- Email: [email protected]
II study of S-1 in combination with sorafenib for metastatic renal cell carcinoma
Annals of Oncology Advance Access published June 27, 2015 1
Phase 1/2 study of S-1 in combination with sorafenib for metastatic renal cell carcinoma
S. Naito1*, H. Sakai2, K. Hashine3, T. Tomita4, N. Shinohara5, M. Fujisawa6, M. Eto7, S. Ozono8, H. Akaza9
1: Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan 2: Department of Nephro-Urology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki,
3: Department of Urology, National Hospital Organization Shikoku Cancer Center, Matsuyama, Japan 4: Department of Urology, Yamagata University Faculty of Medicine, Yamagata, Japan 5: Department of Urology, Hokkaido University Graduate School of Medicine, Sapporo, Japan 6: Department of Urology, Kobe University School of Medicine, Kobe, Japan 7: Department of Urology, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan 8: Department of Urology, Hamamatsu University School of Medicine, Hamamatsu, Japan 9: Department of Strategic Investigation on Comprehensive Cancer Network, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan
*
Correspondence to
Dr. Seiji Naito Department of Urology, Graduate School of Medical Sciences, Kyushu University 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan Tel.: +81-92-642-5603, Fax: +81-92-642-5618 E-mail: [email protected]
© The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected].
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Japan
2
Abstract Background: The potential of S-1 for the treatment of metastatic renal cell carcinoma (mRCC) has been shown in two phase 2 studies. We aimed to assess the safety, tolerance, pharmacokinetics and clinical activity of S-1 combined with sorafenib in patients with mRCC. Patients and methods: In this multicenter, single-arm, open-label, phase 1/2 study of S-1 plus sorafenib, we recruited patients with clear-cell or papillary renal cell carcinoma who had received a maximum of one prior
recommended dose (RD). S-1 was administered orally at 60, 80, 100 or 120 mg/day on days 1 to 28 of a 42-day cycle in combination with sorafenib (400 or 800 mg/day), given daily with dose adjustment. In phase 2, the primary endpoint was to assess the overall response rate (ORR) at the RD. Results: Nine patients were enrolled into phase 1 and 21 (including 6 patients who received the RD in the phase 1 portion) were enrolled into phase 2. In the phase 1 portion, the MTD could not be determined, and the RD was defined as S-1 80 mg/m2/day on days 1–28 + sorafenib 800 mg/day on days 1–42. In the phase 2 portion, 21 patients were fully assessable for efficacy and safety. The confirmed ORR was 52% (95% CI, 29.8-74.3), including one complete response (5%) and 10 partial responses (48%). The median progression free survival was 9.9 (95% CI, 6.5-17.1) months. The most frequently reported treatment-related adverse event for all grades was hand-foot skin reaction (100%). The major reasons for dose reduction were hand-foot skin reaction (38%) and rash (14%). Conclusion: Combination therapy with S-1 plus sorafenib is effective and tolerable for patients with mRCC. However, skin events management is important in S-1 plus sorafenib combination therapy. Key words: S-1, sorafenib, metastatic renal cell carcinoma.
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cytokine-based regimen. The phase 1 primary endpoints were the maximum tolerated dose (MTD) and
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Introduction The recent development of novel therapies that target tumor angiogenesis and mammalian target of rapamycin pathways has improved outcomes in patients with advanced renal cell carcinoma (RCC) [1, 2]. Sequential therapy with targeted agents is the current standard of care; however, combination regimens including targeted agents have also been studied to enhance efficacy and combat resistance. Current combination therapy strategies have not been proven to be beneficial, and many combination regimens have
[2]. We previously reported promising single-agent results for S-1, an oral fluoropyrimidine-based anticancer agent, with an overall response rate (ORR) of 24.4% in patients with cytokine-refractory metastatic RCC (mRCC) at the dose of 80, 100 or 120 mg/day based on body surface area [3]. High sensitivity to S-1 monotherapy was associated low thymidylate synthase (TS) expression in tumors, although myelosuppression was frequently observed. Because molecular targeting agents other than sunitinib rarely cause myelosuppression, S-1 might be a good candidate for combination therapy with molecular targeting agents such as sorafenib. We therefore assessed the efficacy and safety profile of combination therapy with S-1 and sorafenib in patients with mRCC.
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shown excessive toxicity with marginal or inferior efficacy compared with that of the sequential-use agents
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Methods This was a nonrandomized, open-label, multicenter phase 1/2 trial in Japanese patients with mRCC who had undergone nephrectomy. This trial was conducted in accordance with the World Medical Association Declaration of Helsinki and Japanese Good Clinical Practice guidelines. The protocol was approved by the institutional review boards of all participating institutions. This study is registered with the Japan Pharmaceutical Information Center (number JapicCTI-090973).
Patients were eligible if they were 20 years of age or older, and had: a history of nephrectomy; a histologically confirmed diagnosis of clear-cell or papillary RCC; received no previous treatment or only one regimen of cytokine therapy; an Eastern Cooperative Oncology Group performance status of 0 or 1; measurable lesions as defined by the Response Evaluation Criteria in Solid Tumours [4] (RECIST; version 1.0); adequate hematological, hepatic, and renal function. We excluded patients who had brain metastasis, a known hypersensitivity to S-1 or sorafenib, or severe complications, concurrent malignancy, marked pleural effusion or ascites, watery diarrhea or peptic ulcer. Written informed consent was obtained from all patients before enrollment.
Study design and treatment In the phase 1 portion, we studied four S-1 and sorafenib dose levels. Patients were administered sorafenib orally at a dose of 400 or 800 mg/day. Treatment included S-1 doses, based on body surface area as follows: 60, 80, 100 or 120 mg/day. Dosing levels were as follows: level 0, days 1-28 S-1 60, 80 or
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Eligibility criteria
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100 mg/day plus days 1-42 sorafenib 400 mg/day; level 1A, days 1-28 S-1 80, 100 or 120 mg/day plus days 1-42 sorafenib 400 mg/day; level 1B, days 1-28 S-1 60, 80 or 100 mg/day plus days 1-42 sorafenib 800 mg/day; and level 2, days 1-28 S-1 80, 100 or 120 mg/day plus days 1-42 sorafenib 800 mg/day(for more detail See S1). Treatment was administered in 42-day cycles and continued until disease progression, refusal to continue treatment or unacceptable adverse events (AEs). The initially dose administered was level 1B, and dose adjustment then followed a standard three-plus-three design. Given possible interactions between
dose-limiting toxicity (DLT) during the first cycle, the dose was escalated to level 2. If DLT occurred in one or two of the first three patients given a particular level, then three additional patients were enrolled to receive the same dose level, for a total of six patients. The maximum tolerated dose (MTD) was reached when three or more of six patients at one dose level had DLTs. Thus, this dose was defined as the MTD, and one dose level below was designated as the recommended dose (RD) for phase 2. If less than three of the six patients had DLTs at the last dose level, then this dose level was the RD for phase 2. If patients less than three of the six had DLTs at the dose level 2, no MTD was determined in this study and the dose level 2 will be fixed as the RD. No intra-patient dose escalation was allowed. In the phase 2 portion, patients received combination treatment with S-1 plus sorafenib at the RD determined in the phase 1. Treatment was continued until any of the following occurred: unacceptable toxicity, refusal to continue treatment or definite tumor progression. When the predefined toxic events in the protocol occurred, dose adjustment or interruption required (for more detail See S2).
