Pharmacokinetics of gefitinib in elderly patients with EGFR-mutated advanced non-small cell lung cancer: a prospective study.

BACKGROUND: Gefitinib is recommended as a first-line treatment option for elderly patients with non-small cell lung cancer (NSCLC). Because no pharmacokinetics of gefitinib have been examined, we prospectively assessed the pharmacokinetics of gefitinib in patients with epidermal growth factor receptor gene-mutated advanced NSCLC who were 75 years or older. METHODS: Gefitinib was orally administered once daily at a dose of 250 mg. The concentrations of gefitinib and its major metabolite O-desmethyl gefitinib in plasma were measured by high-performance liquid chromatography. The area under the plasma concentration-time curve from time 0 to 48 h (AUC0-48) was calculated. Polymorphisms in CYP3A5, CYP2D6, ABCG2, ABCB1, and OATP1B1 were analyzed by direct sequencing. RESULTS: Eighteen patients with a median age of 80.5 years (range, 75-89) with adequate liver and kidney functions were examined. AUC0-48 values of gefitinib and O-desmethyl gefitinib in this population were 9.49 ± 3.5 and 10.6 ± 14 µM h, respectively. Compared to the gefitinib pharmacokinetics observed in a previous phase I study in Japan, systemic exposure to gefitinib in elderly patients was slightly higher than that in younger patients. Three patients experienced grade 3 diarrhea, increases in alanine aminotransferase, and aspartate aminotransferase levels 30 days after starting gefitinib treatment. The CYP2D6 genotype was associated with CYP2D6-mediated metabolism of gefitinib to O-desmethyl gefitinib. CONCLUSIONS: We demonstrated for the first time the systemic exposure to gefitinib in elderly patients with NSCLC. TRIAL REGISTRATION: The study was registered with the University Hospital Medical Information Network-Clinical Trials Registry Japan (UMIN000026409) on November 8, 2013.

Alteration in the Plasma Concentrations of Endogenous Organic Anion-Transporting Polypeptide 1B Biomarkers in Patients with Non-Small Cell Lung Cancer Treated with Paclitaxel.

Paclitaxel has been considered to cause OATP1B-mediated drug-drug interactions at therapeutic doses; however, its clinical relevance has not been demonstrated. This study aimed to elucidate in vivo inhibition potency of paclitaxel against OATP1B1 and OATP1B3 using endogenous OATP1B biomarkers. Paclitaxel is an inhibitor of OATP1B1 and OATP1B3, with Ki of 0.579 ± 0.107 and 5.29 ± 3.87 µM, respectively. Preincubation potentiated its inhibitory effect on both OATP1B1 and OATP1B3, with Ki of 0.154 ± 0.031 and 0.624 ± 0.183 µM, respectively. Ten patients with non-small cell lung cancer who received 200 mg/m2 of paclitaxel by a 3-hour infusion were recruited. Plasma concentrations of 10 endogenous OATP1B biomarkers-namely, coproporphyrin I, coproporphyrin III, glycochenodeoxycholate-3-sulfate, glycochenodeoxycholate-3-glucuronide, glycodeoxycholate-3-sulfate, glycodeoxycholate-3-glucuronide, lithocholate-3-sulfate, glycolithocholate-3-sulfate, taurolithocholate-3-sulfate, and chenodeoxycholate-24-glucuronide-were determined in the patients with non-small cell lung cancer on the day before paclitaxel administration and after the end of paclitaxel infusion for 7 hours. Paclitaxel increased the area under the plasma concentration-time curve (AUC) of the endogenous biomarkers 2- to 4-fold, although a few patients did not show any increment in the AUC ratios of lithocholate-3-sulfate, glycolithocholate-3-sulfate, and taurolithocholate-3-sulfate. Therapeutic doses of paclitaxel for the treatment of non-small cell lung cancer (200 mg/m2) will cause significant OATP1B1 inhibition during and at the end of the infusion. This is the first demonstration that endogenous OATP1B biomarkers could serve as surrogate biomarkers in patients. SIGNIFICANCE STATEMENT: Endogenous biomarkers can address practical and ethical issues in elucidating transporter-mediated drug-drug interaction (DDI) risks of anticancer drugs clinically. We could elucidate a significant increment of the plasma concentrations of endogenous OATP1B biomarkers after a 3-hour infusion (200 mg/m2) of paclitaxel, a time-dependent inhibitor of OATP1B, in patients with non-small cell lung cancer. The endogenous OATP1B biomarkers are useful to assess the possibility of OATP1B-mediated DDIs in patients and help in appropriately designing a dosing schedule to avoid the DDIs.

