MR-guided focused ultrasound liquid biopsy enriches circulating biomarkers in patients with brain tumors

BackgroundLiquid biopsy is promising for early detection, monitoring of response, and recurrence of cancer. The blood-brain barrier (BBB) limits the shedding of biomarker, such as cell-free DNA (cfDNA), into the blood from brain tumors, and their detection by conventional assays. Transcranial MR-guided focused ultrasound (MRgFUS) can safely and transiently open the BBB, providing an opportunity for less-invasive access to brain pathology. We hypothesized that MRgFUS can enrich the signal of circulating brain-derived biomarkers to aid in liquid biopsy.MethodsNine patients were treated in a prospective single-arm, open-label trial to investigate serial MRgFUS and adjuvant temozolomide combination in patients with glioblastoma ({"type":"clinical-trial","attrs":{"text":"NCT03616860","term_id":"NCT03616860"}}NCT03616860). Blood samples were collected as an exploratory measure within the hours before and after sonication, with control samples from non-brain tumor patients undergoing BBB opening (BBBO) alone ({"type":"clinical-trial","attrs":{"text":"NCT03739905","term_id":"NCT03739905"}}NCT03739905).ResultsBrain regions averaging 7.8 ± 6.0 cm³ (range 0.8-23.1 cm³) were successfully treated within 111 ± 39 minutes without any serious adverse events. We found MRgFUS acutely enhanced plasma cfDNA (2.6 ± 1.2-fold, P < .01, Wilcoxon signed-rank test), neuron-derived extracellular vesicles (3.2 ± 1.9-fold, P < .01), and brain-specific protein S100b (1.4 ± 0.2-fold, P < .01). Further comparison of the cfDNA methylation profiles suggests a signature that is disease- and post-BBBO-specific, in keeping with our hypothesis. We also found cfDNA-mutant copies of isocitrate dehydrogenase 1 (IDH1) increased, although this was in only one patient known to harbor the tumor mutation.ConclusionsThis first-in-human proof-of-concept study shows MRgFUS enriches the signal of circulating brain-derived biomarkers, demonstrating the potential of the technology to support liquid biopsy for the brain.     

Efficacy and safety of cabozantinib for patients with advanced hepatocellular carcinoma based on albumin-bilirubin grade

Background Albumin-bilirubin (ALBI) grade is an objective measure of liver function for patients with hepatocellular carcinoma (HCC). The tyrosine kinase inhibitor cabozantinib is approved for patients with advanced HCC who have received prior sorafenib based on the phase 3 CELESTIAL trial ({"type":"clinical-trial","attrs":{"text":"NCT01908426","term_id":"NCT01908426"}}NCT01908426). Cabozantinib improved overall survival (OS) and progression-free survival (PFS) versus placebo in patients with previously treated HCC.Methods Patients were randomised 2:1 to receive cabozantinib 60 mg or placebo orally every day. Clinical outcomes in patients with ALBI grade 1 or 2 at baseline were evaluated in CELESTIAL. ALBI scores were retrospectively calculated based on baseline serum albumin and total bilirubin, with an ALBI grade of 1 defined as  ≤ −2.60 score and a grade of 2 as a score of > −2.60 to  ≤ −1.39.Results Cabozantinib improved OS and PFS versus placebo in both ALBI grade 1 (hazard ratio [HR] [95% CI]: 0.63 [0.46–0.86] and 0.42 [0.32–0.56]) and ALBI grade 2 (HR [95% CI]: 0.84 [0.66–1.06] and 0.46 [0.37–0.58]) subgroups. Adverse events were consistent with those in the overall population. Rates of grade 3/4 adverse events associated with hepatic decompensation were generally low and were more common among patients in the ALBI grade 2 subgroup.Discussion These results provide initial support of cabozantinib in patients with advanced HCC irrespective of ALBI grade 1 or 2.Trial registration number ClinicalTrials.gov number, {"type":"clinical-trial","attrs":{"text":"NCT01908426","term_id":"NCT01908426"}}NCT01908426.Subject terms: Drug development, Hepatocellular carcinoma     

VinCaP: a phase II trial of vinflunine in locally advanced and metastatic squamous carcinoma of the penis

