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Phase I study of highly selective inhibitor of VEGFR tyrosine kinase, tivozanib, in Japanese patients with solid tumors

Authors


To whom correspondence should be addressed.

E-mail: nbyamamo@wakayama-med.ac.jp

Abstract

Tivozanib is a potent and selective inhibitor of vascular endothelial growth factor receptor (VEGFR) tyrosine kinases. A previous clinical trial in the EU and USA indicated that tivozanib at the maximum tolerated dose of 1.5 mg/day showed an antitumor activity in patients with renal cell carcinoma. This Japanese phase I study was designed to determine the recommended phase II dose of tivozanib for Japanese patients; secondary objectives included pharmacokinetic/pharmacodynamic profiles and preliminary efficacy. Daily treatment with tivozanib in a 3-weeks-on/1-week-off cycle was examined in nine Japanese patients with advanced solid tumors in the 3 + 3 design (Level 1, 1.0 mg; Level 2, 1.5 mg). No dose-limiting toxicity was observed throughout the study, and the maximum tolerated dose was not reached. The most commonly observed drug-related adverse events were diarrhea, dysphonia, rash, thyroid stimulating hormone increase, and with severity grade ≥3, hand-foot skin reaction, hypertension, and proteinuria. Those adverse events were generally well-manageable and mostly resolved within the tolerability evaluation period. Serum exposure to tivozanib resulted in t1/2 of more than >60 h. Increase of plasma VEGF and decrease of plasma VEGFR-1 and VEGFR-2 were observed 1–3 weeks after tivozanib treatment. Although no complete or partial response was observed, long-term stable disease continuing more than 170 days was observed in three renal cell carcinoma patients who had failed prior VEGFR inhibitors. In conclusion, 1.5 mg/day of tivozanib in a 3-weeks-on/1-week-off setting was tolerable in Japanese patients, and was recommended for further clinical trials in the Japanese population. Clinical trial Registration No: JapicCTI-090854.

Vascular endothelial growth factors (VEGFs) play important roles in physiological angiogenesis. They are also involved in pathological angiogenesis associated with tumor progression and metastases. In a signaling pathway induced by increasingly hypoxic conditions in tumors, various VEGFs become upregulated and, in turn, facilitate the neovascularization and progression of solid tumors.[1, 2] VEGF receptors (VEGFRs), to accelerate angiogenic signaling pathways; thus, targeting the VEGF signaling pathway in tumor tissues is beneficial for cancer therapy.[3] Recently, various antitumor agents that inhibit or neutralize the VEGF/VEGFR signaling pathway have become available on the market and widely used for the treatment of various types of tumors, including renal cell carcinoma (RCC), hepatocellular carcinoma, non-small-cell lung cancer, colorectal cancer, breast cancer, and glioblastoma.

Tivozanib (formerly KRN-951 or AV-951; N-{2-chloro-4- [(6,7-dimethoxy-4-quinolyl)oxy]phenyl}-N′-(5-methyl-3-isoxazolyl) urea hydrochloride monohydrate) is a novel small molecule tyrosine kinase inhibitor that potently and selectively inhibits VEGFRs. Tivozanib inhibits VEGFR-1, -2, and -3 with an IC50 of 0.21, 0.16, and 0.24 nM, respectively.[4] Numerous preclinical and clinical studies of tivozanib have been carried out or are ongoing,[4-7] including a global, randomized phase III study, comparing tivozanib and sorafenib as initial targeted therapy for 517 patients with advanced RCC. This phase III study has so far shown that tivozanib demonstrated significant improvement in progression-free survival compared with sorafenib, and the most common grade ≥3 adverse events for tivozanib included hypertension, hand–foot skin reaction, and increase in thyroid-stimulating hormone. The overall efficacy and safety profile of tivozanib was more favorable than that of sorafenib.[5] In Asian countries, however, there has been no clinical study to evaluate the efficacy and safety profiles of tivozanib.