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S-1 and sorafenib, a half-dose of sorafenib was used in levels 0 and 1A. If none of the first three patients had
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Dose Limiting Toxicity DLT was defined as any of following events occurring during the first cycle of treatment: grade 4 or higher hematological toxicity; grade 3 or higher febrile neutropenia; grade 3 or higher non-hematological toxicity except for hand-foot skin reaction and pancreatic enzyme abnormality; drug-related pancreatitis associated with a grade 4 increase in pancreatic enzymes; AEs requiring suspension of treatment for no less than 15 consecutive days; and AEs requiring discontinuation of treatment.
The primary endpoint of the phase 1 portion was the MTD and RD. In the phase 2 portion, the primary endpoint was the proportion of patients who had an objective response and confirmed by a subsequent scan. Secondary endpoints included the safety profile, proportion of patients who achieved disease control (complete response; CR, partial response; PR or stable disease; SD maintained for 28 days or longer), progression-free survival (PFS: the time between the initiation of study treatment and disease progression or death from any cause), overall survival (OS: the time between the initiation of study treatment and death from any cause) and pharmacokinetic (PK) parameters.
Study evaluations Tumor imaging was performed at baseline and at least every 6 weeks thereafter. Complete blood cultures, serum chemical analysis and urinalysis were performed every week during the first cycle of phase 1, followed by every 2 weeks thereafter in phases 1 and 2.
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Endpoints
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Response and Toxicity Criteria The RECIST were used to assess the response to treatment, and the Common Terminology Criteria for Adverse Events (version 3.0) [5] were used to assess toxicity. An independent review committee consisting of radiologists and medical oncologists objectively confirmed treatment responses and drug-related AEs.
Statistical analysis
and an expected response rate (under the alternative hypothesis) of 25%, based on the results of two phase 2 studies of S-1 and a phase 2 study of sorafenib [3, 6]. Under these assumptions, a sample size of 21 patients would ensure a power of at least 80% at a one-sided significance level of 5%. Thus, a response rate of 4 of 21 patients would permit rejection of the null hypothesis. We performed primary analyses on a full analysis set basis; patients who received at least one dose of the assigned study drugs. All analyses were performed using statistical software package (SAS version 9.2; SAS Institute Inc, Cary, NC, USA).
Pharmacokinetics In the phase 1 portion, we obtained blood samples for S-1 PK evaluation at the following time points: pre-dose and 1, 2, 4, 6, 8, 10 and 12 hour after co-administration of S-1 and sorafenib on day 1. For sorafenib PK evaluations, blood samples were taken at the following time points: pre-dose and 1, 2, 4, 6, 8 and 12 hour after co-administration of S-1 on day 28 and after administration of sorafenib alone on day 35. Plasma samples were prepared by centrifugation of the blood samples. Plasma concentrations of S-1
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In the phase 2 portion, we initially used a threshold response rate (under the null hypothesis) of 5%,
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components (5-fluorouracil, 5-FU; tegafur, FT; 5-chloro-2,4-dihydropyridine, CDHP; potassium oxonate, Oxo) on day 1 were measured to evaluate the effect of sorafenib by comparing the results with historical data (Shin Nippon Biomedical Laboratories, Ltd., Wakayama, Japan). Sorafenib plasma concentrations were measured on day 28 (S-1 and sorafenib co-administration) and 35 (sorafenib administration alone) to evaluate the effect of S-1 by comparing PK between day 28 and 35 (Covance Laboratories, Madison, WI, US). The Cmax and AUC0-12 PK parameters were determined for S-1 components and sorafenib.
Patient characteristics Between December 14, 2009 and September 4, 2012, a total of 24 patients (9 in phase 1 and 15 in phase 2) were enrolled. All patients were eligible for the toxicity and efficacy evaluation. The first 3 patients received dose level 1B. The 6 patients who received dose level 2 during phase 1 were included in the phase 2 assessment, along with another 15 patients. The patient characteristic are summarized in Table 1. There were 34 treatment cycles administered overall (median 15.0, range 2-17) to patients at dose level 1B, and 179 treatment cycles administered overall (median 8.0, range 1-20) to patients at dose level 2. The main reasons for treatment discontinuation at dose levels 1B and 2 were tumor progression in two patients (67%) and 10 patients (48%), respectively, and toxicity in one patient (33%) and five patients (24%), respectively.
Dose Limiting Toxicity and Recommended Dose All nine patients (3 in level 1B and 6 in level 2) completed at least one cycle and had at least one AE. No patient who was administered dose level 1B had DLT. One DLT (grade 3 stomatitis) occurred in one
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Results
9
of the first three patients and one additional patient at level 2 (grade 2 acute hepatitis requiring suspension of treatment for at least 15 consecutive days). Thus, the MTD was not reached in this study. Based on DLT and pharmacokinetic results, the planned highest dose (days 1-28 S-1 80, 100 or 120 mg/day plus days 1-42 sorafenib 800 mg/day) was judged to be acceptable as the RD in the phase 2 portion.
Pharmacokinetics
and 7 were available on days 28 and 35. There were also no significant differences in the Cmax or AUC0-12 of any of the S-1 components (5-FU, FT, CDHP, Oxo) between the S-1 plus sorafenib combination chemotherapy and S-1 monotherapy [7-10] (data not shown). At level 1B and level 2, sorafenib plasma concentration-time profiles on day 28 (S-1 and sorafenib co-administration) and day 35 (sorafenib administration alone) were superimposable, with no significant difference in Cmax or AUC0-12 (S3 and S4).
Efficacy A response was evaluated in 24 patients in the phase 1 and 2 portions. In the phase 1 at dose level 1B, one patient (33%) had a PR and two patients (67%) had SD. In the phase 2 at dose level 2, among the 21 patients, one patient (5%) had a CR, 10 patients (48%) had PR and 10 patients (48%) had SD. No patient had progressive disease. Thus, 11 patients (52%, 95% CI, 29.8%-74.3%) had an objective response, and all patients achieved disease control. The subgroup analyses showed that the ORR was higher in groups with a favorable risk, according to Memorial Sloan-Kettering Cancer Center criteria [11] (S5). Almost all of patients had a reduction in tumor size compared with baseline
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Blood samples were taken from all 9 patients, 8 patients were included in the PK analysis on day 1,
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(Figure 1A). Response to treatment was noted early, and 1 of 11 patients reached PR within 6 weeks, and 6 patients did so within 12 weeks. A total of 16 tumor progression events occurred. The median PFS was 9.9 months (95% CI, 6.5-17.1 months, Figure 1B), and the median OS was not reached (median follow-up, 15.9 months).
