Effect of UGT1A1, CYP3A and CES Activities on the Pharmacokinetics of Irinotecan and its Metabolites in Patients with UGT1A1 Gene Polymorphisms.

BACKGROUND AND OBJECTIVES: Irinotecan (CPT-11) is metabolized to an active metabolite 7-ethyl-10-hydroxycamptothecin (SN-38) by carboxylesterase (CES). SN-38 is then converted to the inactive metabolite SN-38 glucuronide (SN-38G) by glucuronosyltransferase 1A1 (UGT1A1). Genetic polymorphisms in UGT1A1 have been associated with altered SN-38 pharmacokinetics, which increase the risk of toxicity in patients. CPT-11 is also converted to 7-ethyl-10-[4-N-(5-aminopentanoic acid)-1-piperidino]carbonyloxycamptothecin (APC) and 7-ethyl-10-(4-amino-1-piperidino) carbonyloxycamptothecin (NPC) by cytochrome P450 3A (CYP3A), and this route also affects the plasma concentration of SN-38. We evaluated the activities of UGT1A1, CYP3A, and CES and the factors affecting the pharmacokinetics of plasma SN-38 in patients with UGT1A1 gene polymorphisms. METHODS: Three male patients aged 56, 65, and 49 years were recruited for the analysis. All patients had pancreatic cancer, received FOLFIRINOX, and had UGT1A1*6/*6 (patients 1 and 3) or *6/*28 (patient 2) genetic polymorphisms. The rate constants for evaluating the enzyme activity were determined from the measured plasma concentration of CPT-11 and its metabolites using a two-compartment model by WinNonlin. RESULTS: The area under the plasma concentration-time curve (AUC) of SN-38 was patient 1 > patient 2 > patient 3. The rate constants obtained from the model analysis indicated the respective enzyme activities of UGT1A1 (k57), CYP3A (k13 + k19), and CES (k15). The order of values for UGT1A1 activity was patient 2 > patient 3 > patient 1. Since UGT1A1 activity was low in patient 1 with a high AUC of SN-38, it can be said that the increase in plasma concentration was due to a decrease in UGT1A1 activity. Conversely, the order of values for CYP3A and CES activities was patient 3 > patient 1 > patient 2 and patient 2 > patient 1 > patient 3, respectively. Patient 3 had the lowest AUC of SN-38, caused by a lower level of CES activity and increased CYP3A activity. CONCLUSION: In this study, we indicated that the plasma AUC of SN-38 and AUC ratio of SN-38G/SN-38 may depend on changes in the activities of CYP3A, CES, and UGT1A1. Using pharmacokinetic analysis, it is possible to directly evaluate enzyme activity and consider what kind of enzyme variation causes the increase in the AUC of SN-38.

Biomarker Analyses in Patients With Advanced Solid Tumors Treated With the LAT1 Inhibitor JPH203.

BACKGROUND/AIM: Amino acids are among the most important nutrients for supplying energy and building protein blocks in cancers. L-type amino acid transporter (LAT) 1 is known to play a critical role in cancer growth. We have completed the first-in-human phase I study using the LAT1-specific inhibitor JPH203. PATIENTS AND METHODS: We evaluated plasma free amino acids (PFAAs), body mass index (BMI), and efficacy of JPH203 in patients enrolled in the phase I study. RESULTS: LAT1-substrate PFAAs and branched chain amino acids (BCAAs) were higher in patients with biliary tract cancer (BTC) than in those with other cancers. High inhibition of uptake of LAT1-substrate PFAAs was associated with survival. BMI of more than the median was associated with disease control and survival. BCAAs tended to be associated with BMI. CONCLUSION: BCAAs and BMI are useful predictors of the efficacy of JPH203, which shows promising activity against BTC.

First-in-human phase I study of JPH203, an L-type amino acid transporter 1 inhibitor, in patients with advanced solid tumors.

