Protocol for a phase II study to evaluate the efficacy and safety of nivolumab as a postoperative adjuvant therapy for patients with esophageal cancer treated with preoperative docetaxel, cisplatin plus 5-fluorouracil treatment (PENTAGON trial).

BACKGROUND: In Japan, preoperative adjuvant chemotherapy followed by surgical resection is the standard treatment for patients with locally advanced esophageal squamous cell carcinoma. However, the risk of recurrence after surgical resection remains high. Although a randomized controlled trial evaluating the efficacy of nivolumab, a fully human monoclonal anti-programmed death 1 antibody, as postoperative adjuvant therapy after neoadjuvant chemoradiotherapy and surgery established its superior efficacy as adjuvant therapy, the efficacy for patients who received preoperative adjuvant chemotherapy has not been demonstrated. This study aims to elucidate the efficacy and safety of nivolumab as postoperative adjuvant therapy for patients with esophageal squamous cell carcinoma after preoperative adjuvant chemotherapy with docetaxel and cisplatin plus 5-fluorouracil followed by surgical resection. METHODS: This study is a multi-institutional, single-arm, Phase II trial. We plan to recruit 130 esophageal squamous cell carcinoma patients, who have undergone preoperative adjuvant chemotherapy with docetaxel and cisplatin plus 5-fluorouracil followed by surgical resection. If the patient did not have a pathological complete response, nivolumab is started as a postoperative adjuvant therapy within 4-16 weeks after surgery. The nivolumab dose is 480 mg/day every four weeks. Nivolumab is administered for up to 12 months. The primary endpoint is disease-free survival; the secondary endpoints are overall survival, distant metastasis-free survival, and incidence of adverse events. DISCUSSION: To our knowledge this study is the first trial establishing the efficacy of nivolumab as postoperative adjuvant therapy for patients with esophageal squamous cell carcinoma after preoperative adjuvant chemotherapy with docetaxel and cisplatin plus 5-fluorouracil followed by surgical resection. In Japan, preoperative adjuvant chemotherapy followed by surgery is a well-established standard treatment for resectable, locally advanced esophageal squamous cell carcinoma. Therefore, developing an effective postoperative adjuvant therapy has been essential for improving oncological outcomes.

Successful treatment switch from lenvatinib to sorafenib in a patient with radioactive iodine-refractory differentiated thyroid cancer intolerant to lenvatinib due to severe proteinuria.

Sorafenib and lenvatinib showed efficacy for patients with radioactive iodine (RAI)-refractory differentiated thyroid cancer (DTC) in pivotal phase 3 clinical trials. Although the efficacy of lenvatinib in patients who received previous treatment with multi-target kinase inhibitors (m-TKIs), including sorafenib, was reported, the efficacy of sorafenib in patients who previously received lenvatinib remains unknown. A 75-year-old woman diagnosed as RAI-refractory poorly differentiated carcinoma with multiple lung metastases and started treatment with lenvatinib. She continued to receive lenvatinib but with repeated dose interruptions and reductions due to continuous proteinuria. Because of severe and persistent proteinuria as well as newly developed renal impairment, lenvatinib was suspended after two years of treatment. After the 7-month suspension, her proteinuria and renal impairment were partially improved, but her lung metastases progressed. Because she was unable to tolerate previous treatment with lenvatinib, sorafenib was started. At 7 months of treatment with sorafenib, her lung metastases shrank and she could continue sorafenib without exacerbation of proteinuria or renal impairment. This case may suggest that sorafenib does not exacerbate the proteinuria or renal impairment induced by lenvatinib, and may be an effective treatment option for RAI-refractory DTC patients who are unable to tolerate lenvatinib.

Safety and effectiveness of sorafenib in Japanese patients with hepatocellular carcinoma in daily medical practice: interim analysis of a prospective postmarketing all-patient surveillance study.

BACKGROUND: Sorafenib was approved for treatment of unresectable hepatocellular carcinoma (HCC) in Japan in 2009. A prospective postmarketing all-patient surveillance (PMS) study was requested by Japanese authorities to confirm safety and effectiveness of sorafenib in Japanese HCC population. METHODS: Patients with unresectable HCC treated with sorafenib were followed up for 12 months. Data on patient demographic characteristics, treatment status, clinical outcome, and adverse events (AEs) were collected. RESULTS: This interim analysis included 1109 and 1065 patients evaluable for safety and effectiveness, respectively. Most patients (83.4 %) received the recommended initial dose of 400 mg twice daily. After a follow-up of 12-months, 89.8 % had discontinued treatment, most because of AEs (44.5 %) or progression (33.8 %). The most common drug-related adverse events (DRAE) were hand-foot skin reaction (51.4 %), liver dysfunction (26.4 %), diarrhea (25.1 %), and hypertension (21.6 %). The median overall survival (OS) was 348 days [95 % confidence interval (CI) 299-389 days], and the median duration of treatment was 87 days (95 % CI 78-98 days). Multivariate analyses identified baseline prognostic factors for longer OS, including female sex, low Child-Pugh score, Eastern Cooperative Oncology Group performance status 0, tumor stage I/II/III, low aspartate aminotransferase level, high hemoglobin level, hepatitis C and history of surgical resection. CONCLUSIONS: In general, the safety and effectiveness findings in this PMS were consistent with findings from previous clinical studies. Sorafenib was well tolerated and clinically useful for Japanese patients. CLINICAL TRIAL REGISTRATION NUMBER: NCT01411436.