Safety
1 and 2. The most frequently reported treatment-related AEs of all grades at dose level 2 were hand-footskin reaction (100%), hypophosphatemia (95%), anemia (91%), rash (86%), leucopenia (86%), thrombocytopenia (86%), neutropenia (81%), stomatitis (76%), fatigue (71%), anorexia (71%), diarrhea (71%), alopecia (71%), increased lipase (67%), increased amylase (67%) and increased bilirubin (67%). The most frequent grade 3 or higher drug-related AE was hypophosphatemia in 2 patients (67%) and 16 patients (76%) at dose levels 1B and 2, respectively. A dose reduction of S-1 plus sorafenib combination therapy was needed in 16 patients (76%) who received dose level 2. The major reasons for dose reduction were hand-foot skin reaction in 8 patients (38%) and rash in 3 patients (14%). Dose interruption of both S-1 and sorafenib was required because of hand-foot skin reaction in 8 patients (38%) and because of rash in 5 patients (24%). Serious adverse events occurred in 2 patients (67%) in dose level 1B (grade 4 acute hepatitis and grade 3 knee contusion, and grade 3 total bilirubin elevation) and in 3 patients (14%) in dose level 2 (grade 2 acute hepatitis, grade 3 hypertension and grade 3 stomatitis). All except for acute cholecystitis and contusion of knee were considered treatment-related toxicities. No deaths occurred during this study.
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Table 2 lists the documented AEs that were attributable to either drug in all 24 patients study phases
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Discussion This multicenter phase 1/2 study was initiated to evaluate the efficacy and safety of S-1 plus sorafenib in patients with mRCC. In the present study, S-1 plus sorafenib combination therapy achieved an ORR of 52% and produced a better response than that reported for S-1 or sorafenib monotherapy [3, 6]. The results of our study are supported by the findings of Takeuchi et al., [12] who reported that sorafenib decreased the
regimens for combination therapy have been studied. However, combination therapy strategies have not been shown to be beneficial, with many combinations showing excessive toxicity and marginal or inferior efficacy compared with the sequential use of agents [2]. S-1 plus sorafenib combination therapy was comparable to standard regimens or interferon plus bevacizumab combination therapy, although we did not directly compare these drugs [2]. Although S-1 combined with sorafenib achieved a high ORR in our study, the median PFS for S-1 combined with sorafenib as a first-line therapy for mRCC was comparable to that obtained with S-1 or sorafenib [3, 6]. This discrepancy may be attributed to the small number of patients and early dose reduction. To prevent these AEs from worsening, the first dose changes occurred within the first 3 months in a Japanese sorafenib phase 2 study [6]. In the present study, a similar tendency was seen. Seven patients (33.3%) had their dose reduced within the first 3 months of treatment because of a grade 1 or 2 adverse event, at the physician’s discretion. S-1 plus sorafenib combination therapy was associated with AEs that are common toxic effects of S-1 or sorafenib [3, 6]. Hand-foot skin reaction, hypophosphatemia and pancreatic enzyme abnormity are
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transcription factor E2F-1 and TS levels in human cell lines in a preclinical study. Recently, several
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common toxicities of sorafenib, and hematological toxicity, rash, stomatitis, and diarrhea are common toxicities of S-1. No unexpected toxicities occurred. The different mechanisms of S-1 and sorafenib were considered to be responsible for the lack of overlapping toxicities. This hypothesis is supported by the results of the PK analysis, which established that combined treatment was not associated with any clinically significant alterations in the PK of either S-1 or sorafenib. However, the incidence of hand-foot skin reaction was higher for S-1 plus sorafenib combination therapy than for sorafenib monotherapy or combination
higher than S-1 monotherapy (40%), and comparable to sorafenib monotherapy (28%), although no skin related serious adverse event occurred. Our results suggest that skin events management is important in S-1 plus sorafenib combination therapy. Furthermore, compared with other combination therapy regimens, the ability of patients to receive treatment on an outpatient basis is considered an important advantage. Our data showed preliminary efficacy for S-1 or sorafenib monotherapy compared with historical data in the small number of patients with mRCC. Larger randomized trials are needed to confirm our results. In conclusion, to our knowledge, this is the first study that showed the efficacy of S-1 in combination with sorafenib as a first-line treatment in patients with mRCC; however, management of toxicity is required.
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therapy with other agents including interferon-alpha [2, 6, 13]. In addition, the rate of dose reduction was
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Acknowledgments We thank the patients, their families, all of the investigators who participated in the study, and all of the committee members. In collaboration with Seiji Naito and Hideyuki Akaza, Taiho Pharmaceuticals, designed the study, data collection, and data analysis. The corresponding author had full access to all data and had final responsibility for the decision to submit for publication. We thank Peter Star of Medical Network K.K., (Tokyo, Japan) for his review of this report, funded by Taiho Pharmaceutical Co., Ltd. The authors thanks to
Kazato Goda and Kentaro Tsuji, Taiho Pharmaceuticals, for overall management of the trial and drafting the manuscript.
Disclosure Seiji Naito has served as a consultant for Ono Pharmaceutical Co., Ltd. and received speaker honoraria from Pfizer, Novartis and GlaxoSmithKline. Hideki Sakai has received speaker honoraria from Pfizer and GlaxoSmithKline. Yoshihiko Tomita has served as a consultant for Ono Pharmaceutical Co., Ltd. and received honoraria from Pfizer. Nobuo Shinohara received speaker honoraria from Pfizer, Novartis, and GlaxoSmithKline. Masatoshi Eto received honoraria from Bayer, Pfizer, Novartis, GlaxoSmithKline and research funding from Pfizer and Novartis. Seiichiro Ozono has served as a consultant for Ono Pharmaceutical Co., Ltd. and received speaker honoraria from Novartis. Hideyuki Akaza has served as a consultant for Taiho Pharmaceutical Co., Ltd., GlaxoSmithKline, Novartis and received speaker honoraria from Pfizer. The other authors report no conflicts of interest.
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Takanori Tanase for his contribution as biostatistician, Taiho Pharmaceuticals. We would like to thank
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Funding This work was supported by Taiho Pharmaceuticals. No grant number applied.
Figure Legends Figure 1. (A) Maximum percentage changes from baseline in size of target lesions according to RECIST (Response Evaluation Criteria in Solid Tumors), (B) progression-free survival, as assessed by an Downloaded from http://annonc.oxfordjournals.org/ at CSU Fresno on July 8, 2015
independent review committee, in patients who received dose level 2 (N=21).
