Prognosis of advanced gastrointestinal stromal tumors (GIST) refractory to tyrosine kinase inhibitors (TKIs) is poor. This randomized, placebo-controlled, phase III trial evaluated the efficacy and ...safety of pimitespib, a novel heat shock protein 90 inhibitor, in advanced GIST refractory to standard TKIs.
Patients with histologically confirmed GIST refractory to imatinib, sunitinib, and regorafenib were randomized 2 : 1 to oral pimitespib 160 mg/day or placebo for 5 consecutive days per week in 21-day cycles. Following disease progression by blinded central radiological review (BCRR), cross-over to open-label pimitespib was permitted. The primary endpoint was progression-free survival (PFS) by BCRR in the full analysis set. Secondary endpoints included overall survival (OS) adjusted using the rank-preserving structural failure time (RPSFT) method to reduce the expected confounding impact of cross-over.
From 31 October 2018 to 30 April 2020, 86 patients were randomized to pimitespib (n = 58) or placebo (n = 28). Median PFS was 2.8 months 95% confidence interval (CI) 1.6-2.9 months with pimitespib versus 1.4 months (0.9-1.8 months) with placebo hazard ratio (HR) 0.51 (95% CI 0.30-0.87); one-sided P = 0.006. Pimitespib showed an improvement in cross-over-adjusted OS compared with placebo HR 0.42 (0.21-0.85), one-sided P = 0.007. Seventeen (60.7%) patients receiving placebo crossed-over to pimitespib; median PFS after cross-over was 2.7 months (95% CI 0.7-4.1 months). The most common (≥30%) treatment-related adverse events (AEs) with pimitespib were diarrhea (74.1%) and decreased appetite (31.0%); the most common (≥10%) grade ≥3 treatment-related AE was diarrhea (13.8%). Treatment-related AEs leading to pimitespib discontinuation occurred in three (5.2%) patients.
Pimitespib significantly improved PFS and cross-over-adjusted OS compared with placebo and had an acceptable safety profile in patients with advanced GIST refractory to standard TKIs.
•Pimitespib improved PFS compared with placebo in patients with previously treated advanced GIST.•OS was improved with pimitespib compared with placebo using the RPSFT model.•Exploratory pharmacogenomic analysis showed a benefit of pimitespib irrespective of KIT mutation status.•The safety profile of pimitespib was acceptable, and quality of life was not deteriorated by pimitespib compared with placebo.
Nivolumab is approved as an option for third- or later-line treatment of advanced gastric/gastroesophageal junction (G/GEJ) cancer in several countries after ATTRACTION-2. To further improve the ...therapeutic efficacy of first-line therapy, exploration of a nivolumab-chemotherapy combination is warranted. In part 1 (phase II) of ATTRACTION-4, the safety and efficacy of nivolumab combined with S-1 plus oxaliplatin (SOX) or capecitabine plus oxaliplatin (CapeOX) as first-line therapy for unresectable advanced or recurrent human epidermal growth factor receptor 2 (HER2)-negative G/GEJ cancer were evaluated.
Patients were randomized (1 : 1) to receive nivolumab (360 mg intravenously every 3 weeks) plus SOX (S-1, 40 mg/m2 orally twice daily for 14 days followed by 7 days off; oxaliplatin, 130 mg/m2 intravenously on day 1 every 3 weeks) or CapeOX (capecitabine, 1000 mg/m2 orally twice daily for 14 days followed by 7 days off; oxaliplatin, 130 mg/m2 intravenously on day 1 every 3 weeks) until disease progression, unacceptable toxicity, or consent withdrawal.
Of 40 randomized patients, 39 (nivolumab plus SOX, 21; nivolumab plus CapeOX, 18) and 38 (21 and 17, respectively) comprised the safety and efficacy populations, respectively. Most frequent (>10%) grade 3/4 treatment-related adverse events were neutropenia (14.3%) in the nivolumab plus SOX group, and neutropenia (16.7%), anemia, peripheral sensory neuropathy, decreased appetite, type 1 diabetes mellitus, and nausea (11.1% each) in the nivolumab plus CapeOX group. No treatment-related death occurred. Objective response rate was 57.1% (95% confidence interval 34.0–78.2) with nivolumab plus SOX and 76.5% (50.1–93.2) with nivolumab plus CapeOX. Median overall survival was not reached (NR) in both groups. Median progression-free survival was 9.7 months (5.8–NR) and 10.6 months (5.6–12.5), respectively.
Nivolumab combined with SOX/CapeOX was well tolerated and demonstrated encouraging efficacy for unresectable advanced or recurrent HER2-negative G/GEJ cancer. ATTRACTION-4 has proceeded to part 2 (phase III) to compare nivolumab plus SOX/CapeOX versus placebo plus SOX/CapeOX.
