A phase I study of E7080, a multitargeted tyrosine kinase inhibitor, in patients with advanced solid tumours

Boss, David S.; Glen, Hilary; Beijnen, Jos H.; Keesen, M; Morrison, Rebecca; Tait, B.; Copalu, William; Mazur, Antonina Joanna; Wanders, J.; O’Brien, James P.; Schellens, Jan H.M.; Evans, T.R. Jeffry

doi:10.1038/bjc.2012.154

Cited by 170 publications

(155 citation statements)

References 36 publications

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“…[20][21][22][23]) that has recently been approved for the treatment of radioiodine-refractory DTC (RR-DTC) on the basis of the results of the SELECT phase III trial (24). Preclinical and phase I evidence of antitumor efficacy in a variety of solid tumor types, including thyroid cancer (25)(26)(27)(28), prompted the initiation of a phase II trial in advanced, unresectable progressive MTC and RR-DTC, stratified by histology (29). Here, we present results from the MTC component of the study.…”

Section: Introductionmentioning

confidence: 99%

A Phase II Trial of the Multitargeted Tyrosine Kinase Inhibitor Lenvatinib (E7080) in Advanced Medullary Thyroid Cancer

Schlumberger

Jarząb

Cabanillas

et al. 2016

Clinical Cancer Research

218

162

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Purpose: Positive results of phase I studies evaluating lenvatinib in solid tumors, including thyroid cancer, prompted a phase II trial in advanced medullary thyroid carcinoma (MTC).Experimental Design: Fifty-nine patients with unresectable progressive MTC per Response Evaluation Criteria In Solid Tumors (RECIST) v1.0 within the prior 12 months received lenvatinib (24-mg daily, 28-day cycles) until disease progression, unmanageable toxicity, withdrawal, or death. Prior anti-VEGFR therapy was permitted. The primary endpoint was objective response rate (ORR) by RECIST v1.0 and independent imaging review.Results: Lenvatinib ORR was 36% [95% confidence interval (CI), 24%-49%]; all partial responses. ORR was comparable between patients with (35%) or without (36%) prior anti-VEGFR therapy. Disease control rate (DCR) was 80% (95% CI, 67%-89%); 44% had stable disease. Among responders, median time to response (TTR) was 3.5 months (95% CI, 1.9-3.7). Median progression-free survival (PFS) was 9.0 months (95% CI, 7.0-not evaluable). Common toxicity criteria grade 3/4 treatment-emergent adverse events included diarrhea (14%), hypertension (7%), decreased appetite (7%), fatigue, dysphagia, and increased alanine aminotransferase levels (5% each). Ret proto-oncogene status did not correlate with outcomes. Low baseline levels of angiopoietin-2, hepatocyte growth factor, and IL8 were associated with tumor reduction and prolonged PFS. High baseline levels of VEGF, soluble VEGFR3, and platelet-derived growth factor BB, and low baseline levels of soluble Tie-2, were associated with tumor reduction.Conclusions: Lenvatinib had a high ORR, high DCR, and a short TTR in patients with documented progressive MTC. Toxicities were managed with dose modifications and medications.

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Section: Introductionmentioning

confidence: 99%

A Phase II Trial of the Multitargeted Tyrosine Kinase Inhibitor Lenvatinib (E7080) in Advanced Medullary Thyroid Cancer

Schlumberger

Jarząb

Cabanillas

et al. 2016

Clinical Cancer Research

218

162

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“…Lenvatinib has shown promising antitumor efficacy in advanced solid tumors (16,17,19,20). Preliminary studies suggested the use of up to 25 mg once daily lenvatinib for solid tumors in phase I studies (19,20) and 24 mg once daily was used as the starting dose in patients with solid tumors in subsequent studies.…”

Section: Introductionmentioning

confidence: 99%

Safety and Pharmacokinetics of Lenvatinib in Patients with Advanced Hepatocellular Carcinoma