Background We investigated the first-line activity of vinflunine in patients with penis cancer. Cisplatin-based combinations are commonly used, but survival is not prolonged; many patients are unfit for such treatment or experience toxicity that outweighs clinical benefit.Methods Twenty-five patients with inoperable squamous carcinoma of the penis were recruited to a single-arm, Fleming–A’Hern exact phase II trial. Treatment comprised 4 cycles of vinflunine 320 mg/m², given every 21 days. Primary endpoint was clinical benefit rate (CBR: objective responses plus stable disease) assessed after 4 cycles. Seven or more objective responses or disease stabilisations observed in 22 evaluable participants would exclude a CBR of <15%, with a true CBR of >40% being probable.Results Twenty-two participants were evaluable. Ten objective responses or disease stabilisations were confirmed. CBR was 45.5%, meeting the primary endpoint; partial response rate was 27.3%. Seven patients received >4 cycles of vinflunine. Dose reduction or treatment delay was required for 20% of cycles. In all, 68% of patients experienced at least one grade 3 adverse event. Two deaths on treatment were not caused by disease progression.Conclusions Pre-specified clinical activity threshold was exceeded. Toxicity was in keeping with experience in other tumours. Vinflunine merits further study in this disease.Trial registration {"type":"clinical-trial","attrs":{"text":"NCT02057913","term_id":"NCT02057913"}}NCT02057913.Subject terms: Penile cancer, Penile cancer, Chemotherapy     

Impact of Iron-Deficiency Management on Quality of Life in Patients with Cancer: A Prospective Cohort Study (CAMARA Study)

BackgroundIron deficiency (ID) is very common in patients with solid tumors and may cause symptoms such as fatigue. However, its impact on clinical outcomes is poorly described. The aim of this prospective monocentric cohort study was to evaluate the evolution of quality of life (QoL) of these patients after iron supplementation.MethodsWe included patients treated for a solid tumor, which were diagnosed with a functional (ferritin <800 ng/mL) or absolute (ferritin <300 ng/mL) ID (transferrin saturation coefficient <20%). The primary endpoint was patients’ QoL evolution between baseline and intermediate visit, 15-30 days after initial intravenous iron supplementation, assessed by the Functional Assessment of Cancer Therapy-Anemia (FACT-An) scale. Secondary endpoints were the same assessment between baseline, intermediate, and final visit at 6 months and the evolution of functional capacities.ResultsFrom 02/2014 to 12/2016, 248 patients were enrolled, of whom 186 were included in the analyses, including 140/186 (75.3%) with absolute ID. Anemia was detected in 141/174 (81.0%) patients at baseline. The FACT-An scores improved significantly between inclusion and intermediate visit (P = .001) and also between the 3 times of evaluation (P < .001). The most improved dimensions were those assessing physical, emotional well-being, and fatigue. Patients who performed the functional tests in all 3 phases had a significant improvement in performance on the majority of tests.ConclusionThe supplementation of ID was associated with an improvement of the QoL and functional capacities in patients with cancer. A randomized control trial is necessary to confirm our results. Our findings underline the importance of supportive care, including screening for ID, in oncology.Clinical trial registration number{"type":"clinical-trial","attrs":{"text":"NCT03625661","term_id":"NCT03625661"}}NCT03625661.     

Safety and impact of dose reductions on efficacy in the randomised MONALEESA-2, -3 and -7 trials in hormone receptor-positive,HER2-negative advanced breast cancer

Background This pooled analysis of MONALEESA trials evaluated the safety of ribociclib plus endocrine therapy (RIB + ET) with a focus on dose reductions in first-line patients.Methods In the dose reduction analysis, data were pooled from MONALEESA-2 (all patients), MONALEESA-3 (patients receiving treatment as first-line ET) and MONALEESA-7 (patients receiving combination therapy with an NSAI as initial ET). Efficacy was analysed by ribociclib relative dose intensity (DI). Safety was analysed in all patients in the trials (except those receiving tamoxifen in MONALEESA-7) and those with/without ≥1 ribociclib dose reduction.Results Of 818 women who received first-line RIB + ET, 41.8% required ≥1 dose reduction due to AEs (most commonly, neutropenia). Median RIB relative DI in patients without and with dose reductions was 99.3% and 65.6% in MONALEESA-2, 98.4% and 67.8% in MONALEESA-3 and 98·0% and 66·3% in MONALEESA-7. Median PFS was 24.8, 24.9 and 29.6 months for patients who received ≤71% (30th percentile), 72–96% (60th percentile) and 97–100% (90th percentile) RIB relative DI, respectively. No new safety signals emerged in the pooled safety analysis.Conclusions This analysis provides reassuring data showing that the clinical benefit of RIB is preserved when dose modifications are undertaken to manage AEs.Trial registration MONALEESA-2 ({"type":"clinical-trial","attrs":{"text":"NCT01958021","term_id":"NCT01958021"}}NCT01958021) first posted October 8, 2013; MONALEESA-3 ({"type":"clinical-trial","attrs":{"text":"NCT02422615","term_id":"NCT02422615"}}NCT02422615) first posted April 21, 2015; MONALEESA-7 ({"type":"clinical-trial","attrs":{"text":"NCT02278120","term_id":"NCT02278120"}}NCT02278120) first posted October 29, 2014.Subject terms: Breast cancer, Cancer     

