A phase 1 study of lenvatinib, multiple receptor tyrosine kinase inhibitor, in Japanese patients with advanced solid tumors

Eligible patients were aged 20 years or older with a cytologically or histologically documented solid tumor that was refractory to standard therapy, or for which no standard therapy was available. Eligible patients also had completed anticancer therapy more than 4 weeks prior to lenvatinib treatment, and their toxicities had recovered to Grade 1 or lower except for alopecia. Additional inclusion criteria were Eastern Cooperative Oncology Group performance status (ECOG PS) of 0–1, adequate bone marrow function (hemoglobin ≥9.0 g/dL, neutrophil count ≥1.5 × 10³/μL, platelet count ≥10 × 10⁴/μL), liver function (total bilirubin ≤1.8 mg/dL, aspartate aminotransferase [AST] ≤100 IU/L, alanine aminotransferase [ALT] ≤100 IU/L), and renal function (creatinine ≤1.5 mg/dL or creatinine clearance ≥50 mL/min). Patients were excluded from the study if they had brain metastasis that was symptomatic or required treatment, complication or history of interstitial pneumonia, complication of pulmonary fibrosis with clinical symptoms, systemic infections requiring treatment, major cardiovascular diseases (ischemic cardiac disease or arrhythmia, angina pectoris or myocardial infarction within 24 weeks prior to enrollment, or QTc greater than 480 ms), hemoptysis, hemorrhagic or thrombotic events within 4 weeks prior to enrollment, hypertension (systolic blood pressure ≥150 mm Hg or diastolic blood pressure ≥90 mm Hg), or proteinuria (≥2+ in a qualitative test for urine protein or if ≥1+ proteinuria remained 2 days or more at ≥1.0 g for 24 h accumulated), history of surgery that would influence absorption of the investigational drug, major surgery within 4 weeks prior to enrollment, and coexisting effusion requiring treatment. Patients were also excluded if they were unable to take oral lenvatinib, were being treated with drugs that strongly inhibit or induce CYP3A4, or were positive for human immunodeficiency virus or hepatitis B or C virus.

This was a single-center, open-label, dose escalation phase 1 study to assess the tolerability, safety, PK, pharmacodynamics (PD), and preliminary efficacy of lenvatinib administered orally up to 24 mg QD on a continuous schedule in patients with solid tumors (clinicaltrials.gov identifier NCT01268293). This study was conducted in accordance with the Declaration of Helsinki and was approved by the institutional review board at the participating institution. Written informed consent was obtained from all patients before any study-related procedures were performed. The study used a conventional 3 + 3 dose escalation scheme. Patients were treated in sequential cohorts of escalating doses of lenvatinib administered in 28-day treatment cycles until disease progression, development of unacceptable toxicity, or withdrawal of consent. Planned lenvatinib doses were 20 and 24 mg. The 24-mg dose was the highest planned dose because prior phase 1 studies determined the recommended dose to be 24 mg QD. If no dose-limiting toxicities (DLTs) were observed in three patients or if one DLT was observed in six patients at the 20-mg dose level, patient enrollment could be initiated for the 24-mg dose level. If zero or one DLT was observed in six patients at the 24-mg dose level, the dose was defined as tolerable. QD oral dose of lenvatinib was administered each morning regardless of food intake except for the day of blood sampling for PK analysis (Day 1 and Day 15 of Cycle 1) at which time lenvatinib was administered in a fasting condition. Planned doses for dose reduction were 20, 14, and 10 mg because 4 and 10 mg capsules were used. When a further dose reduction lower than 10 mg was necessary, the principal investigator and Eisai discussed the next dose on a case-by-case basis. If a DLT occurred, lenvatinib was interrupted until recovered to Grade 0–1 or baseline and then restarted at a reduced dose. All subjects who demonstrated a DLT or completed Cycle 1 could continue treatment after additional written informed consent for continuation in the study was obtained.

Safety assessments measured from baseline through 30 days after the last dose included AE profile, laboratory variables [hematology, chemistry, urinalysis, thyroid-stimulating hormone, free triiodothyronine (T3), free thyroxine (T4), human chorionic gonadotropin], vital signs (systolic and diastolic blood pressure, pulse rate, and body temperature), weight, 12-lead electrocardiograms, ECOG PS, and physical examination. Toxicity was graded using the National Cancer Institute (Washington, DC, USA) Common Terminology Criteria for Adverse Events, version 4.0. All AEs emerging during the study were classified by standardized medical terminology using the Medical Dictionary for Regulatory Activities (MedDRA, version 15.1) and appropriately tabulated.

DLTs were assessed during the first treatment cycle and were defined as Grade 4 neutropenia that persists for more than 7 days, Grade ≥3 febrile neutropenia with ≥38.5 °C and neutrophils <1.0 × 10³/μL, Grade 4 thrombocytopenia or Grade 3 thrombocytopenia that requires blood transfusion, any Grade ≥3 non-hematologic toxicity (except for controlled hypertension, diarrhea/vomiting/nausea controlled by supportive care, Grade ≥3 ALT, AST, γ-glutamyltransferase [γ-GTP], or alkaline phosphatase [ALP] increase that persists for ≤7 days, or other Grade ≥3 abnormal clinical laboratory values that persist for ≤3 days), or any toxicity that necessitates the interruption of lenvatinib for >7 days.

Serial blood samples were collected at predose, 1, 2, 4, 8, and 24 h after the first dose on Day 1 of Cycle 1 and after repeated doses on Day 15 of Cycle 1. Blood samples at predose on Day 8 of Cycle 1 and Day 15 of Cycle 2 were also collected. Validated liquid chromatography/mass spectrometry was used to determine lenvatinib in plasma.