This study is the first clinical trial of tivozanib in Japan. In this open-label, single-center dose-escalation phase I study, the safety and tolerability of tivozanib were examined to determine the recommended phase II/III dose for the Japanese population in future clinical studies. Pharmacodynamic markers (serum soluble VEGFR-1 and -2) and antitumor activity were also examined.

Materials and Methods

Patients

Japanese patients with solid malignant tumors confirmed by cytology or histology that were refractory to standard therapy or had no standard therapy were eligible for this study. Other inclusion criteria were age ≥20 years, Eastern Cooperative Oncology Group performance status of 0–2, and life expectancy ≥3 months. Exclusion criteria included patients with neutrophil count <1500/μL, platelet count <100 000/μL, hemoglobin concentration <9.0 g/dL, blood transfusion or treatment with granulocyte colony-stimulating factor within 2 weeks, myocardial infarction or symptomatic left ventricular failure observed within 3 months, uncontrollable hypertension (diastolic pressure ≥90 mmHg, systolic arterial pressure ≥150 mmHg, requiring more than three medications to control, or history of a hypertension crisis or hypertensive encephalopathy). Other exclusions included symptomatic brain metastases confirmed by image, unhealed injury (including active gastric ulcer and bone fracture), hemophilic diseases, thromboembolism, hepatic or renal dysfunction, digestive organ dysfunction of grade 3 or higher (Common Terminology Criteria for Adverse Events: CTCAE version 3.0; Japanese Society of Clinical Oncology, Kyoto, Japan), active infection, anti-hepatitis B virus antibody positive, anti-hepatitis C virus antibody positive, human immunodeficiency virus positive, and pregnant or lactating women. Patients who had any of the following medication histories were also excluded: previous tivozanib or other anticancer therapy (including chemotherapy, immunotherapy, radiotherapy, hormone therapy, surgery, molecular-targeted medicine, and other trial agents) within 4 weeks; coumarin anticoagulant with dosage >2 mg/day within 7 days, or colony stimulating factor within 2 weeks.

Study design

This was a phase I, single-center (Shizuoka Cancer Center, Shizuoka, Japan), open-label, 3 + 3 dose-escalating study of tivozanib planned for a minimum of three and maximum of 12 Japanese patients. Tivozanib was supplied in 1.0- or 1.5-mg capsules by Kyowa Hakko Kirin Co., Ltd (formerly Kirin Pharma Co., Ltd., Tokyo, Japan) and administration avoided the period from 1 h before and 2 h after meals. The starting dose was set to 1.0 mg/day, and escalated up to 1.5 mg/day in this study.

This study was divided into two parts, the single-dose administration period to assess the pharmacokinetics (PKs), and the continuous administration period to assess the tolerability of tivozanib (Fig. 1). To find the maximum tolerated dose (MTD), a standard 3 + 3 dose escalation design was used. Three patients were enrolled and received an initial, single dose of 1.0 mg tivozanib (day 1). After 6 days of the off-drug period, continuous administration at Level 1 (1.0 mg given once daily for 21 days followed by 7 days off for one cycle) started on day 8. If none of those three patients experienced any dose-limiting toxicity (DLT) during the tolerability evaluation period, the cohort testing Level 2 (1.5 mg given once daily for 21 days followed by 7 days off for one cycle) was opened. If one patient of the three experienced a DLT, an additional three patients would be enrolled to Level 1, and no DLTs were observed in the additional three patients, the cohort testing Level 2 was opened. Safety, tolerability, and MTD would be evaluated by the same procedure at Level 2. The dose level where DLTs were observed in two or more patients was taken to indicate the MTD. A patient was determined to have a DLT if any of the following drug-related adverse events were present: neutrophils <500/μL; hemoglobin <6.5 g/dL; platelet <25 000/μL; or any grade ≥3 non-hematological toxicity, excluding grade 3 hypertension if controllable (systolic and diastolic pressures decrease to <160 and <100 mmHg, respectively, within 7 days of antihypertensive treatment).

Figure 1.