High-throughput method to analyze tegafur and 5-fluorouracil in human tears and plasma using hydrophilic interaction liquid chromatography/tandem mass spectrometry.

RATIONALE: We developed a new high-throughput method to analyze tegafur (FT) and 5-fluorouracil (5-FU) in tear and plasma samples using hydrophilic interaction liquid chromatography (HILIC)/tandem mass spectrometry (MS/MS). METHODS: The tear samples (10 µL) spiked with FT, 5-FU, and 5-chlorouracil (internal standard) were diluted using 40 µL of 2 M ammonium acetate and 250 µL of acetonitrile with 2% formic acid; 20 µL of plasma spiked with the two drugs and internal standard was diluted with 80 µL of 2 M ammonium acetate and 500 µL of acetonitrile with 2% formic acid. After centrifugation, the clear supernatant extract (15 µL) was directly injected into the HILIC/MS/MS instrument, and each drug was separated on a Unison UK-Amino column (50 mm × 3 mm i.d., 3 µm particle size) with a linear gradient elution system composed of 10 mM ammonium acetate (pH 6.8) and acetonitrile at a flow rate of 0.7 mL/min. We performed quantification by multiple reaction monitoring (MRM) with negative-ion atmospheric-pressure chemical ionization. RESULTS: Distinct peaks were observed for the drugs on each MRM channel within 2 min. The regression equations showed good linearity within the range 0.04-4.0 µg/mL for the tear and plasma samples with detection limits at 0.02-0.04 µg/mL. Recoveries for target analytes (FT and 5-FU) for the tear and plasma samples were in the 94-128% and 94-104% ranges, respectively. The intra- and inter-day coefficients of variation for the two drugs were lower than 10.8%. The accuracies of quantitation were 97-115% for both samples. CONCLUSIONS: We established a high-throughput, reproducible, and practical procedure for analyzing FT and 5-FU in human tear and plasma samples using HILIC/MS/MS analysis with an aminopropyl-bonded mixed-mode separation column. This method can be applied to the high-throughput routines used in clinical analyses.

Coadministration of cytotoxic chemotherapeutic agents with irinotecan is a risk factor for irinotecan-induced cholinergic syndrome in Japanese patients with cancer.

BACKGROUND: Cholinergic syndrome is an acute adverse event frequently observed in patients administered irinotecan, and can sometimes negatively affect their quality of life. In some manifestations of the syndrome such as bradycardia, careful monitoring of patients is advised. In this study, we retrospectively investigated the risk factors associated with irinotecan-induced cholinergic syndrome in Japanese patients with cancer. METHODS: Patients who received irinotecan-based chemotherapy between April 2014 and June 2018 were examined. Patient backgrounds and clinical data during the first cycle of an irinotecan-containing regimen, including cholinergic syndrome manifestation within 24 h after the start of treatment, were collected from medical records. Univariate and multivariate analyses were performed to assess the risk of irinotecan-induced cholinergic syndrome. RESULTS: Among 179 patients administered an irinotecan-containing regimen, 51 experienced cholinergic syndrome after the initiation of treatment. The most common symptom was sweating followed by diarrhea, abdominal pain, lacrimation, and nasal discharge. 42 patients developed symptoms of cholinergic syndrome during their first treatment with irinotecan. Multivariate analyses revealed that the incidences of cholinergic syndrome in patients administered 2 or 3 chemotherapeutic agents; i.e., irinotecan plus 1 or 2 other cytotoxic anticancer drug(s), were significantly higher than that in patients administered irinotecan alone [odds ratio (OR) 4.35, 95% confidence interval (CI) 1.5-12, p = 0.0053 and OR 4.50, 95% CI 1.5-14, p = 0.0093, respectively]. The addition of a molecularly targeted drug did not affect the incidence of cholinergic syndrome. CONCLUSION: The incidence rate of irinotecan-induced cholinergic syndrome increased concomitantly with the addition of cytotoxic chemotherapeutic agents administered.

Lack of correlation between the costs of anticancer drugs and clinical benefits in Japan.

