Pharmacokinetic and dose-finding study of osimertinib in patients with impaired renal function and low body weight.

The safety of osimertinib is limited in patients with severe or moderate renal impairment, or low body weight. This study aimed to investigate the safety, pharmacokinetics (PK) and recommended dose (RD) of osimertinib in patients with epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) with impaired renal function and low body weight. Thirty-one eligible patients were enrolled and allocated into four cohorts: A, normal renal function (estimated glomerular filtration rate [eGFR] ≥ 50 mL/min/1.73 m2 ) and normal body weight (≥45 kg); B, moderate renal impairment (eGFR = 30-50 mL/min/1.73 m2 ); C, low body weight (<45 kg); and D, severe renal impairment (eGFR <30 mL/min/1.73 m2 or undergoing dialysis). PK parameters and safety were evaluated with a starting dose of 80 mg osimertinib administered orally once daily in cohorts A, B, and C and 40 mg once daily in cohort D. The PK parameters in cohorts A, B, and C were found to be similar. No dose-limiting toxicity was observed, and the RD was determined to be 80 mg once daily in patients with moderate renal function and low body weight. Four serious adverse events, acneiform rash, diarrhea, QTc prolongation, and interstitial lung disease, were noted. Although the PK parameters of osimertinib were similar across all cohorts, toxicity occurred more frequently in patients with impaired renal function and low body weight. Clinicians should prescribe osimertinib with caution in NSCLC patients with impaired renal function and low body weight.

A feasibility study of a peer discussion group intervention for patients with pancreatobiliary cancer and their caregivers.

OBJECTIVES: The purpose of this feasibility study was to examine the impacts of a peer discussion group intervention called "the pancreatobiliary cancer salon" on psychological distress among patients with pancreatobiliary cancer and their caregivers. METHODS: We recruited patients with pancreatic or biliary tract cancer and their caregivers. We conducted a within-group pre-post comparison study. Participants were grouped by the type of cancer and treatment. Each group consisted of four to five patients or caregivers. Hospital staff members facilitated group discussions where participants freely talked for 1 h. We evaluated participants' psychological condition using the Profile of Mood States (POMS) and their impressions of the pancreatobiliary cancer salon. RESULTS: We analyzed data from 42 patients and 27 caregivers who joined the salon for the first time. Thirty-five patients (83.3%) had pancreatic cancer. Thirty-one patients (71.4%) had unresectable pancreatobiliary cancer and 14 patients (33.3%) were being treated with second-line or third-line chemotherapy at the time of the survey. Twenty-two patients (52.4%) participated in the salon within 6 months after diagnosis. Most participating caregivers were the patient's spouse/partner (51.9%) or child (34.6%). Both patients and caregivers experienced high levels of satisfaction with the pancreatobiliary cancer salon. Both patients and caregivers had significantly lower psychological distress as assessed by POMS after the salon. SIGNIFICANCE OF RESULTS: A peer discussion group intervention might be well-received and has potential to benefit for patients with pancreatobiliary cancer and their caregivers.

Efficacy and safety of osimertinib in a Japanese compassionate use program.

BACKGROUND: Osimertinib is a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) that targets the T790M mutation of EGFR. In 2016, AstraZeneca conducted a compassionate use program for osimertinib in Japan. METHODS: Eighteen consecutive patients with histologically proven non-small-cell lung cancer (NSCLC) and harboring the T790M EGFR mutation participated in the compassionate use program between 1 April and 25 May 2016, at the National Cancer Center Hospital. We examined the efficacy and safety of osimertinib in a compassionate use program. RESULTS: All patients had been previously treated with both cytotoxic chemotherapy and EGFR TKIs. Overall response rate was 62.5% (95% confidence interval (CI): 35.9-89.1%). Among the six patients pretreated with a third-generation EGFR TKI, two (33%) responded to osimertinib. On administration with osimertinib, median progression-free and overall survival rates at six months were 66.7% (95% CI: 44.9-88.5) and 88.9% (95% CI: 74.4-100), respectively. Although the toxicity of osimertinib was mild in most patients, three patients had severe adverse events: two developed interstitial lung disease (ILD) and one developed Grade 3 hepatotoxicity. Among these, two (33%) of the six patients who received osimertinib following nivolumab treatment developed severe adverse events, with one each developing Grade 3 hepatotoxicity and Grade 3 ILD. Only one patient visited our hospital seeking to participate in the compassionate program from another hospital. CONCLUSION: Osimertinib demonstrated efficacy even in patients with heavily pretreated NSCLC harboring the T790M mutation. Some patients pretreated with another third-generation EGFR TKI also responded to osimertinib.