Study assessment and schedule. Among patients who experienced a dose-limiting toxicity at cycle 1, tolerability was monitored until the end of follow-up for patients who discontinued the study drug administration or until the day before re-administration for patients who experienced re-administration of the study drug. For patients who continued tivozanib after the end of cycle 1, informed consent was obtained at the start of cycle 2. PK, pharmacokinetic; wk, week.

All patients provided written informed consent at enrolment and again before the start of cycle 2. Patients could continue tivozanib treatment as long as there were no disease progression or safety issues after cycle 2 started. Protocol treatment was discontinued for patients who experienced DLTs at 1.0 mg. Patients who developed DLTs at 1.5 mg were permitted to resume treatment at 1.0 mg if the DLT recovered to grade ≤2 for hematological toxicity or grade ≤1 for non-hematological toxicity. Physicians could decide to interrupt treatment for reasons other than a DLT, and the protocol treatment was discontinued if it could not restart for more than 4 weeks.

Documented approval from the Japanese regulatory agency PMDA and the Institutional Review Board were obtained for this clinical study. This study was carried out in accordance with revised Good Clinical Practice guidelines and the Declaration of Helsinki. An independent date and safety monitoring committee was established for the review of safety and efficacy data in this study.

Study assessments

Baseline evaluation took place within two weeks before the first dose of tivozanib. Pretreatment evaluation included a medical history and physical examination, laboratory tests, and electrocardiogram (Fig. 1).

The tolerability analysis set included both patients who experienced a DLT in cycle 1 and those who received the study drug for 17 or more days of cycle 1 and followed up for at least 6 days after the last dose. Patients were included in the safety analysis set if they received at least one dose of tivozanib. Adverse events were assessed continuously throughout the daily observation, and assessed by routine laboratory evaluation, including the hematology/biochemical test and electrocardiogram. Adverse events were graded by CTCAE version 3.0, and they were tabulated as lower-level terms of the Medical Dictionary for Regulatory Activities, Japanese translation (version 14; Pharmaceutical and Medical Device Regulatory Science Society of Japan, Tokyo, Japan).

Tumor response was evaluated according to the Response Evaluation Criteria in Solid Tumors (RECIST 1.1),[8] every 8 weeks. Patients who received at least one dose and for whom tumor response could be monitored by RECIST were included in the tumor response analyses set.

For PK assessment, blood samples were collected before treatment began and at 0.5, 1, 2, 4, 6, 8, 10, 24, 36, and 48 h, and every 24 h till the start of the continuous administration period. During the continuous administration period, blood samples were collected on the last day of cycle 1; before administration, and at 0.5, 1, 2, 4, 6, 8, 10, and 24 h after the last administration. Patients in whom at least one sample was collected were included in the PK analysis set. The PK assessment was carried out by Quintiles AB, Analytical Services (Uppsala, Sweden), where serum concentrations of tivozanib were determined by HPLC with tandem mass spectrometry as previously reported.[6] The PK parameters, such as Cmax, tmax, t1/2, and AUC0–t were calculated by WinNonlin (Pharsight, Mountain View, CA, USA).

Plasma biomarkers including VEGF and soluble VEGFR-1 and -2 levels were assessed before the first administration, on day 2 during the single-dose administration period, and on days 8, 22, and 28 during cycle 1. Plasma VEGF and soluble VEGFR-1 and -2 were assayed by a commercial laboratory, Mitsubishi Chemical Medience (Tokyo, Japan) using an appropriate ELISA-based technique. Student's t-test was carried out using Excel 2007 (Microsoft, Redmond, WA, USA).

Results

Patient characteristics

A total of nine Japanese patients with advanced solid tumors were enrolled from September 2009 to February 2010. The dose levels studied were 1.0 mg for three patients and 1.5 mg for six patients. Patient characteristics, including their cancer types, are shown in Table 1. All patients had received systemic chemotherapy including sorafenib or sunitinib prior to receiving tivozanib, except for one patient with oropharyngeal adenoid cystic carcinoma for which no standard therapy was available. At the time of the enrolment, the oropharyngeal adenoid cystic carcinoma was relapsed with bone metastasis and multiple lung metastases, after the complete response to the previous proton-beam therapy.