NCT02746796.
The objective of this randomized phase II trial was to evaluate efficacy and safety of the therapeutic sequence of regorafenib followed by cetuximab, compared with cetuximab followed by regorafenib, ...as the current standard sequence for metastatic colorectal cancer patients.
Patients with KRAS exon 2 wild-type metastatic colorectal cancer after failure of fluoropyrimidine, oxaliplatin, and irinotecan were randomized to receive sequential treatment with regorafenib followed by cetuximab ± irinotecan (R-C arm), or the reverse sequence cetuximab ± irinotecan followed by regorafenib (C-R arm). The primary end point was overall survival (OS). Key secondary end points included progression-free survival (PFS) with initial treatment (PFS1), PFS with second treatment (PFS2), safety, and quality of life. Exploratory end points included serial biomarker analyses, including oncogenic alterations from circulating tumor DNA or multiple serum or plasma proteins.
One-hundred one patients were randomized and eligible for efficacy analysis. Sequential treatment was successful in 86% patients in both arms. Median OS for R-C and C-R was 17.4 and 11.6 months, respectively (P = 0.0293), with a hazard ratio (HR) of 0.61 for OS 95% confidence interval (CI) 0.39–0.96. The HR for PFS1 (regorafenib in R-C versus cetuximab in C-R) was 0.97 (95% CI 0.61–1.54), and PFS2 (C in R-C versus R in C-R) was 0.29 (95% CI 0.17–0.50). No unexpected safety signals were observed. The quality of life scores during the entire treatment period was not significantly different between the two arms. Circulating biomarker analyses showed emerging oncogenic alterations in RAS, BRAF, EGFR, HER2, and MET, which were more commonly detected after cetuximab than after regorafenib.
The therapeutic sequence of regorafenib followed by cetuximab suggests a longer OS than the current standard sequence.
S-1, an oral fluoropyrimidine, plus cisplatin (SP) is a standard regimen for advanced gastric cancer (AGC) in East Asia. To date, no studies have evaluated the efficacy and safety of trastuzumab ...combined with SP in patients with human epidermal growth factor receptor type 2 (HER2)-positive AGC.
Patients with HER2-positive AGC received S-1 (80-120 mg per day) orally on days 1-14, cisplatin (60 mg m(-2)) intravenously on day 1, and trastuzumab (course 1, 8 mg kg(-1); course 2 onward, 6 mg kg(-1)) intravenously on day 1 of a 21-day cycle. The primary end point was response rate (RR); secondary end points included overall survival (OS), progression-free survival (PFS), time to treatment failure (TTF), and adverse events.
A total of 56 patients were enrolled. In the full analysis set of 53 patients, the confirmed RR was 68% (95% confidence interval (CI)=54-80%), and the disease control rate was 94% (95% CI=84-99%). Median OS, PFS, and TTF were estimated as 16.0, 7.8, and 5.7 months, respectively. Major grade 3 or 4 adverse events included neutropaenia (36%), anorexia (23%), and anaemia (15%).
Trastuzumab in combination with SP showed promising antitumour activity and manageable toxic effects in patients with HER2-positive AGC.
In this paper, the performance evaluation of a solid oxide fuel cell (SOFC)–micro gas turbine (MGT) hybrid power generation system under the part-load operation was studied numerically. The present ...analysis code includes distributed parameters model of the cell stack module. The conversions of chemical species for electrochemical process and fuel reformation process are considered. Besides the temperature distributions of the working fluids and each solid part of cell module by accounting heat generation and heat transfers, are taken into calculation. Including all of them, comprehensive energy balance in the cell stack module is calculated. The variable MGT rotational speed operation scheme is adopted for the part-load operation. It will be made evident that the power generation efficiency of the hybrid system decreases together with the power output. The major reason for the performance degradation is the operating temperature reduction in the SOFC module, which is caused by decreasing the fuel supply and the heat generation in the cells. This reduction is also connected to the air flow rate supplement. The variable MGT rotational speed control requires flexible air flow regulations to maintain the SOFC operating temperature. It will lead to high efficient operation of the hybrid system.
Combination therapy with oral fluoropyrimidine and irinotecan has not yet been established as first-line treatment of metastatic colorectal cancer (mCRC). We carried out a randomized, open-label, ...phase III trial to determine whether S-1 and irinotecan plus bevacizumab is noninferior to mFOLFOX6 or CapeOX plus bevacizumab in terms of progression-free survival (PFS).