Both overall survival (OS) and progression-free survival (PFS) are primary endpoints of phase III studies of new anticancer drugs. Medical care expenditures, especially oncology drug prices, are rapidly increasing; however, the impact of oncology drug prices on OS and PFS is unclear. We analyzed the relationship between oncology drug prices and clinical outcomes in Japan. The costs of a full course or 1 year of treatment were estimated on the basis of the latest National Health Insurance Drug Price Standards, and the relationship between costs and improvements in OS or PFS obtained with each drug were analyzed. Cost-effectiveness was compared between new-class drugs and next-in-class drugs. We then developed a simple model for estimating the costs required to prolong OS and PFS by 1 day and used this model to compare cost-effectiveness. Drug costs were not significantly related to treatment outcomes in terms of PFS or OS. There was no significant difference in the median cost between novel drugs and the next-in-class drugs (P = 0.39). The oncology drug cost required to prolong PFS by 1 day was more expensive than the drug cost required for prolong OS by 1 day. Prices of oncology drugs should be decided on the basis of actual clinical benefits for cancer patients, and the drug price evaluation process should be disclosed in Japan.

Organic Cation Transporter 1 Is Responsible for Hepatocellular Uptake of the Tyrosine Kinase Inhibitor Pazopanib.

Pazopanib is an orally active tyrosine kinase inhibitor that exhibits hepatotoxicity in some patients. Despite the clinical importance of its hepatic distribution, the transporter(s) responsible for hepatic uptake of pazopanib in humans remain undetermined. To characterize its hepatic uptake mechanism, we screened the effects of several transporter inhibitors, including tetrapentylammonium (TPeA) for organic cation transporters (OCTs) and cyclosporin A (CsA) for organic anion-transporting polypeptides (OATPs), on both plasma disappearance and hepatic distribution of pazopanib in mice after its i.v. administration. Among the inhibitors, TPeA largely reduced hepatic distribution and plasma clearance of pazopanib, whereas CsA showed only partial reduction. Pazopanib uptake by isolated mouse hepatocytes was similarly reduced by these inhibitors, suggesting that OCTs play a major role in the overall hepatic uptake of pazopanib in mice. In human embryonic kidney cell line HEK293 cells stably transfected with human OCT1, pazopanib uptake was significantly higher than that in vector-transfected cells. Moreover, pazopanib uptake by OCT1 became saturated and was inhibited by TPeA, but not by CsA, confirming that pazopanib is also a substrate of human OCT1. Importantly, OCT1-mediated uptake of a typical OCT1 substrate metformin was inhibited by pazopanib with an IC50 value of 0.253 µM, indicating that pazopanib has the potential for clinically relevant inhibition of human OCT1. Finally, pazopanib was taken up by cryopreserved human pooled hepatocytes in a time-dependent manner, and this uptake was largely reduced by TPeA but only partially reduced by CsA. Thus, the present findings suggest that OCT1 is responsible for hepatocellular uptake of pazopanib.

Phase I/II study of docetaxel combined with resminostat, an oral hydroxamic acid HDAC inhibitor, for advanced non-small cell lung cancer in patients previously treated with platinum-based chemotherapy.

Objectives To determine the recommended dose and efficacy/safety of docetaxel combined with resminostat (DR) in non-small cell lung cancer (NSCLC) patients with previous platinum-based chemotherapy. Materials and Methods A multicenter, open-label, phase I/II study was performed in Japanese patients with stage IIIB/IV or recurrent NSCLC and prior platinum-based chemotherapy. The recommended phase II dose was determined using a standard 3 + 3 dose design in phase I part. Resminostat was escalated from 400 to 600 mg/day and docetaxel fixed at 75 mg/m2. In phase II part, the patients were randomly assigned to docetaxel alone (75 mg/m2) or DR therapy. Docetaxel was administered on day 1 and resminostat on days 1-5 in the DR group. Treatment was repeated every 21 days until progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS). Results A total of 117 patients (phase I part, 9; phase II part, 108) were enrolled. There was no dose-limiting toxicity in phase I part; the recommended dose for resminostat was 600 mg/day with 75 mg/m2 of docetaxel. In phase II part, median PFS (95% confidence interval [CI]) was 4.2 (2.8-5.7) months with docetaxel group and 4.1 (1.5-5.4) months with DR group (hazard ratio [HR]: 1.354, 95% CI: 0.835-2.195; p = 0.209). Grade ≥ 3 adverse events significantly more common with DR group than docetaxel group were leukopenia, febrile neutropenia, thrombocytopenia, and anorexia. Conclusion In Japanese NSCLC patients previously treated with platinum-based chemotherapy, DR therapy did not improve PFS compared with docetaxel alone and increased toxicity.