Table 1. Characteristics of Japanese patients with advanced solid tumors who participated in the phase I study of tivozanib (n = 9)
 1.0 mg1.5 mgOverall
  1. ECOG PS, Eastern Cooperative Oncology Group performance status.

Patient no.369
Age in years, median535854
Gender
Male358
Female011
Primary cancer
Renal044
Esophageal202
Gastric011
Oropharyngeal101
Lung011
ECOG PS
0257
1112
≥2000
No. of prior chemotherapy
0101
1000
2022
3011
≥4235

Dose escalation and DLT

As none of the participants experienced any DLTs during the tolerability evaluation period, MTD was not reached in this study.

Safety and tolerability

At the data cut-off date of January 2011, three patients at 1.5 mg were continuing tivozanib treatment and six patients (three at each level) had discontinued; five patients (three at 1.0 mg, two at 1.5 mg) due to progressive disease (PD) and one patient (at 1.5 mg) due to adverse event (grade 3 proteinuria occurring on treatment cycle 3). The median duration of tivozanib therapy was 169 days (range, 116–424 days) at the date of cut-off.

The drug-related adverse events observed in two or more patients throughout the study are summarized in Table 2. Common drug-related adverse events (>50%) were diarrhea, rash, dysphonia, and increase in thyroid-stimulating hormone, but they were mostly modest and manageable. Grade ≥3 drug-related adverse events were not observed with tivozanib 1.0 mg. Of six patients treated with 1.5 mg tivozanib, grade 3 hypertension in two patients, grade 3 proteinuria in two patients, and grade 3 hand–foot skin reaction in one patient were observed. Grade 3 hypertension in these patients was controllable with antihypertensive therapy, and a patient with grade 3 hand–foot skin reaction recovered to grade 1 during the off-drug period in a treatment cycle. Of those two patients with RCC that developed grade 3 proteinuria, one discontinued the study on cycle 3 as drug administration was interrupted for longer than 28 days. No serious adverse event prolonging the duration of hospitalization was reported throughout the study, except one pleural hemorrhage in a patient who died 22 days after the withdrawal of tivozanib treatment due to PD (evaluated at the end of cycle 2). The pleural hemorrhage was accompanied with rapid expansion of both multiple lung metastases and mediastinal lymph node, which would be the direct cause for the severe pleural hemorrhage. However, a cystic change in the mediastinal lymph node was already observed during the treatment of tivozanib, and the cystic change was thought to be caused by tivozanib. It would be possible that the cystic change would exacerbate the pleural hemorrhage, and hence, the pleural hemorrhage was recognized as an adverse event possibly related to the study drug. The pleural hemorrhage was not dose-limiting, because this event occurred after the withdrawal of tivozanib due to PD. The pleural hemorrhage was not recognized as a DLT, in agreement with the independent data and safety monitoring committee.

Table 2. Drug-related adverse events occurring in ≥2 patients with advanced solid tumors who participated in the Japanese phase I study of tivozanib
Drug-related adverse events1.0 mg (n = 3)1.5 mg (= 6)Overall (= 9)
Gr.1Gr.2Gr.3Gr.4Gr.5Gr.1Gr.2Gr.3Gr.4Gr.5All Grades≥Gr.3
n n n n n n n n n n n (%) n (%)
  1. Gr., grade; TSH, thyroid-stimulating hormone.