Roflumilast (Daliresp®) to reduce acute pulmonary events in fibrotic sarcoidosis: a multi-center,double blind,placebo controlled,randomized clinical trial

Background:Fibrotic sarcoidosis patients often have acute events of increased cough and sputum production. We evaluated the impact of roflumilast in fibrotic sarcoidosis patients with repeated episodes of increased cough and sputum.Methods:Sarcoidosis patients with pulmonary fibrosis and at least two acute episodes in the previous year were randomized to receive either roflumilast (ROF) or placebo (PLA) in a double blind, placebo controlled multi-center trial. Subjects were assessed initially and every three months for 12 months. At each visit, spirometry and health related quality of life questionnaires were completed. For each subject, the best forced expiratory volume at 1 second (FEV-1) was noted.Results:Of the 38 subjects who enrolled in the study, 28 subjects (14 in each group) received at least three months of treatment and 10 in each arm completing all 12 months of study. During the treatment, patients treated with ROF were less likely to have visits in which the FEV-1 was less than 90% of the best FEV-1 (Odds ratio=0.34 (0.16 to 0.76 95% confidence interval, p=0.0073). At the end of treatment with ROF, patients had a significant improvement in their KSQ LUNG (Initial visit: 45.3 ± 6.89 (Mean ± S.D.); Last visit: 52.6± 7.91, p<0.05) with no change for PLA treated patients.Conclusion:Patients treated with at least three months of roflumilast had fewer follow-up visits with an FEV-1 of less than 90% of best value. At the end of treatment, ROF treated patients had a better quality of life as assessed by KSQ LUNG.Clinical Trial Registration:{"type":"clinical-trial","attrs":{"text":"NCT01830959","term_id":"NCT01830959"}}NCT01830959     

Phase 1 studies comparing safety,tolerability, pharmacokinetics and pharmacodynamics of HLX01 (a rituximab biosimilar) to reference rituximab in Chinese patients with CD20-positive B-cell lymphoma

ObjectiveThis study aimed to compare the pharmacokinetic, pharmacodynamic and safety profiles of HLX01 (a rituximab biosimilar) and reference rituximab sourced from China (MabThera^®; rituximab-CN). MethodsHere we report the results of two phase 1 studies. In the phase 1a, open-label, dose-escalation study ({"type":"clinical-trial","attrs":{"text":"NCT03218072","term_id":"NCT03218072"}}NCT03218072, CTR20140400), eligible patients received 250, 375 and 500 mg/m² HLX01 sequentially at 7-day intervals, after confirming no dose-limiting toxicity (DLT). In the phase 1b, double-blind study ({"type":"clinical-trial","attrs":{"text":"NCT02584920","term_id":"NCT02584920"}}NCT02584920, CTR20140764), eligible patients were given a single dose of 375 mg/m² HLX01 or rituximab-CN. The primary endpoints included safety and tolerability parameters for the phase 1a and the area under the plasma concentration-time curve from time zero to day 91 (AUC_{0−91 d}) for the phase 1b study. Equivalence was concluded if 90% confidence interval (90% CI) for the geometric least squares mean ratio (GLSMR) fell in the pre-specified equivalence criteria (80%−125%). ResultsBetween June 20, 2014 and January 5, 2015, 12 patients were enrolled in the phase 1a study. The pharmacokinetics of HLX01 showed dose proportionality and accumulation to steady state. HLX01 was well tolerated, with no serious adverse events (AEs), discontinuations or DLTs. Between November 8, 2014 and August 13, 2015, 87 eligible patients were enrolled in the phase 1b study, including 43 who received HLX01 and 44 who were treated with rituximab-CN. The equivalence endpoint was met with GLSMR for AUC_{0−91 d} being 89.6% (90% CI: 80.4%−99.8%). AEs, anti-drug antibodies, and CD19+ and CD20+ B lymphocyte counts were similar between the HLX01 and rituximab-CN treatment groups. ConclusionsTreatment with HLX01 was safe and well tolerated in Chinese patients with B-cell lymphoma. HLX01 and rituximab-CN have similar pharmacokinetic, pharmacodynamic and safety profiles.     

