Phase 1b study of lenvatinib (E7080) in combination with temozolomide for treatment of advanced melanoma |
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Authors: | 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 John Nemunaitis |
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Institution: | 1. The University of Texas MD Anderson Cancer Center, Houston, TX, USA;2. Sarah Cannon Research Institute at HealthONE, Denver, CO, USA;3. Former employees of Eisai Inc., Woodcliff Lake, NJ, USA;4. Eisai Inc., Oncology, Woodcliff Lake, NJ, USA;5. Mary Crowley Cancer Research Center, Dallas, TX, USA |
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Abstract: | Objective and MethodsIn 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.ResultsDose-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.ConclusionLenvatinib 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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Keywords: | lenvatinib melanoma pharmacodynamic phase 1b advanced solid tumors |
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