Blood samples for PD markers were collected on Days 1, 8, and 15. Circulating endothelial cells (CECs) and circulating endothelial progenitor cells (CEPs), which reflect active vascular turnover and angiogenesis, were measured as described previously [9]. Plasma samples were analyzed in triplicate for baseline and post-treatment levels of 10 angiogenic proteins and cytokines using BioPlex PRO™ human group I cytokine 6-plex (VEGF, platelet-derived growth factor-BB, interleukin [IL]-6, IL-8, IL-10, and granulocyte colony-stimulating factor) and group II 3-plex (stem cell factor, stromal cell-derived factor-1α, and hepatocyte growth factor [HGF]) panel assays (Bio-Rad Laboratories Inc.) and the Invitrogen™ FGF-basic singleplex bead kit (Life Technologies) by LSI Medience Corporation.

Efficacy was assessed using Response Evaluation Criteria in Solid Tumors version 1.1, and assessments were conducted every 8 weeks or sooner if clinically indicated. Tumor response was defined as complete response (CR), partial response (PR), and stable disease (SD) defined as ≥7 weeks after the start of treatment or progressive disease. Disease control rate was defined as the percentage of patients with a best overall response (BOR) of CR, PR, or SD.

Nine patients (three patients in the 20-mg dose level and six patients in the 24-mg dose level) were enrolled at the National Cancer Center Hospital, Tokyo, Japan. Baseline characteristics are summarized in Table 1. The median age was 41 years (range 30–59), and seven patients were female. All patients had ECOG PS score of 0 at baseline. Eight patients had undergone two or more prior chemotherapy regimens before enrollment in this study. Six patients had a primary diagnosis of leiomyosarcoma, one had endometrial stromal sarcoma, one had colorectal cancer, and one had melanoma. The median duration of treatment with lenvatinib was 56 days (range 28–172) in the 20-mg dose level and 209 days (range 59–520) in the 24-mg dose level. The median percentage of the received dose of lenvatinib versus the planned dose was 97 % (range 77–100) in the 20-mg dose level and 82 % (range 73–100) in the 24-mg dose level. Seven patients discontinued lenvatinib treatment due to progression of disease, one patient due to an AE, and one patient due to patient choice.

No DLTs were reported in this study, and both the 20- and 24-mg dose levels were judged to be tolerable. The common AEs (≥30 % of patients in the total group) reported during the study are summarized in Table 2. The most frequently observed AEs were thrombocytopenia, blood thyroid stimulating hormone increased, and hypertension (n = 8, 89 %), followed by leukopenia, headache, and proteinuria (n = 7, 78 %). There were no Grade 4 AEs. The observed Grade 3 AEs were neutropenia (n = 3, 33 %), blood cholesterol increased (n = 2, 22 %), weight decreased, diarrhoea, hypertension, hypertriglyceridemia, leukopenia, anemia, lymphopenia, and proteinuria (n = 1, 11 %). No patient died or had an AE that resulted in death on treatment or within 30 days of the last dose. One serious AE, Grade 3 diarrhoea occurred in one patient in the 24-mg dose level and was considered possibly related to the study drug by the investigator. The patient recovered from this with supportive care and dose interruption. AEs leading to study drug withdrawal occurred in one patient (11 %) (Grade 1 arthralgia and Grade 2 palmar-plantar erythrodysesthesia [PPE] syndrome) in the 24-mg dose level. AEs leading to study drug dose reduction occurred in two patients (22 %): one patient with Grade 3 proteinuria in the 20-mg dose level and one patient with Grade 2 stomatitis and Grade 2 oropharyngeal pain in the 24-mg dose level. AEs leading to study drug interruption occurred in six patients (67 %): one patient in the 20-mg dose level and five patients in the 24-mg dose level. The most frequently occurring AEs leading to study drug interruption included proteinuria (n = 3, 33 %), followed by hypothyroidism, abdominal pain upper, malaise, hypoalbuminemia, and edema peripheral (n = 2, 22 %).

PK parameters of lenvatinib on Day 1 and Day 15 of Cycle 1 are summarized in Table 3, and the mean plasma concentration versus time profiles are shown in Fig. 1. Following oral administration, lenvatinib was absorbed rapidly, with a maximum concentration reached within 2 h.

The mean exposure, as measured by maximum observed concentration (C _max) and area under the concentration–time curve (AUC), increased with an increasing dose of lenvatinib. The mean accumulation index (R _ac) of C _max and AUC ranged from 1.27 to 1.42 and 1.32 to 1.44, respectively. Plasma trough concentrations of lenvatinib on Day 8, Day 15 of Cycle 1, and Day 15 of Cycle 2 remained at almost the same level, indicating that a steady state was attained with ~8 days of QD dosing (Fig. 2).

At 15 days after lenvatinib treatment, the total number of CEPs was significantly decreased compared with baseline levels (P < 0.01); this was attributable to a significant decrease in the number of c-Kit (+) CEPs (P < 0.01; Fig. 3a). The total number of CECs remained unchanged (P > 0.05), but the number of c-Kit (+) CECs was decreased significantly (P < 0.01; Fig. 3b). Among plasma angiogenic factors and cytokines, VEGF increased significantly (P < 0.01) on Day 15 compared with baseline levels (Fig. 3c, d).

The BOR, duration of treatment, and maximum tumor shrinkage from baseline (%) for each patient are shown in Fig. 2. One patient with leiomyosarcoma in the 24-mg QD group had a BOR of PR with treatment duration of 390 days. This gave the overall response rate of 11 %. Five patients had a BOR of SD. Of these, four patients had durable (≥23 weeks) SD: three patients with leiomyosarcoma and one patient with melanoma. The disease control rate (CR + PR + SD) was 67 %. Tumor shrinkage from baseline was observed in five patients: one patient in the 20-mg dose level and four patients in the 24-mg dose level.