Anlotinib vs placebo as third- or further-line treatment for patients with small cell lung cancer: a randomised,double-blind,placebo-controlled Phase 2 study

Background This study aimed to evaluate the efficacy and safety of anlotinib as a third-line and subsequent treatment for patients with small cell lung cancer (SCLC).Methods We conducted this Phase 2 trial at 11 institutions in China. Patients with pathologically confirmed SCLC who failed at least two lines of chemotherapy were enrolled. Subjects were randomly assigned in a 2:1 ratio to receive either anlotinib 12 mg orally once daily for 14 days every 3 weeks or placebo. The primary endpoint was progression-free survival (PFS).Results Between March 30, 2017 and June 8, 2018, a total of 82 and 38 patients were randomly assigned to receive anlotinib and placebo. The median PFS was significantly longer in the anlotinib group compared with the placebo group (4.1 months [95% confidence interval (CI), 2.8–4.2] vs 0.7 months [95% CI, 0.7–0.8]; hazard ratio (HR) 0.19 [95% CI, 0.12–0.32], p < 0.0001). Overall survival (OS) was significantly longer with anlotinib than placebo (7.3 months [95% CI, 6.1–10.3] vs 4.9 months [95% CI, 2.7–6.0]; HR 0.53 [95% CI, 0.34–0.81], p = 0.0029).Conclusions Anlotinib as a third-line or subsequent treatment for Chinese patients with SCLC showed improved PFS and OS than placebo with favourable safety profile.Clinical Trial Registration ClinicalTrials.gov, number {"type":"clinical-trial","attrs":{"text":"NCT03059797","term_id":"NCT03059797"}}NCT03059797.Subject terms: Tumour angiogenesis, Small-cell lung cancer     

Phase 1b/2 trial of tepotinib in sorafenib pretreated advanced hepatocellular carcinoma with MET overexpression

Background This Phase 1b/2 study evaluated tepotinib, a highly selective MET inhibitor, in US/European patients with sorafenib pretreated advanced hepatocellular carcinoma (aHCC) with MET overexpression.Methods Eligible adults had aHCC, progression after ≥4 weeks of sorafenib, and, for Phase 2 only, MET overexpression. Tepotinib was administered once daily at 300 or 500 mg in Phase 1b (‘3 + 3’ design), and at the recommended Phase 2 dose (RP2D) in Phase 2. Primary endpoints were dose-liming toxicities (DLTs; Phase 1b) and 12-week investigator-assessed progression-free survival (PFS; Phase 2).Results In Phase 1b (n = 17), no DLTs occurred and the RP2D was confirmed as 500 mg. In Phase 2 (n = 49), the primary endpoint was met: 12-week PFS was 63.3% (90% CI: 50.5–74.7), which was significantly greater than the predefined null hypothesis of ≤15% (one-sided binomial exact test: P < 0.0001). Median time to progression was 4 months. In Phase 2, 28.6% of patients had treatment-related Grade ≥3 adverse events, including peripheral oedema and lipase increase (both 6.1%).Conclusions Tepotinib was generally well tolerated and the RP2D (500 mg) showed promising efficacy and, therefore, a positive benefit–risk balance in sorafenib pretreated aHCC with MET overexpression.Trial Registration ClinicalTrials.gov: {"type":"clinical-trial","attrs":{"text":"NCT02115373","term_id":"NCT02115373"}}NCT02115373.Subject terms: Hepatocellular carcinoma, Molecularly targeted therapy     

A Phase Ib Study of Lucitanib (AL3810) in a Cohort of Patients with Recurrent and Metastatic Nasopharyngeal Carcinoma