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12.
17
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p.1
Table 1. Baseline demographics and clinical characteristics Dose Level 2 (N=21)
62.0 (53-74)
62.0 (41-78)
2 (67%) 1 (33%)
18 (86%) 3 (14%)
2 (67%) 1 (33%)
20 (95%) 1 (5%)
3 (100%) 0 (0%)
19 (90%) 2 (10%)
3 (100%) 0 (0%)
8 (38%) 13 (62%)
1 (33%)
6 (29%)
Intermediate Poor Number of Metastatic Organs 1 2 3 4 Metastatic Sites Lung Lymph nodes Adrenal Bone Pancreatic Pleura Pleural effusion
1 (33%) 1 (33%)
14 (67%) 1 (5%)
0 (0%) 1 (33%) 2 (67%) 0 (0%)
5 (24%) 11 (52%) 3 (14%) 2 (10%)
2 (67%) 2 (67%) 0 (0%) 0 (0%) 1 (33%) 0 (0%) 1 (33%)
15 (71%) 11 (52%) 5 (24%) 3 (14%) 2 (10%) 2 (10%) 1 (5%)
Liver Retroperitoneal Skeletal muscle Kidney Diaphragm
0 (0%) 0 (0%) 1 (33%) 1 (33%) 0 (0%)
2 (10%) 1 (5%) 0 (0%) 0 (0%) 1 (5%)
Age (years) Sex Male Female ECOG performance status 0 1 Histological Type Clear-cell Papillary History of prior treatment Cytokine treatment No prior treatment MSKCC risk score Favorable
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Dose Level 1B (N=3)
p.2
Spleen
0 (0%)
1 (5%)
Data are median (range) or number (%) ECOG, Eastern Cooperative Oncology Group; MSKCC, Memorial Sloan-Kettering Cancer Center
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p.1
Table 2. Treatment-related adverse events reported in at least 20% of patients Grade in level 1B (N=3) Grade in level 2 (N=21) 2
3
4
1
2
3
4
1 (33) ･･ 2 (67) 2 (67) ･･
･･ 3 (100) 1 (33) 1 (33) ･･
1 (33) ･･ ･･ ･･ 1 (33)
･･ ･･ ･･ ･･ ･･
6 (29) 2 (10) 6 (29) 4 (19) 6 (29)
8 (38) 9 (43) 8 (38) 11 (52) 5 (24)
4 (19) 6 (29) 3 (14) 3 (14) 1 (5)
1 (5) ･･ 1 (5) ･･ ･･
1 (33) 2 (67) 2 (67) 2 (67) 3 (100) 1 (33) 3 (100) 2 (67)
2 (67) ･･ ･･ ･･ ･･ ･･ ･･ ･･
･･ ･･ ･･ ･･ ･･ ･･ ･･ ･･
･･ ･･ ･･ ･･ ･･ ･･ ･･ ･･
2 (10) 8 (38) 15 (71) 12 (57) 12 (57) 8 (38) 11 (52) 10 (48)
15 (71) 10 (48) ･･ 2 (10) 2 (10) 6 (29) 4 (19) 2 (10)
4 (19) ･･ ･･ 2 (10) 1 (5) 1 (5) ･･ ･･
･･ ･･ ･･ ･･ ･･ ･･ ･･ ･･
Hypertension Epistaxis Nausea Watery eyes Hyperpigmentation Constipation Weight decreased Hypophosphatemia Increased lipase Increased amylase Increased bilirubin Increased ALT Increased AST Increased alkaline phosphatase
･･ 2 (67) 1 (33) ･･ ･･ ･･ 2 (67) ･･ ･･ ･･ ･･ 1 (33) 1 (33) 3 (100)
･･ ･･ ･･ 1 (33) ･･ 1 (33) 1 (33) 1 (33) 1 (33) ･･ ･･ 1 (33) ･･ ･･
1 (33) ･･ ･･ ･･ ･･ ･･ ･･ 2 (67) ･･ 1 (33) 1 (33) ･･ 1 (33) ･･
･･ ･･ ･･ ･･ ･･ ･･ ･･ ･･ 1 (33) ･･ ･･ ･･ ･･ ･･
3 (14) 8 (38) 5 (24) 7 (33) 9 (43) 5 (24) 5 (24) ･･ 5 (24) 8 (38) 7 (33) 8 (38) 9 (43) 7 (33)
2 (10) ･･ 2 (10) 2 (10) ･･ 1 (5) 3 (14) 4 (19) 2 (10) 4 (19) 7 (33) ･･ 1 (5) 1 (5)
6 (29) 1 (5) ･･ ･･ ･･ ･･ ･･ 15 (71) 4 (19) 2 (10) ･･ 2 (10) 2 (10)
･･ ･･ ･･ ･･ ･･ ･･ ･･ 1 (5) 3 (14) ･･ ･･ 1 (5) ･･
･･
･･
Hypoalbuminemia Proteinuria Increased creatinine
2 (67) 2 (67) 1 (33)
1 (5) 1 (5) ･･
･･ ･･ ･･
Hematological events Anemia Neutropenia Thrombocytopenia Leukopenia Lymphopenia Non-hematological events Hand-foot syndrome Rash Alopecia Stomatitis Fatigue Diarrhea Anorexia Taste alteration
･･ 1 (33) ･･
･･ ･･ ･･
･･ ･･ ･･
8 (38) 3 (14) 4 (19)
3 (14) 7 (33) 2 (10)
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1
p.2
Hyponatremia
2 (67)
･･
･･
･･
5 (24)
･･
1 (5)
･･
Data are number of patients ALT, alanine aminotransferase; AST, aspartate aminotransferase No patients are showed middle dots.
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Phase 1/2 study of S-1 in combination with sorafenib for metastatic renal cell carcinoma
S. Naito1*, H. Sakai2, K. Hashine3, T. Tomita4, N. Shinohara5, M. Fujisawa6, M. Eto7, S. Ozono8, H. Akaza9
1: Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan 2: Department of Nephro-Urology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki,
3: Department of Urology, National Hospital Organization Shikoku Cancer Center, Matsuyama, Japan 4: Department of Urology, Yamagata University Faculty of Medicine, Yamagata, Japan 5: Department of Urology, Hokkaido University Graduate School of Medicine, Sapporo, Japan 6: Department of Urology, Kobe University School of Medicine, Kobe, Japan 7: Department of Urology, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan 8: Department of Urology, Hamamatsu University School of Medicine, Hamamatsu, Japan 9: Department of Strategic Investigation on Comprehensive Cancer Network, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan
*
Correspondence to
Dr. Seiji Naito Department of Urology, Graduate School of Medical Sciences, Kyushu University 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan Tel.: +81-92-642-5603, Fax: +81-92-642-5618 E-mail: [email protected]
© The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected].
