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


CONCLUSIONS
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.
The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
David S
DS
Hong
The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Razelle
R
Kurzrock
Sarah Cannon Research Institute at HealthONE, Denver, CO, USA.
Gerald S
GS
Falchook
Former employees of Eisai Inc., Woodcliff Lake, NJ, USA.
Corina
C
Andresen
Former employees of Eisai Inc., Woodcliff Lake, NJ, USA.
Jennifer
J
Kwak
Eisai Inc., Oncology, Woodcliff Lake, NJ, USA.
Min
M
Ren
Eisai Inc., Oncology, Woodcliff Lake, NJ, USA.
Lucy
L
Xu
The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Goldy C
GC
George
The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Kevin B
KB
Kim
The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Ly M
LM
Nguyen
Former employees of Eisai Inc., Woodcliff Lake, NJ, USA.
James P
JP
O'Brien
Mary Crowley Cancer Research Center, Dallas, TX, USA.
John
J
Nemunaitis
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D003606:Dacarbazine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008545:Melanoma / Q000188:drug therapy*; D008875:Middle Aged; D010671:Phenylurea Compounds / Q000008:administration & dosage* / Q000009:adverse effects; D011804:Quinolines / Q000008:administration & dosage* / Q000009:adverse effects; D000077204:Temozolomide; D055815:Young Adult
D010671:Phenylurea Compounds; D011804:Quinolines; D003606:Dacarbazine; C531958:lenvatinib; D000077204:Temozolomide
advanced solid tumors; lenvatinib; melanoma; pharmacodynamic; phase 1b