BackgroundLucitanib is a novel multi-target inhibitor of FGFR1-3, VEGFR 1-3, and PDGFR α/β. Here, we evaluated the safety, tolerability, and preliminary efficacy of lucitanib in recurrent and metastatic nasopharyngeal carcinoma (RM-NPC).MethodsPatients with pretreated RM-NPC were randomly divided into two treatment arms: continuous or intermittent treatment. The primary endpoint was safety and tolerability. Secondary endpoints were objective response rate (ORR), disease control rate (DCR), and progression-free survival (PFS).ResultsOne hundred percent of patients in the continuous arm and 90% of patients in the intermittent arm had at least one treatment-related AE (TRAE). Grade ≥3 related TRAEs occurred in 5 patients in the continuous arm (5/10, 50%). No TRAEs grade >3 occurred in the intermittent arm. The ORR and DCR of the continuous arm was 20% and 90%, and the intermittent arm was 10% and 60%, respectively. All responses were observed by the first evaluation. The duration of response was more than 1 year, with two patients still on treatment with sustained response at more than 3 years.ConclusionLucitanib has promising clinical activity and tolerable safety profile in heavily pretreated patients with NPC. Patients who responded to lucitanib treatment generally achieved a long DoR. Lucitanib is now being evaluated in phase II/III studies.ClinicalTrials.gov identifier{"type":"clinical-trial","attrs":{"text":"NCT03260179","term_id":"NCT03260179"}}NCT03260179     

Efficacy and safety of larotrectinib in TRK fusion-positive primary central nervous system tumors

BackgroundLarotrectinib is a first-in-class, highly selective tropomyosin receptor kinase (TRK) inhibitor approved to treat adult and pediatric patients with TRK fusion-positive cancer. The aim of this study was to evaluate the efficacy and safety of larotrectinib in patients with TRK fusion-positive primary central nervous system (CNS) tumors.MethodsPatients with TRK fusion-positive primary CNS tumors from two clinical trials ({"type":"clinical-trial","attrs":{"text":"NCT02637687","term_id":"NCT02637687"}}NCT02637687, {"type":"clinical-trial","attrs":{"text":"NCT02576431","term_id":"NCT02576431"}}NCT02576431) were identified. The primary endpoint was investigator-assessed objective response rate (ORR).ResultsAs of July 2020, 33 patients with TRK fusion-positive CNS tumors were identified (median age: 8.9 years; range: 1.3–79.0). The most common histologies were high-grade glioma (HGG; n = 19) and low-grade glioma (LGG; n = 8). ORR was 30% (95% confidence interval [CI]: 16–49) for all patients. The 24-week disease control rate was 73% (95% CI: 54–87). Twenty-three of 28 patients (82%) with measurable disease had tumor shrinkage. The 12-month rates for duration of response, progression-free survival, and overall survival were 75% (95% CI: 45–100), 56% (95% CI: 38–74), and 85% (95% CI: 71–99), respectively. Median time to response was 1.9 months (range 1.0–3.8 months). Duration of treatment ranged from 1.2–31.3+ months. Treatment-related adverse events were reported for 20 patients, with grade 3–4 in 3 patients. No new safety signals were identified.ConclusionsIn patients with TRK fusion-positive CNS tumors, larotrectinib demonstrated rapid and durable responses, high disease control rate, and a favorable safety profile.     

CEA,CA19-9, circulating DNA and circulating tumour cell kinetics in patients treated for metastatic colorectal cancer (mCRC)

Background We previously reported that CEA kinetics are a marker of progressive disease (PD) in metastatic colorectal cancer (mCRC). This study was specifically designed to confirm CEA kinetics for predicting PD and to evaluate CA19-9, cell-free DNA (cfDNA), circulating tumour DNA (ctDNA) and circulating tumour cell (CTC) kinetics.Methods Patients starting a chemotherapy (CT) with pre-treatment CEA > 5 ng/mL and/or CA19.9 > 30 UI/mL were prospectively included. Samples were collected from baseline to cycle 4 for CEA and CA19-9 and at baseline and the sixth week for other markers. CEA kinetics were calculated from the first to the third or fourth CT cycle.Results A total of 192 mCRC patients were included. CEA kinetics based on the previously identified >0.05 threshold was significantly associated with PD (p < 0.0001). By dichotomising by the median value, cfDNA, ctDNA and CA19-9 were associated with PD, PFS and OS in multivariate analysis. A circulating scoring system (CSS) combining CEA kinetics and baseline CA19-9 and cfDNA values classified patients based on high (n = 58) and low risk (n = 113) of PD and was independently associated with PD (ORa = 4.6, p < 0.0001), PFS (HRa = 2.07, p < 0.0001) and OS (HRa = 2.55, p < 0.0001).Conclusions CEA kinetics alone or combined with baseline CA19-9 and cfDNA are clinically relevant for predicting outcomes in mCRC.Trial registration number {"type":"clinical-trial","attrs":{"text":"NCT01212510","term_id":"NCT01212510"}}NCT01212510.Subject terms: Colon cancer, Genetic markers     

Deleterious BRCA1/2 mutation is an independent risk factor for carboplatin hypersensitivity reactions

Background:

We tested the hypothesis that BRCA1/2 mutation carriers with ovarian cancer are at higher risk of carboplatin hypersensitivity reactions (HSRs).