Diarrhea1000033000777.800.0
Nausea2000010000333.300.0
Stomatitis1000020000333.300.0
Weight loss1000011000333.300.0
Vomiting1000010000222.200.0
Dyspepsia1000010000222.200.0
Rash1000032000666.700.0
Hand–foot skin reaction1000011100444.4111.1
Dry skin1000020000333.300.0
TSH increase3000030000666.700.0
Hypothyroidism0000002000222.200.0
Dysphonia2000050000777.800.0
Hypertension0100001200444.4222.2
Proteinuria1000001200444.4222.2
Headache0000020000222.200.0

Pharmacokinetics and pharmacodynamics

Pharmacokinetic sampling was carried out in all nine patients. Table 3 shows these parameters following the single-dose administration period and at the end of the continuous administration period. One patient (Patient ID 1206) at Level 2 reached an extraordinarily high serum tivozanib concentration at 168 h after the single-dose administration (Fig. 2), although the reason could not be clarified. The incident was omitted from the PK analysis shown in Table 3, due to the inability to calculate the PK parameters if it was included. Figure 2 shows the time course of serum tivozanib concentration per patient, indicating that individual deviation in tivozanib exposure was modest at respective dose levels. Serum exposure to tivozanib was higher in the 1.5 mg group than in the 1.0 mg group, at both single-dose and continuous administration periods. Tivozanib resulted in long t1/2 (>60 h), and AUC0–t for the continuous administration was six and eightfold higher at 1.0 mg and 1.5 mg, respectively, compared to the single-dose administration.

Table 3. Pharmacokinetic parameters (mean ± SD, range) in nine Japanese patients with advanced solid tumors after single-dose administration or one cycle of continuous administration of tivozanib (1.0 mg or 1.5 mg)
Sampling periodPharmacokinetic parameterDose level
1.0 mg (n = 3)1.5 mg (n = 6)
  1. a

    Data for one patient, for whom tmax was at 168 h, was excluded.

Single-dose administrationtmax (h)8.056 ± 0.059(8.00–8.12)9.681 ± 7.062a(6.00–23.95)a
Cmax (ng/mL)11.27 ± 6.00(5.40–17.40)14.26 ± 5.54a(9.87–25.20)a
AUC0–t (ng h/mL)159.7 ± 55.0(100–209)231.3 ± 75.4(180–378)
t1/2 (h)78.65 ± 13.77(63.4–90.1)106.63 ± 39.65(75.5–165.3)
Continuous administration (cycle 1, days 21–22)tmax (h)16.661 ± 12.726(1.97–24.02)10.147 ± 11.062(0.47–24.03)
Cmax (ng/mL)48.27 ± 18.88(34.1–69.7)95.23 ± 47.74(39.0–179.0)
AUC0–t (ng h/mL)1017.9 ± 406.6(744–1485)1857.7 ± 795.6(787–3054)
Figure 2.

Time course of serum tivozanib concentration. Serum tivozanib concentration following single dose of 1.0 mg (a) and 1.5 mg (b), and continuous administration of 1.0 mg (c) and 1.5 mg (d). Blood samples were collected before administration and at 0.5, 1, 2, 4, 6, 8, 10, 24, and 36 h and thereafter every 24 h up to 168 h after single-dose administration (a,b). During the continuous administration period, samples were collected before administration and at 0.5, 1, 2, 4, 6, 8, 10, and 24 h after the last administration during cycle 1 (c,d).

On day 22 of the cycle 1 continuous administration, plasma VEGF values were 1.595 and 3.569 times higher than baseline values for Levels 1 and 2, respectively. At the same time point, VEGFR-1 levels tended to decrease to 0.617 and 0.674, respectively, whereas VEGFR-2 levels decreased to 0.717 and 0.647, respectively. Both VEGF and VEGFR-1 levels tended to recover equivalent to baseline levels at day 28, whereas VEGFR-2 levels remained low (Fig. 3). Of interest, patients with renal cancer showed a significantly lower level of soluble VEGFR-1 at the baseline, compared to the patient with non-renal cancer (P < 0.001, Student's t-test; Fig. S1).

Figure 3.

Pharmacodynamic biomarkers. Plasma levels of vascular endothelial growth factor (VEGF) (a), soluble VEGF receptor (VEGFR)-1 (b), and VEGFR-2 (c) for patients treated with 1.0 mg (closed circle) or 1.5 mg (open circle) are indicated individually. Blood samples were collected at baseline, on days 8 and 22, and on day 28 of the cycle 1 continuous administration.