Ikeda

Okusaka

Mitsunaga

et al. 2016

Clinical Cancer Research

164

139

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Purpose: To determine the maximum tolerable dose (MTD), safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy of lenvatinib in patients with advanced hepatocellular carcinoma (HCC).Experimental Design: This multicenter, open-label, phase I, dose-escalation study included patients aged 20 to 80 years, refractory to standard therapy, and stratified by hepatic function measured using Child-Pugh (CP) scores: CP-A (score, 5-6) and CP-B (score, 7-8). Lenvatinib was administered continually once daily for 4-week cycles. MTD was defined as the maximum dose associated with 1 dose-limiting toxicity (DLT) occurring in cycle 1 among 6 patients.Results: In total, 20 patients (9 in CP-A and 11 in CP-B) were enrolled. The MTD was 12 and 8 mg once daily in CP-A and CP-B, respectively; DLTs included proteinuria, hepatic encephalopathy, and hyperbilirubinemia. The most common grade 3 toxicities included hypertension in CP-A and hyperbilirubinemia in CP-B. Lenvatinib plasma concentration at 24 hours after administration (C 24 h ) for 12 mg once daily was higher in patients with HCC than in patients with other solid tumors shown in a previous phase I study, but C 24 h for 25 mg once daily lenvatinib was comparable. After lenvatinib treatment, the number of circulating endothelial and c-Kit þ cells decreased and the levels of interleukin (IL)-6, IL10, granulocyte-colony stimulating factor, and vascular endothelial growth factor increased (P < 0.05). Partial responses were observed in 3 patients and tumor shrinkage occurred in 14 patients. Conclusions: Lenvatinib (12 mg once daily) demonstrated preliminary efficacy with manageable toxicity and is the recommended dose for phase II studies in patients with HCC and CP-A.

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“…Apart from inhibiting angiogenesis by targeting endothelial cells [4][5][6][7], lenvatinib exerts a direct effect on tumor cells, by inhibiting their migration and invasion [8]. Promising antitumor effects of lenvatinib were observed in Phase I trials [9,10], leading to a number of disease-specific phase 2 and phase 3 trials with lenvatinib as a single agent or in combination with other anticancer agents.…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetics and excretion of 14C-lenvatinib in patients with advanced solid tumors or lymphomas

et al. 2014

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Summary Lenvatinib is an orally available multi-targeted tyrosine kinase inhibitor with anti-angiogenic and antitumor activity. To get more insight into the disposition of lenvatinib, a mass balance study was performed in patients with advanced solid tumors. A single oral 24 mg (100 μCi) dose of 14 Clenvatinib was administered to six patients, followed by collection of blood, plasma, urine and feces for 7 to 10 days. The collected material was analyzed for total radioactivity, unchanged lenvatinib and selected metabolites. The safety and antitumor effect of a daily oral dose of 24 mg non-labeled lenvatinib were assessed in the extension phase of the study. Peak plasma concentrations of lenvatinib and total radioactivity were reached 1.6 and 1.4 h after administration, respectively, and their terminal phase half-lifes were 34.5 and 17.8 h, respectively. Unchanged lenvatinib systemic exposure accounted for 60 % of the total radioactivity in plasma. Peak concentrations of the analyzed metabolite were over 700-fold lower than the peak plasma concentration of lenvatinib. Ten days after the initial dose, the geometric mean (± CV) recovery of administered dose was 89 % ±10 %, with 64 % ±11 % recovered in feces and 25 % ±18 % in urine. Unchanged lenvatinib in urine and feces accounted for 2.5 % ±68 % of the administered dose, indicating a major role of metabolism in the elimination of lenvatinib. In conclusion, lenvatinib is rapidly absorbed and extensively metabolized, with subsequent excretion in urine and, more predominantly, in feces. Additionally, lenvatinib showed acceptable safety and preliminary antitumor activity.

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A phase I study of E7080, a multitargeted tyrosine kinase inhibitor, in patients with advanced solid tumours

Cited by 170 publications

References 36 publications

A Phase II Trial of the Multitargeted Tyrosine Kinase Inhibitor Lenvatinib (E7080) in Advanced Medullary Thyroid Cancer

A Phase II Trial of the Multitargeted Tyrosine Kinase Inhibitor Lenvatinib (E7080) in Advanced Medullary Thyroid Cancer

Safety and Pharmacokinetics of Lenvatinib in Patients with Advanced Hepatocellular Carcinoma

Pharmacokinetics and excretion of 14C-lenvatinib in patients with advanced solid tumors or lymphomas

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