Methods:

Medical records of women enrolled in two carboplatin+olaparib clinical trials ({"type":"clinical-trial","attrs":{"text":"NCT01237067","term_id":"NCT01237067"}}NCT01237067/{"type":"clinical-trial","attrs":{"text":"NCT01445418","term_id":"NCT01445418"}}NCT01445418) were reviewed. A maximum of eight cycles containing carboplatin were administered.

Results:

All women (N=87) had good performance status and end-organ function. Incidences of carboplatin HSR before enrolment and on study were 17% and 21%, respectively. Most patients who developed carboplatin HSR had a deleterious BRCA1/2 mutation (93%) vs 50% in patients without HSR (P<0.0001). Multivariable analysis accounting for potential confounding variables including age, history of allergies, and cumulative prior carboplatin cycles confirmed deleterious BRCA1/2 mutation as an independent risk factor for carboplatin HSR (odds ratio 13.1 (95% confidence interval 2.6–65.4), P=0.0017). Mutation carriers had onset of carboplatin HSR at lower cumulative exposure (P=0.003). No significant difference in outcome was observed on our study between patients with and without a history of HSR.

Conclusion:

Deleterious BRCA1/2 mutation increased susceptibility and shortened time to carboplatin HSR, independently of other reported factors. These data suggest that at-risk women should be counselled regarding likelihood, symptoms, and potential earlier onset of carboplatin HSRs.     

Olaparib plus bevacizumab as maintenance therapy in patients with newly diagnosed,advanced ovarian cancer: Japan subset from the PAOLA-1/ENGOT-ov25 trial

ObjectiveThe addition of maintenance olaparib to bevacizumab demonstrated a significant progression-free survival (PFS) benefit in patients with newly diagnosed, advanced ovarian cancer in the PAOLA-1/ENGOT-ov25 trial ({"type":"clinical-trial","attrs":{"text":"NCT02477644","term_id":"NCT02477644"}}NCT02477644). We evaluated maintenance olaparib plus bevacizumab in the Japan subset of PAOLA-1.MethodsPAOLA-1 was a randomized, double-blind, phase III trial. Patients received maintenance olaparib tablets 300 mg twice daily or placebo twice daily for up to 24 months, plus bevacizumab 15 mg/kg every 3 weeks for up to 15 months in total. This prespecified subgroup analysis evaluated investigator-assessed PFS (primary endpoint).ResultsOf 24 randomized Japanese patients, 15 were assigned to olaparib and 9 to placebo. After a median follow-up for PFS of 27.7 months for olaparib plus bevacizumab and 24.0 months for placebo plus bevacizumab, median PFS was 27.4 versus 19.4 months, respectively (hazard ratio [HR]=0.34; 95% confidence interval [CI]=0.11–1.00). In patients with tumors positive for homologous recombination deficiency, the HR for PFS was 0.57 (95% CI=0.16–2.09). Adverse events in the Japan subset were generally consistent with those of the PAOLA-1 overall population and with the established safety and tolerability profiles of olaparib and bevacizumab.ConclusionResults in the Japan subset of PAOLA-1 support the overall conclusion of the PAOLA-1 trial demonstrating that the addition of maintenance olaparib to bevacizumab provides a PFS benefit in patients with newly diagnosed, advanced ovarian cancer.Trial RegistrationClinicalTrials.gov Identifier: {"type":"clinical-trial","attrs":{"text":"NCT02477644","term_id":"NCT02477644"}}NCT02477644     

Apatinib plus S-1 for previously treated,advanced gastric or gastro-oesophageal junction adenocarcinoma: a phase 2, single-arm,prospective study