Antitumor activity

Table 4 shows the patient backgrounds and their efficacies observed in this study. Six of nine patients had measurable lesions for the evaluation of antitumor efficacy. No patient showed complete response (CR) or partial response (PR); four patients showed stable disease (SD). The best response of the other three patients without measurable lesion showed non-CR/non-PD, as defined in RECIST version 1.1. Among three patients at Level 1, the disease control rate (CR + PR + SD + non-CR/non-PD) was 100% with a median time to progression of 170 days. Among six patients at Level 2, the disease control rate was 66.7% (4/6), with the median time to progression of ≥365 days (Table 4). Of note, three of four patients with RCC treated with continuous administration of tivozanib 1.5 mg achieved long-term (>1 year) disease control with well-controllable adverse events, although all the patients had failed previous VEGFR inhibitor therapies. In detail: Patient 1201 had failed previous sunitinib treatment due to PD after approximately 4 years of disease control; Patient 1203 had failed both sorafenib and sunitinib treatments due to PD after approximately 3 years of disease control; and Patient 1205 had failed prior sorafenib treatment due to adverse events (mainly, hand-foot skin reaction and diarrhea) after approximately 1 week of treatment.

Table 4. Best response and duration of treatment in Japanese patients (n = 9) with advanced solid tumors after treatment with tivozanib (1.0 or 1.5 mg)
Patient IDPatient backgroundResults in this study
DiseasePrior VEGF/VEGFR inhibitorTivozanib dose (mg/day)Best responseDuration of treatment (cycles)Time to progression (days)Reason for withdrawal
  1. †Best response was determined according to RECIST criteria. ‡Patient was still on study on the date of cut-off. §Adverse event (AE), proteinuria persisting more than 4 weeks of drug interruption, which met the withdrawal criteria. ¶Dose was reduced from 1.5 to 1.0 mg due to an AE on cycle 6. This patient continued tivozanib treatment with the reduced dose. CR, complete response; PD, progressive disease; SD, stable disease; VEGF, vascular endothelial growth factor; VEGFR, vascular endothelial growth factor receptor.

1101EsophagealNone1.0Non-CR/non-PD4111PD
1102OropharyngealNone1.0Non-CR/non-PD14401PD
1103EsophagealNone1.0SD6170PD
1201RenalSunitinib1.5SD>15>424Ongoing
1202RenalSorafenib1.5SD3112AE§
1203RenalSorafenib, Sunitinib1.5SD>15>421Ongoing
1204GastricBevacizumab1.5SD257PD
1205RenalSorafenib1.5 (1.0)Non-CR/non-PD>12>351Ongoing
1206LungNone1.5SD258PD

Discussion

This study was the first Japanese trial to examine the safety and tolerability of tivozanib to determine the recommended phase II/III dose for the Japanese population in future clinical trials. Our results showed that tivozanib at the dose of 1.5 mg with a 3-weeks-on/1-week-off cycle was well tolerated with manageable toxicity in Japanese patients. Pharmacokinetic analysis demonstrated that few differences were observed in PK parameters between this Japanese phase I and the previous phase I study in the Netherlands, although one patient was excluded from the analysis of PK, where the t1/2 and AUC0-24 were 112 h and 159.2 (±SD: 69.4) h ng/mL, respectively, at the same dose of 1.5 mg tivozanib on a single-dose phase.[6] We presume that the high value which led to the exclusion of the patients would be an artifact caused by some errors, because the high value was dotted during the clear elimination phase identified by other dots observed after the single dose of tivozanib, and such high values were found only once and never observed again in the two series of PK sampling during the single and repeating phases in this patient, as likely as the other patients in the same cohort. Taken together, the recommended dose setting of tivozanib for a phase II/III study in the Japanese population would be 1.5 mg using a 3-weeks-on/1-week-off cycle, which is the same dose as the phase II/III studies completed in the EU and USA.