Incidence of Ophthalmic Disorders in Patients Treated with the Antineoplastic Agent S-1.

S-1 is an oral antineoplastic agent containing tegafur, gimeracil, and oteracil potassium. Recently, ophthalmic disorders, particularly epiphora, have been reported. We retrospectively investigated the incidence of ophthalmic disorders in patients treated with a regimen containing S-1 at our institution. Ophthalmic disorders were noted in 28 of 261 patients(10.7%). These included epiphora(17 cases), eye discharge(10 cases), conjunctivitis(6cases ), blurred vision(3 cases), and eye discomfort(2 cases), as well as eye pain, pruritus, dry eye, hordeolum, and visual loss(1 case each). The median time from starting treatment to appearance of the condition was 3.0(interquartile range 1.5-4.5)months and the median cumulative S-1 dose was 4.2(interquartile range 2.2-9.5)g. More men than women developed ophthalmic disorders on S-1. The median total dose and duration of treatment were higher in those developed ophthalmic disorders than in those who did not (12.4 g vs 6.3g and 8.6 months vs 4.4 months). Epiphora was the most common of a number of ophthalmic disorders seen in our patients treated with S-1. Patients and physicians should be fully informed of the potential association between S-1 and ophthalmic disorders, and patients receiving this treatment need to be carefully monitored.

Optimal dose of gemcitabine for the treatment of biliary tract or pancreatic cancer in patients with liver dysfunction.

A clear consensus does not exist about whether the initial dose of gemcitabine, an essential anticancer antimetabolite, should be reduced in patients with liver dysfunction. Adult patients with biliary tract or pancreatic cancer were divided into three groups according to whether they had mild, moderate, or severe liver dysfunction, evaluated on the basis of serum bilirubin and liver transaminase levels at baseline. As anticancer treatment, gemcitabine at a dose of 800 or 1000 mg/m(2) was given as an i.v. infusion once weekly for 3 weeks of a 4-week cycle. The patients were prospectively evaluated for adverse events during the first cycle, and the pharmacokinetics of gemcitabine and its inactive metabolite, difluorodeoxyuridine, were studied to determine the optimal initial dose of gemcitabine as monotherapy according to the severity of liver dysfunction. A total of 15 patients were studied. Liver dysfunction was mild in one patient, moderate in six, and severe in eight. All 15 patients had been undergoing biliary drainage for obstructive jaundice when they received gemcitabine. Grade 3 cholangitis developed in one patient with moderate liver dysfunction who received gemcitabine at the dose level of 1000 mg/m(2). No other patients had severe treatment-related adverse events resulting in the omission or discontinuation of gemcitabine treatment. The plasma concentrations of gemcitabine and difluorodeoxyuridine were similar among the groups. An initial dose reduction of gemcitabine as monotherapy for the treatment of biliary tract or pancreatic cancers is not necessary for patients with hyperbilirubinemia, provided that obstructive jaundice is well managed. (Clinical trial registration no. UMIN000005363.)

Patritumab plus trastuzumab and paclitaxel in human epidermal growth factor receptor 2-overexpressing metastatic breast cancer.

Human epidermal growth factor receptor 3 (HER3) expression in lung and breast cancers has a negative impact on survival. Patritumab, a human anti-HER3 mAb, has shown anticancer activity in preclinical models. This study examined the safety and pharmacokinetics of patritumab in combination with trastuzumab and paclitaxel in patients with HER2-overexpressing metastatic breast cancer. In this open-label, multicenter, dose-escalation, phase Ib study, patients received patritumab 9 or 18 mg/kg plus trastuzumab and paclitaxel at known tolerated doses. Safety and tolerability were assessed based on dose-limiting toxicities and other non-life threatening adverse events. The pharmacokinetic profile for patritumab was determined based on the target trough level. Clinical efficacy was evaluated based on the overall response rate and progression-free survival. Six patients received patritumab 9 mg/kg and 12 received 18 mg/kg. The most common adverse events were diarrhea, alopecia, leukopenia, neutropenia, and maculopapular rash. No dose-limiting toxicities were observed. The target trough serum concentration was achieved in all patients at a dose of 18 mg/kg. Overall response rate was 38.9% and median progression-free survival was 274 days. In conclusion, patritumab plus trastuzumab and paclitaxel was tolerable and efficacious at both doses. We recommend the dose level of 18 mg/kg for future phase II studies. (Clinical trial registration: JapicCTI-121772.).