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Japan
2
Abstract Background: The potential of S-1 for the treatment of metastatic renal cell carcinoma (mRCC) has been shown in two phase 2 studies. We aimed to assess the safety, tolerance, pharmacokinetics and clinical activity of S-1 combined with sorafenib in patients with mRCC. Patients and methods: In this multicenter, single-arm, open-label, phase 1/2 study of S-1 plus sorafenib, we recruited patients with clear-cell or papillary renal cell carcinoma who had received a maximum of one prior
recommended dose (RD). S-1 was administered orally at 60, 80, 100 or 120 mg/day on days 1 to 28 of a 42-day cycle in combination with sorafenib (400 or 800 mg/day), given daily with dose adjustment. In phase 2, the primary endpoint was to assess the overall response rate (ORR) at the RD. Results: Nine patients were enrolled into phase 1 and 21 (including 6 patients who received the RD in the phase 1 portion) were enrolled into phase 2. In the phase 1 portion, the MTD could not be determined, and the RD was defined as S-1 80 mg/m2/day on days 1–28 + sorafenib 800 mg/day on days 1–42. In the phase 2 portion, 21 patients were fully assessable for efficacy and safety. The confirmed ORR was 52% (95% CI, 29.8-74.3), including one complete response (5%) and 10 partial responses (48%). The median progression free survival was 9.9 (95% CI, 6.5-17.1) months. The most frequently reported treatment-related adverse event for all grades was hand-foot skin reaction (100%). The major reasons for dose reduction were hand-foot skin reaction (38%) and rash (14%). Conclusion: Combination therapy with S-1 plus sorafenib is effective and tolerable for patients with mRCC. However, skin events management is important in S-1 plus sorafenib combination therapy. Key words: S-1, sorafenib, metastatic renal cell carcinoma.
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cytokine-based regimen. The phase 1 primary endpoints were the maximum tolerated dose (MTD) and
3
Introduction The recent development of novel therapies that target tumor angiogenesis and mammalian target of rapamycin pathways has improved outcomes in patients with advanced renal cell carcinoma (RCC) [1, 2]. Sequential therapy with targeted agents is the current standard of care; however, combination regimens including targeted agents have also been studied to enhance efficacy and combat resistance. Current combination therapy strategies have not been proven to be beneficial, and many combination regimens have
[2]. We previously reported promising single-agent results for S-1, an oral fluoropyrimidine-based anticancer agent, with an overall response rate (ORR) of 24.4% in patients with cytokine-refractory metastatic RCC (mRCC) at the dose of 80, 100 or 120 mg/day based on body surface area [3]. High sensitivity to S-1 monotherapy was associated low thymidylate synthase (TS) expression in tumors, although myelosuppression was frequently observed. Because molecular targeting agents other than sunitinib rarely cause myelosuppression, S-1 might be a good candidate for combination therapy with molecular targeting agents such as sorafenib. We therefore assessed the efficacy and safety profile of combination therapy with S-1 and sorafenib in patients with mRCC.
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shown excessive toxicity with marginal or inferior efficacy compared with that of the sequential-use agents
4
Methods This was a nonrandomized, open-label, multicenter phase 1/2 trial in Japanese patients with mRCC who had undergone nephrectomy. This trial was conducted in accordance with the World Medical Association Declaration of Helsinki and Japanese Good Clinical Practice guidelines. The protocol was approved by the institutional review boards of all participating institutions. This study is registered with the Japan Pharmaceutical Information Center (number JapicCTI-090973).
Patients were eligible if they were 20 years of age or older, and had: a history of nephrectomy; a histologically confirmed diagnosis of clear-cell or papillary RCC; received no previous treatment or only one regimen of cytokine therapy; an Eastern Cooperative Oncology Group performance status of 0 or 1; measurable lesions as defined by the Response Evaluation Criteria in Solid Tumours [4] (RECIST; version 1.0); adequate hematological, hepatic, and renal function. We excluded patients who had brain metastasis, a known hypersensitivity to S-1 or sorafenib, or severe complications, concurrent malignancy, marked pleural effusion or ascites, watery diarrhea or peptic ulcer. Written informed consent was obtained from all patients before enrollment.
Study design and treatment In the phase 1 portion, we studied four S-1 and sorafenib dose levels. Patients were administered sorafenib orally at a dose of 400 or 800 mg/day. Treatment included S-1 doses, based on body surface area as follows: 60, 80, 100 or 120 mg/day. Dosing levels were as follows: level 0, days 1-28 S-1 60, 80 or
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Eligibility criteria
5
100 mg/day plus days 1-42 sorafenib 400 mg/day; level 1A, days 1-28 S-1 80, 100 or 120 mg/day plus days 1-42 sorafenib 400 mg/day; level 1B, days 1-28 S-1 60, 80 or 100 mg/day plus days 1-42 sorafenib 800 mg/day; and level 2, days 1-28 S-1 80, 100 or 120 mg/day plus days 1-42 sorafenib 800 mg/day(for more detail See S1). Treatment was administered in 42-day cycles and continued until disease progression, refusal to continue treatment or unacceptable adverse events (AEs). The initially dose administered was level 1B, and dose adjustment then followed a standard three-plus-three design. Given possible interactions between
dose-limiting toxicity (DLT) during the first cycle, the dose was escalated to level 2. If DLT occurred in one or two of the first three patients given a particular level, then three additional patients were enrolled to receive the same dose level, for a total of six patients. The maximum tolerated dose (MTD) was reached when three or more of six patients at one dose level had DLTs. Thus, this dose was defined as the MTD, and one dose level below was designated as the recommended dose (RD) for phase 2. If less than three of the six patients had DLTs at the last dose level, then this dose level was the RD for phase 2. If patients less than three of the six had DLTs at the dose level 2, no MTD was determined in this study and the dose level 2 will be fixed as the RD. No intra-patient dose escalation was allowed. In the phase 2 portion, patients received combination treatment with S-1 plus sorafenib at the RD determined in the phase 1. Treatment was continued until any of the following occurred: unacceptable toxicity, refusal to continue treatment or definite tumor progression. When the predefined toxic events in the protocol occurred, dose adjustment or interruption required (for more detail See S2).
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S-1 and sorafenib, a half-dose of sorafenib was used in levels 0 and 1A. If none of the first three patients had
6
Dose Limiting Toxicity DLT was defined as any of following events occurring during the first cycle of treatment: grade 4 or higher hematological toxicity; grade 3 or higher febrile neutropenia; grade 3 or higher non-hematological toxicity except for hand-foot skin reaction and pancreatic enzyme abnormality; drug-related pancreatitis associated with a grade 4 increase in pancreatic enzymes; AEs requiring suspension of treatment for no less than 15 consecutive days; and AEs requiring discontinuation of treatment.