This open-label first-in-human study evaluated JPH203, which is a novel selective L-type amino acid transporter 1 inhibitor. We also evaluated the association between the N-acetyltransferase 2 phenotype and outcomes. Japanese patients with advanced solid tumors received daily intravenous JPH203 treatment for 7 days, followed by a 21-day rest period, at escalating doses of 12-85 mg/m2. Dose-limiting toxicities were evaluated during the first cycle using a 3 + 3 design. The study enrolled 17 patients, although grade 3 liver dysfunction was detected in one of six patients receiving 60 mg/m2 and in the first patient to receive 85 mg/m2. Further enrollment was terminated and the maximum tolerated dose was defined as 60 mg/m2. The AUC∞ increased between 12 mg/m2 and 25 mg/m2, although no differences were observed at 25-40 mg/m2. Partial response was observed for one patient with biliary tract cancer (BTC) at the 12 mg/m2 dose, and disease control was achieved by 3 of 6 patients at the 12 mg/m2 and 25 mg/m2 dose levels. Based on these results, we recommend a phase II dose of 25 mg/m2. The disease control rate for BTC was 60%. Two patients with grade 3 liver dysfunction had the rapid N-acetyltransferase 2 phenotype, and disease control was more common for the non-rapid phenotype (50% vs. 12.5%). It appears that JPH203 was well-tolerated and provided promising activity against BTC. The N-acetyltransferase 2 phenotype might help predict the safety and efficacy of JPH203. Clinical trial registration: UMIN000016546.

Tramadol/Acetaminophen Combination Tablets in Cancer Patients with Chemotherapy-Induced Peripheral Neuropathy: A Single-Arm Phase II Study.

Background: Chemotherapy-induced peripheral neuropathy (CIPN) is a frequent complication in patients receiving anticancer chemotherapy, but no effective treatment is yet available. Objective: To evaluate the efficacy and safety of a tramadol/acetaminophen combination tablets for CIPN. Design: This is a single-arm phase II study of tramadol/acetaminophen. Setting/subjects: Eligible patients had received oxaliplatin, paclitaxel, or nab-paclitaxel, and were experiencing CIPN. The patients were given one tablet (37.5 mg tramadol plus 325 mg acetaminophen) twice a day for 7 days, then four times a day for 21 days. Measurements: The primary endpoint was the numerical rating scale of neuropathic pain. Other endpoints included the potential of CYP2D6 genetic variants to effective response or toxicity. Results: Of the 34 patients enrolled, 23 completed the protocol treatment. The mean neuropathic pain score decreased insignificantly from 5.53 at baseline to 5.00 at 28 days (95% confidence interval -0.21 to 1.43; p = 0.139). However, 13 of the 23 (56.5%) patients who completed the protocol treatment showed improvement of the neuropathic pain score by at least 1 point. No severe adverse events were observed. Tramadol/acetaminophen may be more effective in patients with the intermediate metabolizer phenotype of the CYP2D6 single nucleotide polymorphisms (SNPs) although at the cost of increased toxicity. Conclusions: Although tramadol/acetaminophen tablets did not reduce neuropathic pain to a statistically significant degree, the neuropathic pain severity reduced in more than a half of the patients.

[Investigation of the Cases of Deaths at Home after Discharge from Palliative Care Unit].

Recently, palliative care units are required to provide home-care support. In our palliative care unit, we support withh ospital discharge according to patient's wishes. In 2 years since April 2016, 104 of 536 hospitalized patients were discharged home (home discharge rate 19.4%). Among these patients, 30 died at home. Using the cases of the 30 patients, we investigated proper discharge and home-care support. As a background factor, the existence of"care by a woman"and"opioid unused" was likely to facilitate death at home. The patient was widely introduced to 18 clinics in the local area, not a specific medical institution. As reasons for home discharge,"Advanced understanding of medical condition" and"Recognition of the goodness of home"was cited. The median time from discharge to death at home is as short as 14 days, and so cooperation between the hospital and the home medical team is indispensable. To that end, the hospital guarantees emergency hospitalization, and the home medical team needs to accept discharge of the patient who is approaching death.

An early clinical trial of Salirasib, an oral RAS inhibitor, in Japanese patients with relapsed/refractory solid tumors.