Increased Plasma Concentrations of Unbound SN-38, the Active Metabolite of Irinotecan, in Cancer Patients with Severe Renal Failure.

PURPOSE: Delayed plasma concentration profiles of the active irinotecan metabolite SN-38 were observed in cancer patients with severe renal failure (SRF), even though SN-38 is eliminated mainly via the liver. Here, we examined the plasma concentrations of unbound SN-38 in such patients. METHODS: Plasma unbound concentrations were examined by ultrafiltration. Physiologically-based pharmacokinetic (PBPK) models of irinotecan and SN-38 were established to quantitatively assess the principal mechanism for delayed SN-38 elimination. RESULTS: The area under the plasma unbound concentration-time curve (AUC(u)) of SN-38 in SRF patients was 4.38-fold higher than that in normal kidney patients. The unbound fraction of SN-38 was also 2.6-fold higher in such patients, partly because SN-38 protein binding was displaced by the uremic toxin 3-carboxy-4-methyl-5-propyl-2-furanpropionate (CMPF). This result was supported by correlation of the unbound fraction of SN-38 with the plasma CMPF concentration, which negatively correlated with renal function. PBPK modeling indicated substantially reduced influx of SN-38 into hepatocytes and approximately one-third irinotecan dose for SRF patients to produce an unbound concentration profile of SN-38 similar to normal kidney patients. CONCLUSION: The AUC(u) of SN-38 in SRF cancer patients is much greater than that of normal kidney patients primarily because of the reduced hepatic uptake of SN-38.

Safety and pharmacokinetics of ramucirumab in combination with docetaxel in Japanese patients with locally advanced or metastatic breast cancer: a Phase Ib study.

OBJECTIVE: The primary objective of this study was to investigate the safety and tolerability and to confirm the recommended dose of the anti-vascular endothelial growth factor receptor 2 monoclonal antibody ramucirumab in combination with docetaxel in Japanese patients with metastatic/locally advanced breast cancer. METHODS: In this multicenter, single-arm, Phase Ib trial, eligibility criteria included: 20 years or older, Eastern Cooperative Oncology Group performance status of 0/1 and confirmed diagnosis of human epidermal growth factor receptor 2-negative metastatic/locally recurrent inoperable breast adenocarcinoma. Patients received docetaxel (75 mg/m2) followed by ramucirumab (10 mg/kg) on Day 1 of 21-day cycles. Recommended dose was defined as <33% dose-limiting toxicities in dose-limiting toxicity-evaluable patients in Cycle 1. The safety, pharmacokinetics, immunogenicity and antitumor activity were examined. RESULTS: Seven patients were treated. Most adverse events were mild to moderate. Two patients during Cycle 1 experienced a dose-limiting toxicity; one patient each experienced Grade 3 febrile neutropenia and Grade 3 gingivitis. Both dose-limiting toxicities subsequently resolved. No patients discontinued study therapies during Cycle 1. Four serious adverse events were possibly related to ramucirumab in combination with docetaxel. Anti-ramucirumab antibodies were not detected. Pharmacokinetic analysis revealed low total body clearance and long apparent terminal elimination half-life (~7-12 days). Partial response was reported in four patients. CONCLUSIONS: The combination of ramucirumab and docetaxel was tolerable in female Japanese patients with breast cancer. Ramucirumab 10 mg/kg in combination with docetaxel (75 mg/m2) was confirmed as the recommended dose among Japanese patients, supporting its use in future studies.

Phase 1 combination study of eribulin mesylate with trastuzumab for advanced or recurrent human epidermal growth factor receptor 2 positive breast cancer.