The primary endpoint of the phase 1 portion was the MTD and RD. In the phase 2 portion, the primary endpoint was the proportion of patients who had an objective response and confirmed by a subsequent scan. Secondary endpoints included the safety profile, proportion of patients who achieved disease control (complete response; CR, partial response; PR or stable disease; SD maintained for 28 days or longer), progression-free survival (PFS: the time between the initiation of study treatment and disease progression or death from any cause), overall survival (OS: the time between the initiation of study treatment and death from any cause) and pharmacokinetic (PK) parameters.
Study evaluations Tumor imaging was performed at baseline and at least every 6 weeks thereafter. Complete blood cultures, serum chemical analysis and urinalysis were performed every week during the first cycle of phase 1, followed by every 2 weeks thereafter in phases 1 and 2.
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Endpoints
7
Response and Toxicity Criteria The RECIST were used to assess the response to treatment, and the Common Terminology Criteria for Adverse Events (version 3.0) [5] were used to assess toxicity. An independent review committee consisting of radiologists and medical oncologists objectively confirmed treatment responses and drug-related AEs.
Statistical analysis
and an expected response rate (under the alternative hypothesis) of 25%, based on the results of two phase 2 studies of S-1 and a phase 2 study of sorafenib [3, 6]. Under these assumptions, a sample size of 21 patients would ensure a power of at least 80% at a one-sided significance level of 5%. Thus, a response rate of 4 of 21 patients would permit rejection of the null hypothesis. We performed primary analyses on a full analysis set basis; patients who received at least one dose of the assigned study drugs. All analyses were performed using statistical software package (SAS version 9.2; SAS Institute Inc, Cary, NC, USA).
Pharmacokinetics In the phase 1 portion, we obtained blood samples for S-1 PK evaluation at the following time points: pre-dose and 1, 2, 4, 6, 8, 10 and 12 hour after co-administration of S-1 and sorafenib on day 1. For sorafenib PK evaluations, blood samples were taken at the following time points: pre-dose and 1, 2, 4, 6, 8 and 12 hour after co-administration of S-1 on day 28 and after administration of sorafenib alone on day 35. Plasma samples were prepared by centrifugation of the blood samples. Plasma concentrations of S-1
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In the phase 2 portion, we initially used a threshold response rate (under the null hypothesis) of 5%,
8
components (5-fluorouracil, 5-FU; tegafur, FT; 5-chloro-2,4-dihydropyridine, CDHP; potassium oxonate, Oxo) on day 1 were measured to evaluate the effect of sorafenib by comparing the results with historical data (Shin Nippon Biomedical Laboratories, Ltd., Wakayama, Japan). Sorafenib plasma concentrations were measured on day 28 (S-1 and sorafenib co-administration) and 35 (sorafenib administration alone) to evaluate the effect of S-1 by comparing PK between day 28 and 35 (Covance Laboratories, Madison, WI, US). The Cmax and AUC0-12 PK parameters were determined for S-1 components and sorafenib.
Patient characteristics Between December 14, 2009 and September 4, 2012, a total of 24 patients (9 in phase 1 and 15 in phase 2) were enrolled. All patients were eligible for the toxicity and efficacy evaluation. The first 3 patients received dose level 1B. The 6 patients who received dose level 2 during phase 1 were included in the phase 2 assessment, along with another 15 patients. The patient characteristic are summarized in Table 1. There were 34 treatment cycles administered overall (median 15.0, range 2-17) to patients at dose level 1B, and 179 treatment cycles administered overall (median 8.0, range 1-20) to patients at dose level 2. The main reasons for treatment discontinuation at dose levels 1B and 2 were tumor progression in two patients (67%) and 10 patients (48%), respectively, and toxicity in one patient (33%) and five patients (24%), respectively.
Dose Limiting Toxicity and Recommended Dose All nine patients (3 in level 1B and 6 in level 2) completed at least one cycle and had at least one AE. No patient who was administered dose level 1B had DLT. One DLT (grade 3 stomatitis) occurred in one
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Results
9
of the first three patients and one additional patient at level 2 (grade 2 acute hepatitis requiring suspension of treatment for at least 15 consecutive days). Thus, the MTD was not reached in this study. Based on DLT and pharmacokinetic results, the planned highest dose (days 1-28 S-1 80, 100 or 120 mg/day plus days 1-42 sorafenib 800 mg/day) was judged to be acceptable as the RD in the phase 2 portion.
Pharmacokinetics
and 7 were available on days 28 and 35. There were also no significant differences in the Cmax or AUC0-12 of any of the S-1 components (5-FU, FT, CDHP, Oxo) between the S-1 plus sorafenib combination chemotherapy and S-1 monotherapy [7-10] (data not shown). At level 1B and level 2, sorafenib plasma concentration-time profiles on day 28 (S-1 and sorafenib co-administration) and day 35 (sorafenib administration alone) were superimposable, with no significant difference in Cmax or AUC0-12 (S3 and S4).
Efficacy A response was evaluated in 24 patients in the phase 1 and 2 portions. In the phase 1 at dose level 1B, one patient (33%) had a PR and two patients (67%) had SD. In the phase 2 at dose level 2, among the 21 patients, one patient (5%) had a CR, 10 patients (48%) had PR and 10 patients (48%) had SD. No patient had progressive disease. Thus, 11 patients (52%, 95% CI, 29.8%-74.3%) had an objective response, and all patients achieved disease control. The subgroup analyses showed that the ORR was higher in groups with a favorable risk, according to Memorial Sloan-Kettering Cancer Center criteria [11] (S5). Almost all of patients had a reduction in tumor size compared with baseline
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Blood samples were taken from all 9 patients, 8 patients were included in the PK analysis on day 1,
10
(Figure 1A). Response to treatment was noted early, and 1 of 11 patients reached PR within 6 weeks, and 6 patients did so within 12 weeks. A total of 16 tumor progression events occurred. The median PFS was 9.9 months (95% CI, 6.5-17.1 months, Figure 1B), and the median OS was not reached (median follow-up, 15.9 months).
Safety
1 and 2. The most frequently reported treatment-related AEs of all grades at dose level 2 were hand-footskin reaction (100%), hypophosphatemia (95%), anemia (91%), rash (86%), leucopenia (86%), thrombocytopenia (86%), neutropenia (81%), stomatitis (76%), fatigue (71%), anorexia (71%), diarrhea (71%), alopecia (71%), increased lipase (67%), increased amylase (67%) and increased bilirubin (67%). The most frequent grade 3 or higher drug-related AE was hypophosphatemia in 2 patients (67%) and 16 patients (76%) at dose levels 1B and 2, respectively. A dose reduction of S-1 plus sorafenib combination therapy was needed in 16 patients (76%) who received dose level 2. The major reasons for dose reduction were hand-foot skin reaction in 8 patients (38%) and rash in 3 patients (14%). Dose interruption of both S-1 and sorafenib was required because of hand-foot skin reaction in 8 patients (38%) and because of rash in 5 patients (24%). Serious adverse events occurred in 2 patients (67%) in dose level 1B (grade 4 acute hepatitis and grade 3 knee contusion, and grade 3 total bilirubin elevation) and in 3 patients (14%) in dose level 2 (grade 2 acute hepatitis, grade 3 hypertension and grade 3 stomatitis). All except for acute cholecystitis and contusion of knee were considered treatment-related toxicities. No deaths occurred during this study.