Simultaneous optimization of limited sampling points for pharmacokinetic analysis of amrubicin and amrubicinol in cancer patients.

AIM: Limited sampling points for both amrubicin (AMR) and its active metabolite amrubicinol (AMR-OH) were simultaneously optimized using Akaike's information criterion (AIC) calculated by pharmacokinetic modeling. METHODS: In this pharmacokinetic study, 40 mg/m(2) of AMR was administered as a 5-min infusion on three consecutive days to 21 Japanese lung cancer patients. Blood samples were taken at 0, 0.08, 0.25, 0.5, 1, 2, 4, 8 and 24 h after drug infusion, and AMR and AMR-OH concentrations in plasma were quantitated using a high-performance liquid chromatography. The pharmacokinetic profile of AMR was characterized using a three-compartment model and that of AMR-OH using a one-compartment model following a first-order absorption process. These pharmacokinetic profiles were then integrated into one pharmacokinetic model for simultaneous fitting of AMR and AMR-OH. After fitting to the pharmacokinetic model, 65 combinations of four sampling points from the concentration profiles were evaluated for their AICs. Stepwise regression analysis was applied to select the sampling points for AMR and AMR-OH to predict the area under the concentration-time curves (AUCs) at best. RESULTS: Of the three combinations that yielded favorable AIC values, 0.25, 2, 4 and 8 h yielded the best AUC prediction for both AMR (R(2) = 0.977) and AMR-OH (R(2) = 0.886). The prediction error for AUC was less than 15%. CONCLUSION: The optimal limited sampling points of AMR and AMR-OH after AMR infusion were found to be 0.25, 2, 4 and 8 h, enabling less frequent blood sampling in further expanded pharmacokinetic studies for both AMR and AMR-OH.

Phase I dose-finding and pharmacokinetic study of docetaxel and gefitinib in patients with advanced or metastatic non-small-cell lung cancer: evaluation of drug-drug interaction.

PURPOSE: Docetaxel and gefitinib play key roles in the treatment of non-small-cell lung cancer (NSCLC), and their combination could be of interest. Both drugs are mainly metabolized by CYP3A4, and drug-drug interactions are a major concern. This phase I dose-finding study was designed to assess the tolerability and drug-drug interactions in this combination using full pharmacokinetic (PK) samplings. METHODS: Docetaxel was intravenously administered on days 1 and 22 at a dose of 45 or 60 mg/m(2). Gefitinib (250 mg/day) was orally administrated starting on day 2. Ten PK samplings of docetaxel were performed on days 1 and 22. Seven PK samplings of gefitinib were performed on day 18 ± 3 and on day 22. RESULTS: Twelve patients with advanced or metastatic NSCLC were enrolled without considering EGFR mutation status. The major toxicity was neutropenia. Two patients withdrew from this study due to dose-limiting toxicities; however, the toxicity profiles in this combination were generally acceptable. The docetaxel AUC0-24 and C max did not differ whether administered alone or with gefitinib, and the geometric mean ratios (GMRs) of AUC0-24 and C max (co-administrated/administrated alone) were 0.95 (90 % CI 0.85-1.06) and 0.95 (90 % CI 0.85-1.05), respectively. Furthermore, the GMRs of the steady state gefitinib AUC0-24 and C max were 0.93 (90 % CI 0.84-1.03) and 0.98 (90 % CI 0.88-1.09), respectively. CONCLUSION: The tolerability of 60 mg/m(2) docetaxel with 250 mg/day gefitinib was confirmed, and we observed no drug-drug interaction in this combination.

Gender difference in hematological toxicity among lung cancer patients receiving amrubicin monotherapy.

BACKGROUND: Severe hematological toxicity has been frequently observed during amrubicin monotherapy for patients with lung cancer despite the favorable anti-tumor response. The purpose of this retrospective study was to identify pretreatment factors associated with severe hematological toxicity. METHODS: The medical records of lung cancer patients treated with amrubicin monotherapy were reviewed, and univariate and multivariate analyses were conducted. RESULTS: From January 2003 to December 2006, the medical records of 103 patients were extracted. Grade 4 neutropenia was frequently observed in females (male, 66% and female, 90%, P = 0.036 in a univariate analysis). In a multivariate analysis, female gender (P = 0.019), body weight loss (P = 0.021) and amrubicin dose (P = 0.028) were significantly correlated with Grade 4 neutropenia. CONCLUSION: Gender could be considered as one of the important predictive factors associated with Grade 4 neutropenia in patients receiving amrubicin monotherapy.