Hypertension was the most common adverse event related to tivozanib, and developed most frequently to grade ≥3. In addition to hypertension, hand–foot skin reaction, proteinuria, and hypothyroidism were common adverse events related to tivozanib treatment. These findings are consistent with the previous findings from phase I–III tivozanib studies.[5-7] Furthermore, these adverse events are observed in patients who have been treated with other agents inhibiting the VEGF/VEGFR axis, such as sorafenib,[9] sunitinib,[10] axitinib,[11] and pazopanib,[12] suggesting that these are “on target” toxicities.

Diarrhea was already recognized as a common adverse event related to tivozanib, as shown in the previous phase II study.[7] However, the frequency of diarrhea in this Japanese study was 77.8%, which is in sharp contrast with the frequency (12%) in the previous phase II study in which most participants were Caucasians.[7] First, hospitalization, which involved frequent monitoring of patients, was mandatory in our protocol, leading to more frequent adverse events. Second, racial or cultural differences among Asians and Caucasians could lead to different susceptibilities and/or sensitivities against diarrhea. Due to the small number of patients in our study, the contrast should be confirmed in the future. However, we think there are several reasons why there was a higher frequency of diarrhea in Japanese patients. Pharmacodynamic markers, which were evaluated in the previous phase I study in the Netherlands,[6] were also confirmed in this Japanese study. The results are mostly consistent with those from the previous phase I study. It is suggested that tivozanib in human beings would hit the same target as the agents recognized as a VEGFR inhibitor, according to the results that the effects of tivozanib on serum levels of VEGF-A and sVEGFR-2 are similar to those in patients treated with other VEGFR inhibitors, including sunitinib,[13] telatinib,[14] pazopanib,[15] cediranib,[16] ramucirumab,[17] and linifanib.[18] In these reports, there appears to be few differences in pharmacodynamics between Japanese and other populations. It is of interest in our study that a lower level of soluble VEGFR-1 was found in renal cancer, as compared to non-renal cancer (Fig. S1). It should be investigated whether soluble VEGFR-1 might be related to the contribution of VEGF/VEGFR signaling in the progress of each cancer.

A randomized phase III study of approximately 500 patients with advanced RCC has shown that tivozanib demonstrated significant improvement in progression-free survival compared with sorafenib. In this study, tivozanib at the dose of 1.5 mg showed some notable benefit in four RCC patients. Although no tumor response was observed among the patients in this study, three of them showed long-term SD continuing for almost 1 year with modest and well manageable toxicities. Notably, these long-term controlled RCC patients were previously treated with other inhibitors targeting VEGFR tyrosine kinases. Reasons for failure of previous VEGFR inhibitors include disease progression (two of three) and intolerable adverse event (one of three). Therefore, tivozanib may be able to complement existing VEGFR inhibitors and could constitute new treatment option of RCC.

In conclusion, tivozanib was well tolerated in Japanese patients with solid tumor, at the dose of 1.5 mg using a 3-weeks-on/1-week-off cycle. This dose setting corresponded to the preceding international phase II/III studies for patients with RCC, and was determined as the recommendation for further clinical trials in the Japanese population. Similar to other VEGFR inhibitors, tivozanib showed an encouraging sign of efficacy in RCC patients who were not only naïve to VEGFR inhibitors,[5] but also recurrent or refractory to previous VEGFR inhibitors. A further clinical trial evaluating the efficacy of tivozanib in Japanese patients is warranted.

Acknowledgments

We thank the patients, their families and caregivers, and all of the personnel who contribute to patient care and data collection for this study of tivozanib. We also thank the members of the independent data and safety monitoring committee, Dr Hironobu Minami, Dr Tetsu Shinkai, and Dr Yutaka Ariyoshi.

Disclosure Statement

This study was financially sponsored by Kyowa Hakko Kirin Co., Ltd. S.A. is an employee of Kyowa Hakko Kirin Co., Ltd.

Ancillary