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Table 2 lists the documented AEs that were attributable to either drug in all 24 patients study phases
11
Discussion This multicenter phase 1/2 study was initiated to evaluate the efficacy and safety of S-1 plus sorafenib in patients with mRCC. In the present study, S-1 plus sorafenib combination therapy achieved an ORR of 52% and produced a better response than that reported for S-1 or sorafenib monotherapy [3, 6]. The results of our study are supported by the findings of Takeuchi et al., [12] who reported that sorafenib decreased the
regimens for combination therapy have been studied. However, combination therapy strategies have not been shown to be beneficial, with many combinations showing excessive toxicity and marginal or inferior efficacy compared with the sequential use of agents [2]. S-1 plus sorafenib combination therapy was comparable to standard regimens or interferon plus bevacizumab combination therapy, although we did not directly compare these drugs [2]. Although S-1 combined with sorafenib achieved a high ORR in our study, the median PFS for S-1 combined with sorafenib as a first-line therapy for mRCC was comparable to that obtained with S-1 or sorafenib [3, 6]. This discrepancy may be attributed to the small number of patients and early dose reduction. To prevent these AEs from worsening, the first dose changes occurred within the first 3 months in a Japanese sorafenib phase 2 study [6]. In the present study, a similar tendency was seen. Seven patients (33.3%) had their dose reduced within the first 3 months of treatment because of a grade 1 or 2 adverse event, at the physician’s discretion. S-1 plus sorafenib combination therapy was associated with AEs that are common toxic effects of S-1 or sorafenib [3, 6]. Hand-foot skin reaction, hypophosphatemia and pancreatic enzyme abnormity are
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transcription factor E2F-1 and TS levels in human cell lines in a preclinical study. Recently, several
12
common toxicities of sorafenib, and hematological toxicity, rash, stomatitis, and diarrhea are common toxicities of S-1. No unexpected toxicities occurred. The different mechanisms of S-1 and sorafenib were considered to be responsible for the lack of overlapping toxicities. This hypothesis is supported by the results of the PK analysis, which established that combined treatment was not associated with any clinically significant alterations in the PK of either S-1 or sorafenib. However, the incidence of hand-foot skin reaction was higher for S-1 plus sorafenib combination therapy than for sorafenib monotherapy or combination
higher than S-1 monotherapy (40%), and comparable to sorafenib monotherapy (28%), although no skin related serious adverse event occurred. Our results suggest that skin events management is important in S-1 plus sorafenib combination therapy. Furthermore, compared with other combination therapy regimens, the ability of patients to receive treatment on an outpatient basis is considered an important advantage. Our data showed preliminary efficacy for S-1 or sorafenib monotherapy compared with historical data in the small number of patients with mRCC. Larger randomized trials are needed to confirm our results. In conclusion, to our knowledge, this is the first study that showed the efficacy of S-1 in combination with sorafenib as a first-line treatment in patients with mRCC; however, management of toxicity is required.
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therapy with other agents including interferon-alpha [2, 6, 13]. In addition, the rate of dose reduction was
13
Acknowledgments We thank the patients, their families, all of the investigators who participated in the study, and all of the committee members. In collaboration with Seiji Naito and Hideyuki Akaza, Taiho Pharmaceuticals, designed the study, data collection, and data analysis. The corresponding author had full access to all data and had final responsibility for the decision to submit for publication. We thank Peter Star of Medical Network K.K., (Tokyo, Japan) for his review of this report, funded by Taiho Pharmaceutical Co., Ltd. The authors thanks to
Kazato Goda and Kentaro Tsuji, Taiho Pharmaceuticals, for overall management of the trial and drafting the manuscript.
Disclosure Seiji Naito has served as a consultant for Ono Pharmaceutical Co., Ltd. and received speaker honoraria from Pfizer, Novartis and GlaxoSmithKline. Hideki Sakai has received speaker honoraria from Pfizer and GlaxoSmithKline. Yoshihiko Tomita has served as a consultant for Ono Pharmaceutical Co., Ltd. and received honoraria from Pfizer. Nobuo Shinohara received speaker honoraria from Pfizer, Novartis, and GlaxoSmithKline. Masatoshi Eto received honoraria from Bayer, Pfizer, Novartis, GlaxoSmithKline and research funding from Pfizer and Novartis. Seiichiro Ozono has served as a consultant for Ono Pharmaceutical Co., Ltd. and received speaker honoraria from Novartis. Hideyuki Akaza has served as a consultant for Taiho Pharmaceutical Co., Ltd., GlaxoSmithKline, Novartis and received speaker honoraria from Pfizer. The other authors report no conflicts of interest.
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Takanori Tanase for his contribution as biostatistician, Taiho Pharmaceuticals. We would like to thank
14
Funding This work was supported by Taiho Pharmaceuticals. No grant number applied.
Figure Legends Figure 1. (A) Maximum percentage changes from baseline in size of target lesions according to RECIST (Response Evaluation Criteria in Solid Tumors), (B) progression-free survival, as assessed by an Downloaded from http://annonc.oxfordjournals.org/ at CSU Fresno on July 8, 2015
independent review committee, in patients who received dose level 2 (N=21).
15
References 1.
Motzer RJ, Hutson TE, Tomczak P et al. Overall survival and updated results for sunitinib
compared with interferon alfa in patients with metastatic renal cell carcinoma. J Clin Oncol 2009; 27: 3584-3590. 2.
Albiges L, Choueiri T, Escudier B et al. A systematic review of sequencing and combinations of
systemic therapy in metastatic renal cancer. Eur Urol 2015; 67: 100-110. Naito S, Eto M, Shinohara N et al. Multicenter phase II trial of S-1 in patients with
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Cancer Therapy Evaluation Program. Common Terminology Criteria for Adverse Events v3.0. Aug
9, 2006. http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/ctcaev3.pdf (accessed April 20, 2009). 6.
Naito S, Tsukamoto T, Murai M et al. Overall survival and good tolerability of long-term use of
sorafenib after cytokine treatment: final results of a phase II trial of sorafenib in Japanese patients with metastatic renal cell carcinoma. BJU Int 2011; 108: 1813-1819. 7.