Patients from 53 institutions who had previously untreated mCRC were randomly assigned (1 : 1) to receive either mFOLFOX6 or CapeOX plus bevacizumab (control group) or S-1 and irinotecan plus bevacizumab (experimental group; a 3-week regimen: intravenous infusions of irinotecan 150mg/m2 and bevacizumab 7.5mg/kg on day 1, oral S-1 80mg/m2 twice daily for 2weeks, followed by a 1-week rest; or a 4-week regimen: irinotecan 100mg/m2 and bevacizumab 5mg/kg on days 1 and 15, S-1 80mg/m2 twice daily for 2weeks, followed by a 2-week rest). The primary end point was PFS. The noninferiority margin was 1.25; noninferiority would be established if the upper limit of the 95% confidence interval (CI) for the hazard ratio (HR) of the control group versus the experimental group was less than this margin.
Between June 2012 and September 2014, 487 patients underwent randomization. Two hundred and forty-three patients assigned to the control group and 241 assigned to the experimental group were included in the primary analysis. Median PFS was 10.8months (95% CI 9.6–11.6) in the control group and 14.0months (95% CI 12.4–15.5) in the experimental group (HR 0.84, 95% CI 0.70–1.02; P<0.0001 for noninferiority, P=0.0815 for superiority). One hundred and fifty-seven patients (64.9%) in the control group and 140 (58.6%) in the experimental group had adverse events of grade 3 or higher.
S-1 and irinotecan plus bevacizumab is noninferior to mFOLFOX6 or CapeOX plus bevacizumab with respect to PFS as first-line treatment of mCRC and could be a new standard treatment.
UMIN000007834
•Transient characterization of planar solid oxide fuel cell (SOFC) cell stack.•Attempting on the control of an electric current to assumed load changes.•Attempts on leveling the fuel utilization ...factor during the manipulation.•Discussion on overpotentials appearing in the transient response of the cell voltage.•Proper control of cell temperature eliminating the negative effect of overpotentials.
This paper presents the results of an experimental investigation of transient characterizations of 300W planar type Solid Oxide Fuel Cell (SOFC) cell stack during load change. It indicates the transient characterization obtained during a ramped electric current with a Current-Based Fuel Control (CBFC) strategy. The fuel utilization factor is chosen for a reference of the CBFC strategy and is kept constant to the ramping electric current. The fuel utilization factor can be described as a ratio of consumed fuel (expressed as a function with an applied electric current) to supplied fuel. For the simplification of discussion, hydrogen was used as fuel by mixing it with nitrogen in order to satisfy the constant gas residential time in all cases and instances. The transient response of the cell voltage obtained under several thermal conditions was shown for discussion. The effect of overpotentials, associated with the cell’s operating temperature, on the transient response of the cell voltage is primarily discussed. The paper indicates that reducing the fuel flow rate, namely, setting a higher set-point for the fuel utilization factor, may decrease the OCV, increase concentration polarization and finally degrade cell performance. This paper also pointed out the importance of operating temperature management on both improving the steady-state cell performance and eliminating the negative effect of the overpotentials that appear on the transient response of the cell voltage.
The phase II J003 (N = 169) and phase III RECOURSE (N = 800) trials demonstrated a significant improvement in survival with trifluridine (FTD)/tipiracil (TPI) versus placebo in patients with ...refractory metastatic colorectal cancer. This post hoc analysis investigated pharmacokinetic data of FTD/TPI exposure and pharmacodynamic markers, such as chemotherapy-induced neutropenia (CIN) and clinical outcomes.
A total of 210 patients from RECOURSE were enrolled in this substudy. A limited sampling approach was used, with three pharmacokinetic samples drawn on day 12 of cycle 1. Patients were categorized as being above or below the median area under the plasma concentration–time curve (AUC) for FTD and TPI. We conducted a post hoc analysis using the entire RECOURSE population to determine the correlations between CIN and clinical outcome. We then carried out a similar analysis on the J003 trial to validate the results.
In the RECOURSE subset, patients in the high FTD AUC group had a significantly increased CIN risk. Analyses of the entire population demonstrated that FTD/TPI-treated patients with CIN of any grade in cycles 1 and 2 had significantly longer median overall survival (OS) and progression-free survival (PFS) than patients who did not develop CIN and patients in the placebo group. Patients who required an FTD/TPI treatment delay had increased OS and PFS versus those in the placebo group and those who did not develop CIN. Similar results were obtained in the J003 cohort.
In RECOURSE, patients with higher FTD drug exposure had an increased CIN risk. FTD/TPI-treated patients who developed CIN had improved OS and PFS versus those in the placebo group and those who did not develop CIN. Similar findings were reported in the J003 cohort, thus validating the RECOURSE results. The occurrence of CIN may be a useful predictor of treatment outcomes for FTD/TPI-treated patients.
NCT01607957 (RECOURSE).
JapicCTI-090880 (J003).
•Patients with higher FTD exposure had a significantly increased risk of CIN.•In RECOURSE, FTD/TPI-treated patients who developed CIN had improved OS and PFS compared with placebo and those with no CIN.•Similar results from J003 validated the RECOURSE results.
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