BackgroundThe current management of advanced gastric or gastro-oesophageal junction adenocarcinoma remains unsatisfactory. We investigated the efficacy and safety of the combination therapy of apatinib and S-1, considering the potential advantage of home-based treatment without hospital admission, in patients with platinum-refractory gastric or gastro-oesophageal junction adenocarcinoma.MethodsIn this open-label, single-arm, phase 2 trial, in each 21-day cycle, eligible patients received apatinib at an initial dose of 500 mg once daily continuously and S-1 at a dose of 40–60 mg twice daily on days 1–14 until the trail was discontinued disease progression, development of intolerable toxicity, or withdrawal of consent. The primary endpoints were progression-free survival. The secondary endpoints were objective response rates, disease control rates, and safety, and overall survival. This study was registered at ClinicalTrials.gov, {"type":"clinical-trial","attrs":{"text":"NCT04338438","term_id":"NCT04338438"}}NCT04338438.ResultsBetween April 2015 and May 2019, we included 37 patients with advanced gastric or gastro-oesophageal junction adenocarcinoma refractory to first-line platinum-containing therapy. At the data cutoff, the 6-month progression-free survival was 31.5%, the median progression-free survival and overall survival were 4.2 (95% CI: 3.50–4.90) months and 8.2 (95% CI: 4.69–11.71) months, respectively. Of 37 eligible patients, 8 (21.6%) patients reached objective responses, 31 (83.8%) patients reached disease control. Grade 3 or 4 adverse events occurred in 8 (21.6%) patients, including hand-foot syndrome, hypertension, and diarrhea, etc.ConclusionsThe combination of Apatinib and S-1 showed promising efficacy and manageable toxicity as a home-based, second-line therapy in patients with advanced gastric or gastro-oesophageal junction adenocarcinoma, especially for the elder patients with poor performance status.Trial Registration{"type":"clinical-trial","attrs":{"text":"NCT04338438","term_id":"NCT04338438"}}NCT04338438.     

Phase II trial of 7 days on/7 days off temozolmide for recurrent high-grade glioma

Background

A phase II trial was performed to evaluate the efficacy of a dose-dense, 7 days on/7 days off schedule of temozolomide for patients with recurrent high-grade gliomas (HGG).

Methods

Sixty patients with recurrent HGG received temozolomide at 150 mg/m²/day on days 1–7 and days 15–21 during each 4-week cycle. The primary endpoint was 6-month progression-free survival (PFS-6), with a secondary endpoint of overall survival (OS). A further exploratory objective included the investigation of whether methylation status of the O(6)-methylguanine-DNA methyltransferase (MGMT) promoter within tumor tissue predicted outcomes.

Results

Among patients with glioblastoma (n = 40), PFS-6 was 10% (95% CI, 3%–24%) with median OS of 21.6 weeks (95% CI, 16.9–30.6 weeks). PFS-6 for grade III glioma patients (n = 20) was 50% (95% CI, 27%–73%), and median OS was 100.6 weeks (95% CI, 67 weeks to not reached). There were trends towards longer PFS and OS with MGMT promoter methylation (log-rank test; P = .06 for PFS; P = .07 for OS). Additionally, bevacizumab-naïve glioblastoma patients had significantly longer PFS and OS (median PFS was 8.07 weeks [95% CI, 8 weeks to not reached] vs 7.57 weeks [95% CI, 7.29–8.29 weeks], log-rank test, P < .001; median OS was 62 weeks [26.1 weeks to not reached] vs 18.2 weeks [13.9–27.3 weeks], log-rank test, P < .001).

Conclusions

The dose-dense temozolomide regimen was well tolerated, although it has no significant activity in this population. Clinical trials.gov identified. {"type":"clinical-trial","attrs":{"text":"NCT00619112","term_id":"NCT00619112"}}NCT00619112 (available at http://clinicaltrials.gov/ct2/show/{"type":"clinical-trial","attrs":{"text":"NCT00619112","term_id":"NCT00619112"}}NCT00619112).     

Clinical features,neurologic recovery,and risk factors of postoperative posterior fossa syndrome and delayed recovery: a prospective study

BackgroundPosterior fossa syndrome (PFS) is a known consequence of medulloblastoma resection. Our aim was to clinically define PFS, its evolution over time, and ascertain risk factors for its development and poor recovery.MethodsChildren with medulloblastoma treated at St Jude Children’s Research Hospital from 6/2013 to 7/2019 received standardized neurological examinations, before and periodically after radiation therapy. Most (98.3%) were enrolled on the ongoing multi-institutional protocol (SJMB12; {"type":"clinical-trial","attrs":{"text":"NCT 01878617","term_id":"NCT01878617"}}NCT 01878617).ResultsSixty (34%) of 178 evaluated children had PFS. Forty (23%) had complete mutism (PFS1) and 20 (11%) had diminished speech (PFS2). All children with PFS had severe ataxia and 42.5% of PFS1 had movement disorders. By multivariable analysis, younger age (P = .0005) and surgery in a low-volume surgery center (P = .0146) increased PFS risk, while Sonic Hedgehog tumors had reduced risk (P = .0025). Speech and gait returned in PFS1/PFS2 children at a median of 2.3/0.7 and 2.1/1.5 months, respectively, however, 12 (44.4%) of 27 PFS1 children with 12 months of follow-up were nonambulatory at 1 year. Movement disorder (P = .037) and high ataxia score (P < .0001) were associated with delayed speech recovery. Older age (P = .0147) and high ataxia score (P < .0001) were associated with delayed gait return. Symptoms improved in all children but no child with PFS had normal neurologic examination at a median of 23 months after surgery.ConclusionsCategorizing PFS into types 1 and 2 has prognostic relevance. Almost half of the children with PFS1 with 12-month follow-up were nonambulatory. Surgical experience was a major modifiable contributor to the development of PFS.     