Eribulin mesylate (Halaven®) is a novel inhibitor of microtubule dynamics that has demonstrated a survival benefit in patients with locally recurrent or metastatic breast cancer who previously received at least two chemotherapeutic regimens including an anthracycline and a taxane. Although trastuzumab is indicated for patients with human epidermal growth factor receptor 2 positive (HER2+) breast cancer, a phase 1 study to evaluate tolerability/safety of eribulin mesylate with trastuzumab has not been conducted. Therefore, a study of eribulin mesylate in combination with trastuzumab was conducted to evaluate dose limiting toxicity (DLT), tolerability/safety, pharmacokinetics (PK), and efficacy and to estimate the recommended dose in Japanese patients with advanced or recurrent HER2+ breast cancer. Eribulin mesylate (1.4 mg/m(2)) was administered on days 1 and 8 of every 3 week cycle. Trastuzumab was administered with a 4 mg/kg loading dose followed by 2 mg/kg weekly doses or with an 8 mg/kg loading dose followed by 6 mg/kg tri-weekly doses. A total of 12 patients (six for each regimen) received eribulin mesylate and trastuzumab. No DLT was observed and the recommended dose of eribulin mesylate in combination with trastuzumab was estimated as 1.4 mg/m(2). Common adverse events were neutropenia, leukopenia, anaemia and alopecia. This combination therapy was well tolerated and the neutropenia observed was manageable. No PK drug-drug interaction between eribulin and trastuzumab was observed. Since a transient ejection fraction decreased was observed in two patients, cardiac function should be routinely assessed in patients receiving the combination therapy of eribulin mesylate with trastuzumab (ClinicalTrials.gov Identifier: NCT01432886).

A phase I study of farletuzumab, a humanized anti-folate receptor α monoclonal antibody, in patients with solid tumors.

Farletuzumab is a humanized monoclonal antibody against folate receptor α (FRA). The purpose of the study is to assess safety and tolerability, the pharmacokinetic (PK) profile, and preliminary antitumor effect. Patients with ovarian cancer (OC) or FRA-expressing solid tumors who are resistant to standard treatments were eligible for the study. After single-dose administration for PK assessment, farletuzumab was administered by intravenous injection, repeating every week until disease progression. Dose-limiting toxicities (DLTs) were defined as grade 4 hematological and grade 3/4 nonhematological toxicities. Dose escalation was planned in 4 cohorts (50, 100, 200, and 400 mg/m(2)). Fourteen patients with OC and two patients with gastric cancer (GC) received farletuzumab infusion. Neither DLTs nor grade 3/4 toxicities were reported in all cohorts. Major adverse events, including grade 1/2 infusion related reaction (15 patients, 93.8%), headache (seven patients, 43.8%), and nausea and decreased appetite (five patients each, 31.3%), were observed and medically managed. AUC and Cmax increased dose-dependently and linear PK profiles were observed. No tumor shrinkage was recorded, but long-term disease stabilization for 25 and 20 months was observed in one patient with clear cell OC (100 mg/m(2)) and one patient with GC (400 mg/m(2)), respectively. No cumulative toxicity occurred in any patient. Farletuzumab was well tolerated in Japanese patients with a similar PK profile as compared with the US population. Long-term disease stabilization was observed in a subpopulation of clear cell OC and GC; both of them were resistant and progressive after standard chemotherapies (ClinicalTrials.gov Identifier: NCT01049061).

Randomized phase II trial of nimotuzumab plus irinotecan versus irinotecan alone as second-line therapy for patients with advanced gastric cancer.

BACKGROUND: This multicenter, randomized phase II trial was conducted to compare the efficacy and safety of nimotuzumab plus irinotecan (N-IRI) versus irinotecan alone (IRI) in patients with advanced gastric cancer (AGC) showing disease progression after previous 5-fluorouracil-based therapy. METHODS: Irinotecan-naive patients (n = 82) received N-IRI (nimotuzumab 400 mg weekly plus irinotecan 150 mg/m(2) biweekly) or IRI (irinotecan 150 mg/m(2) biweekly) until disease progression. The primary endpoint was progression-free survival (PFS), and the secondary endpoints were overall survival (OS), response rate (RR), safety, tolerability, and the correlation between efficacy and tumor epidermal growth factor receptor (EGFR) expression. RESULTS: Of 83 patients, 40 and 43 patients were randomly assigned to the N-IRI and IRI groups, respectively. In the N-IRI/IRI treatment group, median PFS was 73.0/85.0 days (P = 0.5668), and median OS and RR at 18 months were 250.5/232.0 days (P = 0.9778) and 18.4/10.3 %, respectively. Median PFS and OS in the EGFR 2+/3+ subgroups were 118.5/59.0 and 358.5/229.5 days, respectively. The RR was 33.3/0.0 % in the N-IRI/IRI treatment group. The incidence of grade 3 or higher adverse events was 77.5/64.3 %. No adverse events of grade 3 or higher skin rash or grade 3 or higher infusion-related reaction were reported. CONCLUSIONS: There was no superiority of N-IRI over IRI alone in terms of PFS in 5-fluorouracil-refractory AGC patients. However, N-IRI showed potential improvement in the EGFR 2+/3+ subgroup based on improved RR, PFS, and OS.