PURPOSE: Patients with RAS-positive tumors respond poorly to chemotherapies and have a few treatment options. Salirasib is an oral RAS inhibitor that competitively blocks the membrane association of RAS proteins. The aim of this phase I multiple-ascending-dose clinical trial was to investigate the safety and pharmacokinetics of Salirasib in Japanese patients with relapsed/refractory solid tumors and to explore its efficacy. METHODS: Salirasib was started at a dose of 100-mg twice-daily and escalated to a maximum of 1000-mg twice-daily from days 1 to 21 of a 28-day regimen. The pharmacokinetics was evaluated on days 1 and 21. Dose-limiting toxicity (DLT) and adverse events (AEs) were monitored throughout the trial. Patients with stable disease or better repeated the dosing regimen. RESULTS: A total of 21 patients received Salirasib. Among 14 patients tested, 4 had KRAS mutations. Cmax and AUCinf were maximal at 800 mg. No maximum tolerable dose was discerned, as no DLT was observed in any dosing group. The most frequently observed AEs were gastrointestinal disturbances, including diarrhea, abdominal pain, and nausea. No AEs led to discontinuation. All patients completed the first regimen and 11 patients repeated the regimen (median: 2 cycles; range: 1-13). Patients with KRAS mutations showed median progression-free survival of 227 days (range: 79-373). CONCLUSION: Salirasib was safe and well tolerated in Japanese patients, and 800-mg twice-daily is recommended for phase II trials. Although the number of participants with KRAS mutations was limited, the remarkably long progression-free period warrants further investigation. CLINICAL TRIAL REGISTRATION: JAPIC Clinical Trials Information; JapicCTI-121751.

The Modified Glasgow Prognostic Score in Patients with Gemcitabine-refractory Biliary Tract Cancer.

BACKGROUND: No standard second-line chemotherapy has been yet established for gemcitabine-refractory biliary tract cancer (BTC). PATIENTS AND METHODS: We conducted multivariable Cox regression analysis to examine the prognostic factors for overall survival (OS) in patients who had received gemcitabine-based treatment. RESULTS: Forty-six patients received second-line chemotherapy. The median serum carbohydrate antigen 19-9 (CA 19-9) value was 487 U/ml. The modified Glasgow prognostic score (mGPS) was: 0 (n=24), 1 (n=10), or 2 (n=10). The second-line chemotherapy included: S-1 in 20 patients, gemcitabine-based in 20, and tyrosine kinase inhibitors in five. The median OS was 8.3 months, and the median progression-free survival was 3.0 months. Multivariate analysis identified serum CA 19-9 ≥500 U/ml, mGPS ≥1, and presence of liver metastasis as significant prognostic factors for OS. CONCLUSION: Second-line chemotherapy for gemcitabine-refractory BTC remains inadequate. Randomized trials with appropriate stratification criteria are required.

Factors Influencing Cancer Patients' Choice of End-of-Life Care Place.

BACKGROUND: It is important for cancer patients to receive end-of-life care at the desired place. OBJECTIVE: To identify issues in selection of place for end-of-life care of cancer patients to realize their optimal survivorship. DESIGN AND SETTING: Between September 2015 and January 2016, a questionnaire consisting of 33 items, including end-of-life care place preferences, was administered to cancer patients who attended three university hospitals in Japan. RESULTS: A total of 971 questionnaires were collected (response rate, 88.4%). Fifty-eight percent of patients preferred to stay at home to receive end-of-life care. In contrast, more than 80% of patients did not know the details of healthcare services. The factors significantly associated with patients' choice for place of end-of-life care at home were "male gender" (odds ratio [OR] = 1.43, p = 0.030), "living in a one-person household" (OR = 0.21, p < 0.001), "feeling close to friends" (OR = 0.94, p = 0.049), "thinking that the family is burdened" (OR = 0.55, p < 0.001), "thinking that pain is controllable at home" (OR = 1.39, p < 0.001), and "thinking that society should establish a system of home palliative care" (OR = 1.93, p < 0.001). CONCLUSIONS: This study identified six factors influencing the selection of a place for end-of-life care. Most patients have a desire for a social system that allows end-of-life care at home where they can live with their family, but have anxiety about treatment to deal with symptom change, with concern about burden on their family. These issues should be addressed in the future.

Axitinib for Gemcitabine-refractory Advanced Biliary Tract Cancer: Report of 5 Cases.