A phase I study of sorafenib in combination with S-1 plus cisplatin in patients with advanced gastric cancer.

BACKGROUND: Sorafenib inhibits several receptor tyrosine kinases involved in tumor progression and angiogenesis. S-1, an oral fluorouracil antitumor drug, plus cisplatin (CDDP) is the standard regimen for advanced gastric adenocarcinoma (AGC) in Japan. The purpose of this phase I study was to evaluate the safety, pharmacokinetics, and preliminary efficacy of sorafenib in combination with S-1 plus CDDP. METHODS: Patients with histologically confirmed previously untreated AGC were evaluated for eligibility and treated with sorafenib (400 mg bid, days 1-35), S-1 (40 mg/m(2) bid, days 1-21), and CDDP (60 mg/m(2), day 8). Treatment was continued until disease progression or unacceptable toxicity. Pharmacokinetics for sorafenib, 5-FU, and CDDP were investigated in cycle 1. RESULTS: Thirteen patients were enrolled and received at least one dose of the study treatment. No specific or serious adverse event was newly reported in this study. Five patients had partial response and 8 had stable disease as the best response. Pharmacokinetic analysis showed no significant differences in the exposures of sorafenib when administered alone or in combination with S-1 and CDDP. CONCLUSIONS: The present phase I study demonstrates the acceptable toxicity and preliminary efficacy of combined treatment with S-1, CDDP, and sorafenib.

Alterations in HbA1c resulting from the donation of autologous blood for elective surgery in patients with diabetes mellitus.

BACKGROUND: The aim of this study was to confirm the change in haemoglobin A1c consequent to pre-operative donation of autologous blood for elective surgery in patients with diabetes mellitus. MATERIAL AND METHODS: For enrolment in this prospective study, patients had to be scheduled for multiple autologous blood donations at different times and have a haemoglobin A1c level more than 5.8% at the first donation. The values of four factors, haemoglobin, haemoglobin A1c, glycated albumin, and glycated albumin/haemoglobin A1c ratio were determined. Changes in the values of these four factors between before and after the blood donations were calculated. RESULTS: In all 24 patients studied, haemoglobin and haemoglobin A1c decreased as a result of the autologous blood donations. The group with a reduced glycated albumin/haemoglobin A1c ratio had short intervals between blood donations. Correlations were observed between donation interval and change in haemoglobin A1c (r=-0.63, P=0.003), and between donation interval and change in the glycated albumin/haemoglobin A1c ratio (r=0.489, P=0.045). DISCUSSION: Haemoglobin A1c levels are likely to be underestimated after autologous blood donation by patients with diabetes mellitus, so glycated albumin may be a better indicator of these patients' glycaemic control.

Phase I and pharmacokinetic study of sorafenib, an oral multikinase inhibitor, in Japanese patients with advanced refractory solid tumors.

Sorafenib is a novel oral multikinase inhibitor that targets Raf serine/threonine and receptor tyrosine kinases, and inhibits tumor cell proliferation and angiogenesis. We have conducted a phase I study of sorafenib to determine the safety, tolerability, pharmacokinetics, and potential efficacy of this agent in 31 Japanese patients with advanced refractory solid tumors. Sorafenib (100-600 mg) was given as a single dose followed by a 7-day wash-out period, and then administrated twice daily (bid). The most frequent drug-related adverse events were rash/desquamation (61%), hand-foot skin reactions (39%), diarrhea (36%), and elevations of serum lipase (36%) and amylase (26%) levels. Dose-limiting toxicities (DLTs) were grade 3 diarrhea at 200 mg bid and grade 3 fatigue at 600 mg bid. Grade 3 and 4 pancreatic enzyme elevations were observed at 200-600 mg bid, but they were not deemed dose-limiting because they were asymptomatic and were not associated with pancreatitis or chronic damage to the pancreas. The AUC and C(max) of sorafenib increased linearly with dose up to 400 mg bid. Partial responses were observed in one of 10 patients with non-small cell lung cancer and one of three patients with renal cell carcinoma. In conclusion, sorafenib 400 mg bid was well tolerated in Japanese patients with advanced refractory solid tumors. The recommended dose for future clinical trials is 400 mg bid.