The SOFT trial: a Phase III study of the dihydropyrimidine dehydrogenase inhibitory fluoropyrimidine S-1 and oxaliplatin (SOX) plus bevacizumab as first-line chemotherapy for metastatic colorectal cancer.

A combination of oxaliplatin, leucovorin and 5-fluorouracil (FOLFOX) plus bevacizumab has been widely used for the first-line chemotherapy of metastatic colorectal cancer (mCRC). S-1 is an oral fluoropyrimidine preparation that combines tegafur, a prodrug of 5-fluorouracil, with two modulators. Several studies of combination chemotherapy with oxaliplatin plus S-1 (SOX) conducted in Asia have reported promising efficacy and safety in patients with mCRC, suggesting the potential to replace mFOLFOX6. The SOFT trial (JapicCTI-090699) was a randomized Phase III trial designed to evaluate the noninferiority of SOX plus bevacizumab to mFOLFOX6 plus bevacizumab in patients with mCRC. This review summarizes the drug concept of S-1 and the results of clinical trials of S-1 and SOX in CRC and presents an overview of the SOFT trial.

Safety, pharmacokinetics and efficacy findings in an open-label, single-arm study of weekly paclitaxel plus lapatinib as first-line therapy for Japanese women with HER2-positive metastatic breast cancer.

BACKGROUND: Lapatinib is the human epidermal growth factor receptor 2 (HER2) targeting agent approved globally for HER2-positive metastatic breast cancer (MBC). The efficacy, safety and pharmacokinetics (PK) of lapatinib combined with paclitaxel (L+P) were investigated in this study, to establish clear evidence regarding the combination in Japanese patients. METHODS: In this two-part, single-arm, open-label study, the tolerability of L+P as first-line treatment in Japanese patients with HER2-positive MBC was evaluated in six patients in the first part, and the safety, efficacy and PK were evaluated in a further six patients (making a total of twelve patients) in the second part. Eligible women were enrolled and received lapatinib 1500 mg once daily and paclitaxel 80 mg/m(2) weekly for at least 6 cycles. RESULTS: The only dose-limiting toxicity reported was Grade 3 diarrhea in one patient. The systemic exposure to maximum plasma concentration and area under the plasma concentration curve (AUC) for lapatinib, as well as the AUC of paclitaxel, were increased when combined. The most common adverse events (AEs) related to the study treatment were alopecia, diarrhea and decreased hemoglobin. The majority of drug-related AEs were Grade 1 or 2. The median overall survival was 35.6 months (95 % confidence interval 23.9, not reached). The response rate and clinical benefit rate were both 83 % (95 % confidence interval 51.6, 97.9). CONCLUSIONS: The L+P treatment was well tolerated in Japanese patients with HER2-positive MBC. Although the PK profiles of lapatinib and paclitaxel influenced each other, the magnitudes were not greatly different from those in non-Japanese patients.

Phase II trial of nanoparticle albumin-bound paclitaxel as second-line chemotherapy for unresectable or recurrent gastric cancer.

This multicenter phase II study first investigated the efficacy and safety of nanoparticle albumin-bound paclitaxel (nab-paclitaxel) when given every 3 weeks to patients with unresectable or recurrent gastric cancer who had received a prior round of fluoropyrimidine-containing chemotherapy. Patients with unresectable or recurrent gastric cancer who experienced progression despite fluoropyrimidine-containing treatment were studied. Nab-paclitaxel was given i.v. at 260 mg/m(2) on day 1 of each 21-day cycle without anti-allergic premedication until disease progression or study discontinuation. The primary endpoint was the overall response rate. The secondary endpoints were the disease control rate, progression-free survival, overall survival, and safety. From April 2008 to July 2010, 56 patients were enrolled, 55 patients received the study treatment, and 54 patients were evaluable for responses. According to an independent review committee, the overall response rate was 27.8% (15/54; 95% confidence interval [CI], 16.5-41.6) and the disease control rate was 59.3% (32/54; 95% CI, 45.0-72.4). One patient had a complete response. The median progression-free survival and overall survival were 2.9 months (95% CI, 2.4-3.6) and 9.2 months (95% CI, 6.9-11.4), respectively. The most common grade 3/4 toxicities were neutropenia (49.1%), leucopenia (20.0%), lymphopenia (10.9%), and peripheral sensory neuropathy (23.6%). There were no treatment-related deaths. Nab-paclitaxel, given every 3 weeks, showed promising activity against previously treated unresectable or recurrent gastric cancers, with well-tolerated toxicities. (Trial registration, ClinicalTrials.gov: NCT00661167).