Furuse J, Okusaka T, Kaneko S et al. Phase I/II study of the pharmacokinetics, safety and efficacy
of S-1 in patients with advanced hepatocellular carcinoma. Cancer Sci 2010; 101: 2606-2611. 8.
Ueno H, Okusaka T, Ikeda M et al. Phase II study of S-1 in patients with advanced biliary tract
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Ueno H, Okusaka T, Ikeda M et al. An early phase II study of S-1 in patients with metastatic
pancreatic cancer. Oncology 2005; 68: 171-178. 10.
Hirata K, Horikoshi N, Aiba K et al. Pharmacokinetic study of S-1, a novel oral fluorouracil
antitumor drug. Clin Cancer Res 1999; 5: 2000-2005. 11.
Motzer RJ, Mazumdar M, Bacik J et al. Survival and prognostic stratification of 670 patients with
advanced renal cell carcinoma. J Clin Oncol 1999; 17: 2530-2540. Takeuchi A, Shiota M, Tatsugami K et al. Sorafenib augments cytotoxic effect of S-1 in vitro and in
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12.
17
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p.1
Table 1. Baseline demographics and clinical characteristics Dose Level 2 (N=21)
62.0 (53-74)
62.0 (41-78)
2 (67%) 1 (33%)
18 (86%) 3 (14%)
2 (67%) 1 (33%)
20 (95%) 1 (5%)
3 (100%) 0 (0%)
19 (90%) 2 (10%)
3 (100%) 0 (0%)
8 (38%) 13 (62%)
1 (33%)
6 (29%)
Intermediate Poor Number of Metastatic Organs 1 2 3 4 Metastatic Sites Lung Lymph nodes Adrenal Bone Pancreatic Pleura Pleural effusion
1 (33%) 1 (33%)
14 (67%) 1 (5%)
0 (0%) 1 (33%) 2 (67%) 0 (0%)
5 (24%) 11 (52%) 3 (14%) 2 (10%)
2 (67%) 2 (67%) 0 (0%) 0 (0%) 1 (33%) 0 (0%) 1 (33%)
15 (71%) 11 (52%) 5 (24%) 3 (14%) 2 (10%) 2 (10%) 1 (5%)
Liver Retroperitoneal Skeletal muscle Kidney Diaphragm
0 (0%) 0 (0%) 1 (33%) 1 (33%) 0 (0%)
2 (10%) 1 (5%) 0 (0%) 0 (0%) 1 (5%)
Age (years) Sex Male Female ECOG performance status 0 1 Histological Type Clear-cell Papillary History of prior treatment Cytokine treatment No prior treatment MSKCC risk score Favorable
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Dose Level 1B (N=3)
p.2
Spleen
0 (0%)
1 (5%)
Data are median (range) or number (%) ECOG, Eastern Cooperative Oncology Group; MSKCC, Memorial Sloan-Kettering Cancer Center
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p.1
Table 2. Treatment-related adverse events reported in at least 20% of patients Grade in level 1B (N=3) Grade in level 2 (N=21) 2
3
4
1
2
3
4
1 (33) ･･ 2 (67) 2 (67) ･･
･･ 3 (100) 1 (33) 1 (33) ･･
1 (33) ･･ ･･ ･･ 1 (33)
･･ ･･ ･･ ･･ ･･
6 (29) 2 (10) 6 (29) 4 (19) 6 (29)
8 (38) 9 (43) 8 (38) 11 (52) 5 (24)
4 (19) 6 (29) 3 (14) 3 (14) 1 (5)
1 (5) ･･ 1 (5) ･･ ･･
1 (33) 2 (67) 2 (67) 2 (67) 3 (100) 1 (33) 3 (100) 2 (67)
2 (67) ･･ ･･ ･･ ･･ ･･ ･･ ･･
･･ ･･ ･･ ･･ ･･ ･･ ･･ ･･
･･ ･･ ･･ ･･ ･･ ･･ ･･ ･･
2 (10) 8 (38) 15 (71) 12 (57) 12 (57) 8 (38) 11 (52) 10 (48)
15 (71) 10 (48) ･･ 2 (10) 2 (10) 6 (29) 4 (19) 2 (10)
4 (19) ･･ ･･ 2 (10) 1 (5) 1 (5) ･･ ･･
･･ ･･ ･･ ･･ ･･ ･･ ･･ ･･
Hypertension Epistaxis Nausea Watery eyes Hyperpigmentation Constipation Weight decreased Hypophosphatemia Increased lipase Increased amylase Increased bilirubin Increased ALT Increased AST Increased alkaline phosphatase
･･ 2 (67) 1 (33) ･･ ･･ ･･ 2 (67) ･･ ･･ ･･ ･･ 1 (33) 1 (33) 3 (100)
･･ ･･ ･･ 1 (33) ･･ 1 (33) 1 (33) 1 (33) 1 (33) ･･ ･･ 1 (33) ･･ ･･
1 (33) ･･ ･･ ･･ ･･ ･･ ･･ 2 (67) ･･ 1 (33) 1 (33) ･･ 1 (33) ･･
･･ ･･ ･･ ･･ ･･ ･･ ･･ ･･ 1 (33) ･･ ･･ ･･ ･･ ･･
3 (14) 8 (38) 5 (24) 7 (33) 9 (43) 5 (24) 5 (24) ･･ 5 (24) 8 (38) 7 (33) 8 (38) 9 (43) 7 (33)
2 (10) ･･ 2 (10) 2 (10) ･･ 1 (5) 3 (14) 4 (19) 2 (10) 4 (19) 7 (33) ･･ 1 (5) 1 (5)
6 (29) 1 (5) ･･ ･･ ･･ ･･ ･･ 15 (71) 4 (19) 2 (10) ･･ 2 (10) 2 (10)
･･ ･･ ･･ ･･ ･･ ･･ ･･ 1 (5) 3 (14) ･･ ･･ 1 (5) ･･
･･
･･
Hypoalbuminemia Proteinuria Increased creatinine
2 (67) 2 (67) 1 (33)
1 (5) 1 (5) ･･
･･ ･･ ･･
Hematological events Anemia Neutropenia Thrombocytopenia Leukopenia Lymphopenia Non-hematological events Hand-foot syndrome Rash Alopecia Stomatitis Fatigue Diarrhea Anorexia Taste alteration
･･ 1 (33) ･･
･･ ･･ ･･
･･ ･･ ･･
8 (38) 3 (14) 4 (19)
3 (14) 7 (33) 2 (10)
Downloaded from http://annonc.oxfordjournals.org/ at CSU Fresno on July 8, 2015
1
p.2
Hyponatremia
2 (67)
･･
･･
･･
5 (24)
･･
1 (5)
･･
Data are number of patients ALT, alanine aminotransferase; AST, aspartate aminotransferase No patients are showed middle dots.
Downloaded from http://annonc.oxfordjournals.org/ at CSU Fresno on July 8, 2015