BACKGROUND/AIM: Vascular endothelial growth factor receptor (VEGFR) has been identified as a treatment target for biliary tract cancer (BTC) and axitinib is a selective inhibitor of vascular endothelial growth factor receptor (VEGFR)-1/2/3. This study was conducted as a preliminary evaluation of the safety and efficacy of axitinib for patients with advanced BTC. PATIENTS AND METHODS: Patients refractory to gemcitabine-based regimens were administered axitinib at the dose of 5 mg twice daily. RESULTS: Five patients (3 male and 2 female) with a median age of 68 years were enrolled. Although 3 patients developed treatment-related grade 3/4 adverse events (AEs), none of these patients required discontinuation of the protocol treatment due to the AEs. Partial response (PR) was achieved in 1 patient, with a 67% reduction. The response was classified as stable disease (SD) in 3 patients and as progressive disease (PD) in 1 patient. Overall survival (OS) and progression-free survival (PFS) ranged from 2.0 to 19.9 months and 1.5 to 7.4 months, respectively. CONCLUSION: This preliminary study suggested that axitinib is well-tolerated and might exert promising activity in patients with BTC.

[Geriatric Oncology].

The number of older adults in Japan is rising, and healthcare for older patients differs from those of younger patients.We have limited available data regarding the outcomes of cancer treatment in this population.In addition, we have few guidelines to address the evaluation and treatment of older cancer patients in Japan.The Japan Agency for Medical Research and Development(AMED)has funded clinical research focusing on elderly cancer patients.We organized the Geriatric Study Committee in Japan Clinical Oncology Group(JCOG)to develop geriatric research policy in this area.This policy includes the (1)definition of a selection policy for the subjects of geriatric research,(2)establishment of standard endpoints and methodological schemes for geriatric research, and(3)recommendations for standard tools of geriatric assessment.We are also developing a curriculum in geriatric oncology for medical doctors and oncology nurses to improve the evidence-based evaluation and treatment of elderly cancer patients.Japanese society is progressing to address the increasing number of elderly patients using a team approach in a broad sense, which consists of cancer professionals, healthcare providers, and government.

A Multicenter Phase II Study of Gemcitabine plus S-1 Chemotherapy for Advanced Biliary Tract Cancer.

BACKGROUND: Gemcitabine (GEM) plus cisplatin (CDDP) chemotherapy has been used worldwide as the standard first-line treatment for advanced biliary tract cancer (BTC). A phase II trial has also suggested promising activity of GEM plus S-1 chemotherapy against advanced BTC. The aim of this study was to evaluate the efficacy and safety of GEM plus S-1 chemotherapy in patients with advanced BTC. PATIENTS AND METHODS: The eligibility criteria were as follows: histologically-proven BTC, unresectable or recurrent disease, ECOG performance status (PS) 0-1 regardless of previous treatment. Gemcitabine was administered intravenously at the dose of 1,000 mg/m2 over 30 min on days 1 and 8, and S-1 was administered orally at doses of 60/80/100 mg/day based on the BSA, from day 1 to day 14, every 3 weeks. The primary endpoint was the response rate according to RECIST, ver. 1.1, and the secondary endpoints were the frequency/severity of toxicities, progression-free survival (PFS) and overall survival (OS). RESULTS: A total of 38 patients were enrolled between August 2008 and November 2011. There were 19 men and 19 women, with a median age of 66 years (range=44-81 years). Seven patients had a previous history of first-line or adjuvant chemotherapy after surgery. The PS was 0 and 1 in 30 and 7 patients, respectively. The treatment response was classified as partial response in 6 patients (15.8%) and as stable disease in 18 patients (47.4%). The median PFS and OS were 5.8 and 15.9 months, respectively. The toxicity was generally mild, and the most common grade 3/4 toxicities were leukopenia (31.6%), neutropenia (36.8%), nausea/vomiting (2.6%), and diarrhea (2.6%). There was one treatment-related death due to interstitial pneumonia. CONCLUSION: Our study revealed that gemcitabine plus S-1 chemotherapy was well-tolerated and exhibited favorable antitumor activity in patients with advanced BTC.

[Chemoradiotherapy for Locally Advanced Pancreatic Cancer].

