (lenvatinib) treatment resulted in stable disease in 83% (5/6) of melanoma patients harboring NRAS mutations and wild-type BRAF (PMID: 26169970). 26169970
BRAF mut NRAS mut melanoma sensitive Lenvatinib Phase I Actionable In a Phase I clinical trial, Lenvima (lenvatinib) treatment resulted in stable disease in 50% (1/2) of melanoma patients harboring both BRAF and NRAS mutations (PMID: 26169970). 26169970
Unknown unknown Advanced Solid Tumor not applicable Lenvatinib Phase I Actionable In a Phase I trial, Lenvima (lenvatinib) treatment resulted in partial response in 11.7% (9/77) and stable disease in 51.9% (40/77) of patients with advanced solid tumors (PMID: 26169970). 26169970