Clinical Research Papers:

Phase 1b study of lenvatinib (E7080) in combination with temozolomide for treatment of advanced melanoma

David S. Hong _, Razelle Kurzrock, Gerald S. Falchook, Corina Andresen, Jennifer Kwak, Min Ren, Lucy Xu, Goldy C. George, Kevin B. Kim, Ly M. Nguyen, James P. O’Brien and John Nemunaitis

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Oncotarget. 2015; 6:43127-43134. https://doi.org/10.18632/oncotarget.5756

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David S. Hong1, Razelle Kurzrock1, Gerald S. Falchook2, Corina Andresen3, Jennifer Kwak3, Min Ren4, Lucy Xu4, Goldy C. George1, Kevin B. Kim1, Ly M. Nguyen1, James P. O’Brien3, John Nemunaitis5

1The University of Texas MD Anderson Cancer Center, Houston, TX, USA

2Sarah Cannon Research Institute at HealthONE, Denver, CO, USA

3Former employees of Eisai Inc., Woodcliff Lake, NJ, USA

4Eisai Inc., Oncology, Woodcliff Lake, NJ, USA

5Mary Crowley Cancer Research Center, Dallas, TX, USA

Correspondence to:

David S. Hong, e-mail: [email protected]

Keywords: lenvatinib, melanoma, pharmacodynamic, phase 1b, advanced solid tumors

Received: July 15, 2015     Accepted: September 19, 2015     Published: October 15, 2015


Objective and Methods: In this phase 1b study, patients with stage 4 or unresectable stage 3 melanoma were treated with escalating doses of lenvatinib (once daily) and temozolomide (TMZ) (days 1–5) in 28-day cycles, to determine the maximum tolerated dose (MTD) of the combination. Dose Level (DL)1: lenvatinib 20 mg, TMZ 100 mg/m2; DL2: lenvatinib 24 mg, TMZ 100 mg/m2; DL3: lenvatinib 24 mg, TMZ 150 mg/m2. Adverse events (AEs) were recorded and tumor response assessed per RECIST 1.0.

Results: Dose-limiting toxicity occurred in 1 of 32 treated patients (DL1); MTD was not reached. The highest dose administered was lenvatinib 24 mg + TMZ 150 mg/m2. Most common treatment-related AEs included fatigue (56.3%), hypertension (53.1%), and proteinuria (46.9%). Overall objective response rate was 18.8% (6 patients), all partial response; (DL1, n = 1; DL3, n = 5). Stable disease (SD) ≥ 16 weeks was observed in 28.1% of patients (DL1 and DL2, n = 1 each; DL3, n = 7); 12.5% of patients had SD ≥ 23 weeks. Single and repeat-dose pharmacokinetics of lenvatinib were comparable across cycles and with concomitant TMZ administration.

Conclusion: Lenvatinib 24 mg/day + TMZ 150 mg/m2/day (days 1–5) demonstrated modest clinical activity, an acceptable safety profile, and was administered without worsening of either lenvatinib- or TMZ-related toxicities in this patient group.

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