PubMed | Shizuoka Cancer Center, Osaka University, National Cancer Center Hospital, National Kyusyu Cancer Center and 6 more.
Type: Journal Article | Journal: Cancer science | Year: 2016
We report pharmacokinetics, efficacy and safety data for a new 150-mg alectinib capsule in ALK+ non-small-cell lung cancer in a multicenter, open-label pharmacologic study (JP28927). Eligible patients (20years, locally advanced/metastatic ALK+ disease, ALK inhibitor-nave and -pretreated [including crizotinib refractory]) were randomized 1:1 to receive one of two sequences of alectinib 300mg twice daily (comprising different schedules of 20/40-mg and 150-mg capsules) until investigator-determined lack of clinical benefit. Co-primary endpoints were: bioequivalence of alectinib 20/40mg vs 150mg; food effect with 150mg; and safety. Thirty-five patients were enrolled; median treatment duration was 13.1months (range 1.1-15.0). Under fasting conditions, exposure of the two formulations was similar; mean AUC
PubMed | Shizuoka Cancer Center, Exploratory Oncology Research and Clinical Trial Center, The Cancer Institute Hospital of Japanese Foundation for Cancer Research, National Cancer Center Hospital East and 7 more.
Type: Journal Article | Journal: The Lancet. Respiratory medicine | Year: 2016
RET rearrangements are rare oncogenic alterations in non-small-cell lung cancer (NSCLC). Vandetanib is a multitargeted tyrosine kinase inhibitor exhibiting RET kinase activity. We aimed to assess the efficacy and safety of vandetanib in patients with advanced RET-rearranged NSCLC.In this open-label, multicentre, phase 2 trial (LURET), patients with advanced RET-rearranged NSCLC continuously received 300 mg of oral vandetanib daily. RET-positive patients were screened using a nationwide genomic screening network of about 200 participating institutions. Primary endpoint was the independently assessed objective response in eligible patients. This study is registered with UMIN-CTR, number UMIN000010095.Between Feb 7, 2013, and March 19, 2015, 1536 patients with EGFR mutation-negative NSCLC were screened, of whom 34 were RET-positive (2%) and 19 were enrolled. Among 17 eligible patients included in primary analysis, nine (53% [95% CI 28-77]) achieved an objective response, which met the primary endpoint. In the intention-to-treat population of all 19 patients treated with vandetanib, nine (47% [95% CI 24-71]) achieved an objective response. At the data cutoff, median progression-free survival was 47 months (95% CI 28-85). The most common grade 3 or 4 adverse events were hypertension (11 [58%]), diarrhoea (two [11%]), rash (three [16%]), dry skin (one [5%]), and QT prolongation (two [11%]).Vandetanib showed clinical antitumour activity and a manageable safety profile in patients with advanced RET-rearranged NSCLC. Our results define RET rearrangement as a new molecular subgroup of NSCLC suitable for targeted therapy.The Ministry of Health, Labour and Welfare of Japan and the Practical Research for Innovation Cancer Control from the Japan Agency for Medical Research and Development, AMED.
Kosaka Y.,Kitasato University |
Rai Y.,Hakuaikai Sagara Hospital |
Masuda N.,National Hospital Organization Osaka National Hospital |
Takano T.,Toranomon Hospital |
And 6 more authors.
Supportive Care in Cancer | Year: 2015
Purpose: Pegfilgrastim is a pegylated form of filgrastim, a recombinant protein of granulocyte colony-stimulating factor, that is used to reduce the risk of febrile neutropenia (FN). Here, we report the results of a phase III trial of pegfilgrastim in breast cancer patients receiving docetaxel and cyclophosphamide (TC) chemotherapy. Methods: We conducted a double-blind, placebo-controlled, randomized trial to determine the efficacy of pegfilgrastim in reducing the risk of FN in early-stage breast cancer patients. A total of 351 women (177 in the pegfilgrastim group and 174 in the placebo group) between 20 and 69 years of age with stage I–III invasive breast carcinoma who were to receive TC chemotherapy (docetaxel 75 mg/m2 and cyclophosphamide 600 mg/m2 every 3 weeks) as either neoadjuvant or adjuvant therapy were enrolled; 346 of these patients were treated with either pegfilgrastim (n = 173) or placebo (n = 173). Results: The incidence of FN was significantly lower in the pegfilgrastim group than in the placebo group (1.2 vs. 68.8 %, respectively; P < 0.001). In addition, patients in the pegfilgrastim group required less hospitalization and antibiotics for FN. Most adverse events were consistent with those expected for breast cancer subjects receiving TC chemotherapy. Conclusions: Pegfilgrastim is safe and significantly reduces the incidence of FN in breast cancer patients. © 2015, Springer-Verlag Berlin Heidelberg.
PubMed | The Cancer Institute Hospital of Japanese Foundation for Cancer Research, National Cancer Center Hospital and Chiba University
Type: Journal Article | Journal: Journal of radiation research | Year: 2016
The aim of this study was to evaluate the initial treatment results and toxicities of radiation therapy for patients with early stage low-grade follicular lymphoma (FL) arising from the duodenum. We reviewed 21 consecutive patients with early stage duodenal FL treated with radiation therapy between January 2005 and December 2013 at the Cancer Institute Hospital, Tokyo. The characteristics of patients were: median age 62 years (range, 46-79 years), gender (male, 6; female, 15), clinical stage (I, 20; II1, 1), histological grade (I, 17; II, 4). All patients were treated with radiation therapy alone. The median radiation dose was 30.6 Gy (range, 30.6-39.6) in 17 fractions. The involved-site radiation therapy was delivered to the whole duodenum. The median follow-up time was 43.2 months (range 21.4-109.3). The 3-year overall survival (OS), relapse-free survival (RFS) and local control (LC) rates were 94.7%, 79.3% and 100%, respectively. There were four relapses documented outside the treated volumes: two in the gastrointestinal tract (jejunum, terminal ileum), one in an abdominal lymph node (mesenteric lymph node) and one in the bone marrow. None died of the disease; one death was due to acute myeloid leukemia. No toxicities greater than Grade 1 were observed during treatment and over the follow-up time. The 30.6 Gy of involved-site radiation therapy provided excellent local control with very low toxicities. Radiation therapy could be an effective and safe treatment option for patients with localized low grade FL arising from the duodenum.