The use of FOLFIRINOX and gemcitabine plus nab-paclitaxel for unresectable pancreatic cancer is currently approved in Japan. Although the efficacies of these regimens were investigated only in patients with metastatic pancreatic cancer, they are also expected to be effective for locally advanced pancreatic cancer. Meanwhile, chemoradiotherapy is recognized as a treatment option for locally advanced pancreatic cancer. S-1 or capecitabine-based chemoradiotherapy is being developed in Japan or in Western countries, respectively. Recently, the concept of induction chemotherapy followed by chemoradiotherapy has been accepted and applied in clinical trials. In the JCOG1106 trial, induction gemcitabine followed by S-1 and concurrent radiotherapy demonstrated promising results. This regimen has been recognized as a very promising one for chemoradiotherapy in Japan. However, the optimal therapy for locally advanced pancreatic cancer remains controversial, especially in terms of which between chemotherapy and chemoradiotherapy is superior.

A phase I/Ib study of trametinib (GSK1120212) alone and in combination with gemcitabine in Japanese patients with advanced solid tumors.

BACKGROUND: Trametinib is an inhibitor of MEK1/MEK2 activation and kinase activity. In order to evaluate the safety, tolerability, pharmacokinetics, and preliminary efficacy of single-agent trametinib (part 1) and trametinib in combination with gemcitabine (part 2), we undertook the first clinical study of this combination in Japanese patients with cancer and herein report our results. METHODS: In part 1, 13 patients with advanced solid tumors were enrolled into 3 dose cohorts, receiving trametinib once daily at a dose of 1.0, 2.0, or 3.0 mg. In part 2, 5 patients with pancreatic cancer received trametinib (2.0 mg once daily) in combination with gemcitabine (1000 mg/m(2)). RESULTS: In part 1, a dose-limiting toxicity was observed in a patient in the 2.0-mg dose cohort, but the maximum tolerated dose was not reached at doses up to 3.0 mg daily. The best overall response was a PR in 1 patient, and 6 patients had SD. In part 2, the combination of trametinib and gemcitabine was tolerated for a short period of time. However, serious interstitial lung disease (ILD) was observed in 3 of 5 patients 4 weeks or more after the start of the treatment, including 1 fatal case. Three patients achieved a PR, and 2 patients had SD. The most common adverse event was rash (85 % in part 1 and 100 % in part 2). CONCLUSIONS: Trametinib monotherapy was tolerable in Japanese patients with cancer. However, the combination of trametinib plus gemcitabine carried a higher risk as compared with monotherapy, during which no ILD was observed. (ClinicalTrials.gov number, NCT01324258.).

Retrospective analysis of fixed dose rate infusion of gemcitabine and S-1 combination therapy (FGS) as salvage chemotherapy in patients with gemcitabine-refractory advanced pancreatic cancer: inflammation-based prognostic score predicts survival.

PURPOSE: The purpose of this study was to assess the efficacy and safety of fixed dose rate infusion of gemcitabine and S-1 combination therapy (FGS) in patients with gemcitabine (GEM)-refractory pancreatic cancer (PC) and to explore independent variables associated with survival. METHODS: We retrospectively reviewed consecutive patients with GEM-refractory PC who received FGS at our institution from March 2009 to December 2013. GEM was administered by fixed dose rate intravenous infusion of 1,200 mg/m(2) as a 120-min infusion on day 1, and S-1 was administered orally twice a day at a dose of 40 mg/m(2) on days 1-7. Cycles were repeated every 14 days. RESULTS: Sixty-one patients with GEM-refractory PC received FGS. Sixteen patients received FGS as third-line treatment. Twenty-nine patients (48 %) had a history of S-1 administration. The objective response rate was 13 %, and the disease control rate was 49 %. The median progression-free survival time was 2.7 months, and the median overall survival time was 6.0 months. Major Grade 3 or 4 adverse events included neutropenia (15 %), diarrhea (3 %), anorexia (2 %), and fatigue (2 %). A high inflammation-based prognostic score (modified Glasgow prognostic score (mGPS), which incorporates C-reactive protein and albumin), a performance status >0, and serum carbohydrate antigen 19-9 level >2,000 IU/ml were independently associated with a poor outcome. CONCLUSIONS: FGS might be effective and well tolerated as salvage chemotherapy in a practical setting. The inflammation-based prognostic score is a simple and reliable indicator of survival in the setting of salvage chemotherapy.