Erlotinib is effective in pancreatic cancer with epidermal growth factor receptor mutations: a randomized,open-label,prospective trial

Objective

To analyze the efficacy of gemcitabine with or without erlotinib for pancreatic cancer, and to determine the predictive role of epidermal growth factor receptor (EGFR) and KRAS mutations in these patients.

Methods

This was a single-center, randomized, open-label, prospective trial. Eighty-eight chemotherapy-naïve metastatic pancreatic cancer patients were randomized for treatment with gemcitabine or gemcitabine plus erlotinib. EGFR and KRAS mutations were analyzed, respectively. The primary endpoint was the disease control rate.

Results

Disease control rate (64% vs. 25%; P < 0.001), progression-free survival (median 3.8 vs. 2.4 months; P < 0.001), and overall survival (median 7.2 vs. 4.4 months; P < 0.001) were better in the gemcitabine plus erlotinib group than in the gemcitabine alone group. In the gemcitabine plus erlotinib group, disease control (85% vs. 33%; P = 0.001), progression-free survival (median 5.9 vs. 2.4 months; P = 0.004), and overall survival (median 8.7 vs. 6.0 months; P = 0.044) were better in patients with EGFR mutations than in those without EGFR mutations. KRAS mutation was not associated with treatment response or survival.

Conclusions

Gemcitabine plus erlotinib is more effective than gemcitabine alone for treating metastatic pancreatic cancer patients, especially those with EGFR mutations. ClinicalTrials.gov number, {"type":"clinical-trial","attrs":{"text":"NCT01608841","term_id":"NCT01608841"}}NCT01608841.     

A Randomized Controlled Trial for Doing vs. Omitting Intraoperative Frozen Section Biopsy for Resection Margin Status in Selected Patients Undergoing Breast-Conserving Surgery (OFF-MAP Trial)

PurposeIntraoperative frozen section biopsy is used to reduce the margin positive rate and re-excision rate and has been reported to have high diagnostic accuracy. A majority of breast surgeons in the Republic of Korea routinely perform frozen section biopsy to assess margins intraoperatively, despite its long turnaround time and high resource requirements. This study aims to determine whether omitting frozen section biopsy for intraoperative margin evaluation in selected patients is non-inferior to performing frozen section biopsy in terms of resection margin positivity rate.MethodsThis study is a phase III, randomized controlled, parallel-group, multicenter non-inferiority clinical trial. Patients meeting the inclusion criteria and providing written informed consent will be randomized to the “frozen section biopsy” or “frozen section biopsy omission” group after lumpectomy. Patients with clinical stage T1–T3 disease who are diagnosed with invasive breast cancer by core-needle biopsy and plan to undergo breast-conserving surgery will be included in this study. If a daughter nodule, non-mass enhancement, or microcalcification is identified on preoperative imaging, these features must be within 1 cm of the main mass for inclusion in the trial. The target sample size is 646 patients per arm. The primary endpoint will be the resection margin positive rate, and the secondary endpoints include the reoperation rate, operating time, residual cancer after reoperation, residual cancer after re-excision according to the frozen section biopsy result, resection volume, patient quality of life, and cost-effectiveness.DiscussionThis is the first randomized clinical trial utilizing frozen section biopsy for intraoperative margin evaluation and aims to determine the non-inferiority of omitting frozen section biopsy in selected patients compared to performing frozen section biopsy. We expect that this trial will help surgeons perform the procedure more efficiently while ensuring patient safety.Trial RegistrationClinicalTrials.gov Identifier: {"type":"clinical-trial","attrs":{"text":"NCT03975179","term_id":"NCT03975179"}}NCT03975179; Clinical Research Information Service Identifier: KCT0004606