Phase II study of erlotinib plus tivantinib (ARQ 197) in patients with locally advanced or metastatic EGFR mutation-positive non-small-cell lung cancer just after progression on EGFR-TKI, gefitinib or erlotinib
PubMed | Shizuoka Cancer Center, Aichi Cancer Center Hospital, Kyowa Hakko Kirin Co, Kanazawa University and 8 more.
Type: Journal Article | Journal: ESMO open | Year: 2016
Patients with epidermal growth factor receptor (EGFR) activation mutation-positive non-small-cell lung cancer (NSCLC) respond well to EGFR tyrosine kinase inhibitors (EGFR-TKIs), but eventually become resistant in most cases. The hepatocyte growth factor/c-Met (HGF/c-Met) pathway is reported as a poor prognostic factor in various cancers. As c-Met is involved in EGFR-TKI resistance, a c-Met inhibitor and EGFR-TKI combination may reverse the resistance. This study evaluated the efficacy and safety of a c-Met selective inhibitor, tivantinib (ARQ 197), in combination with erlotinib, in Japanese EGFR mutation-positive patients with NSCLC who progressed while on EGFR-TKIs.This study enrolled 45 patients with NSCLC with acquired resistance to EGFR-TKIs, who were orally administered a daily combination of tivantinib/erlotinib. The primary end point was the overall response rate (ORR) and secondary end points included disease control rate, progression-free survival (PFS) and overall survival (OS). The patients underwent a mandatory second biopsy just after progression on EGFR-TKIs. The predictive biomarkers were extensively analysed using tumour and blood samples.The ORR was 6.7% (95% CI 1.4% to 18.3%), and the lower limit of 95% CI did not exceed the target of 5%. The median PFS (mPFS) and median OS (mOS) were 2.7months (95% CI 1.4 to 4.2) and 18.0months (95% CI 13.4 to 22.2), respectively. Both were longer in c-Met high patients (c-Met high vs low: mPFS 4.1 vs 1.4months; mOS 20.7 vs 13.9months). Partial response was observed in three patients, all of whom were c-Met and HGF high. The common adverse events and their frequencies were similar to those known to occur with tivantinib or erlotinib alone.Although this study did not prove clinical benefit of tivantinib in patients with acquired resistance to EGFR-TKIs, activated HGF/c-Met signalling, a poor prognostic factor, may define a patient subset associated with longer survival by the tivantinib/erlotinib combination.NCT01580735.
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
PubMed | Kanagawa Cardiovascular and Respiratory Center, Shizuoka Cancer Center, Juntendo University, Miyagi Cancer Center and 12 more.
Type: | Journal: Investigational new drugs | Year: 2017
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 600mg/day and docetaxel fixed at 75mg/m
Phase Ia/Ib study of the pan-class I PI3K inhibitor pictilisib (GDC-0941) administered as a single agent in Japanese patients with solid tumors and in combination in Japanese patients with non-squamous non-small cell lung cancer
PubMed | The Cancer Institute Hospital of Japanese Foundation for Cancer Research, National Cancer Center Hospital and Chugai Pharmaceutical Co.
Type: | Journal: Investigational new drugs | Year: 2016
Pictilisib (GDC-0941) is an oral class I phosphatidylinositol-3-phosphate kinase inhibitor. This phase Ia/Ib study investigated the safety, tolerability, pharmacokinetics, and pharmacodynamics of pictilisib in monotherapy or in combination with carboplatin-paclitaxel and bevacizumab (CP+BEV) in Japanese patients with advanced solid tumors or non-squamous non-small cell lung cancer. A standard 3+3 dose escalation design was applied. In stage 1, 140, 260, or 340mg/day of pictilisib was administered once daily to 12 patients with advanced solid tumors. In stage 2, 260 or 340mg/day of pictilisib was administered in combination with CP+BEV to 7 patients with advanced non-squamous non-small cell lung cancer. In stage 1, 1 of 6 patients in the 340mg/day cohort exhibited dose limiting toxicity (DLT) of grade 3 maculopapular rash. The maximum plasma concentration and area under the curve of pictilisib were dose-dependent. A reduction in phosphorylated AKT in platelet rich plasma was observed. No patient had an objective anti-tumor response. In stage 2, DLT was observed in 1 of 3 patients in the 260mg/day cohort (grade 3 febrile neutropenia), and 2 of 4 patients in the 340mg/day cohort (1 each of grade 3 febrile neutropenia and grade 3 febrile neutropenia/erythema multiforme). Partial responses were observed in 3 out of 7 patients. In conclusion, pictilisib was shown to have good safety and tolerability in Japanese patients with advanced solid tumors. A recommended dose of pictilisib in monotherapy was determined to be 340mg once daily. For combination with CP+BEV, tolerability up to 260mg/day was confirmed.