Regorafenib in Japanese patients with solid tumors: phase I study of safety, efficacy, and pharmacokinetics.

The safety, pharmacokinetics, and antitumor activity of the multikinase inhibitor regorafenib in Japanese patients was assessed in this multicenter, single-arm, phase I trial. Fifteen patients with treatment-refractory advanced solid tumors received regorafenib 160 mg once daily for the first 3 weeks of each 4-week cycle until disease progression, unacceptable toxicity, or investigator or patient decision to stop. The median duration of treatment was 2.1 months (range, 0.9-20.1 months). At data cutoff, one patient was still receiving regorafenib in cycle 21. Reasons for treatment discontinuation were disease progression (n = 12) and adverse events (liver enzyme elevation n = 1; anemia n = 1). Adverse events necessitated dose reduction in six patients, interruption of daily treatment in seven patients, and cycle delay in four patients. All patients experienced at least one drug-related adverse event, particularly gastrointestinal (87 %), dermatologic (73 %), or hematologic (67 %) events. There was no significant change in time to maximum concentration or terminal half-life of regorafenib and its active metabolites M2 and M5 between single dosing and 21-day continuous dosing. The area under the concentration-time curve was 2.1-fold higher for regorafenib, 5.2-fold higher for M2, and 37.3-fold higher for M5, and the maximum concentration was 2.0-fold, 4.8-fold, and 36.0-fold higher, respectively, after continuous dosing than after single dosing. One patient had a partial response (duration 10.5 months) and seven patients had stable disease. This study indicates that regorafenib 160 mg orally once daily (21 days on/7 days off treatment) can be given to Japanese patients who have solid tumors, without undue toxicity.

Direct inhibition and down-regulation by uremic plasma components of hepatic uptake transporter for SN-38, an active metabolite of irinotecan, in humans.

PURPOSE: Clinical study has previously revealed that plasma concentration of 7-ethyl-10-hydroxycamptothecin (SN-38), an active metabolite of irinotecan, was higher in patients with end-stage renal failure than those with normal kidney function although SN-38 is mainly eliminated in the liver. Here, we focused on inhibition by uremic toxins of hepatic SN-38 uptake and down-regulation of uptake transporter(s) by uremic plasma in humans. METHODS: We evaluated SN-38 uptake and its inhibition by uremic toxins, 3-carboxy-4-methyl-5-propyl-2-furanpropionate (CMPF), indoxyl sulfate (Indox), hippuric acid (HA) and indole acetate (IA), with cryopreserved human hepatocytes and HEK293 cells stably expressing hepatic uptake transporters, organic anion transporting polypeptides (OATPs). We also collected plasma samples from patients with severe renal failure to examine their effects on mRNA level of OATPs in primary cultured human hepatocytes. RESULTS: SN-38 was taken up by hepatocytes, which showed biphasic saturation patterns. The SN-38 uptake by hepatocytes was significantly inhibited by a uremic toxin mixture including clinically relevant concentrations of CMPF, Indox, HA and IA. Kinetic analyses for OATP-mediated transport revealed that the uptake of SN-38 by OATP1B1 was the highest, followed by OATP1B3. Among the uremic toxins, CMPF exhibited most potent inhibition of OATP1B1-mediated SN-38 uptake and directly inhibited the uptake of SN-38 also in hepatocytes. In addition, gene expression of OATP1B1 and OATP1B3 in hepatocytes was significantly down-regulated by the treatment with the uremic plasma. CONCLUSIONS: OATP1B1-mediated hepatic uptake of SN-38 was inhibited by uremic toxins, and gene expression of OATP1B1 was down-regulated by uremic plasma.