For patients with recurrent SCLC, topotecan remains the only approved second-line treatment, and the outcomes are poor. CheckMate 032 is a phase 1/2, multicenter, open-label study of nivolumab or ...nivolumab plus ipilimumab in SCLC or other advanced/metastatic solid tumors previously treated with one or more platinum-based chemotherapies. We report results of third- or later-line nivolumab monotherapy treatment in SCLC.
In this analysis, patients with limited-stage or extensive-stage SCLC and disease progression after two or more chemotherapy regimens received nivolumab monotherapy, 3 mg/kg every 2 weeks, until disease progression or unacceptable toxicity. The primary end point was objective response rate. Secondary end points included duration of response, progression-free survival, overall survival, and safety.
Between December 4, 2013, and November 30, 2016, 109 patients began receiving third- or later-line nivolumab monotherapy. At a median follow-up of 28.3 months (from first dose to database lock), the objective response rate was 11.9% (95% confidence interval: 6.5–19.5) with a median duration of response of 17.9 months (range 3.0–42.1). At 6 months, 17.2% of patients were progression-free. The 12-month and 18-month overall survival rates were 28.3% and 20.0%, respectively. Grade 3 to 4 treatment-related adverse events occurred in 11.9% of patients. Three patients (2.8%) discontinued because of treatment-related adverse events.
Nivolumab monotherapy provided durable responses and was well tolerated as a third- or later-line treatment for recurrent SCLC. These results suggest that nivolumab monotherapy is an effective third- or later-line treatment for this patient population.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Purpose: To determine the safety, dose-limiting toxicity, maximum tolerated dose, and pharmacokinetic and pharmacodynamic profiles
of the novel hydroxamate histone deacetylase inhibitor belinostat ...(previously named PXD101) in patients with advanced refractory
solid tumors.
Experimental Design: Sequential dose-escalating cohorts of three to six patients received belinostat administered as a 30-min i.v. infusion on
days 1 to 5 of a 21-day cycle. Pharmacokinetic variables were evaluated at all dose levels. Pharmacodynamic measurements included
acetylation of histones extracted from peripheral blood mononuclear cells, caspase-dependent cleavage of cytokeratin-18, and
interleukin-6 levels.
Results: Forty-six patients received belinostat at one of six dose levels (150-1,200 mg/m 2 /d). Dose-limiting toxicities were grade 3 fatigue (one patient at 600 mg/m 2 ; one patient at 1,200 mg/m 2 ), grade 3 diarrhea combined with fatigue (one patient at 1,200 mg/m 2 ), grade 3 atrial fibrillation (one patient at 1,200 mg/m 2 ; one patient at 1,000 mg/m 2 ), and grade 2 nausea/vomiting leading to inability to complete a full 5-day cycle (two patients at 1,000 mg/m 2 ). The maximum tolerated dose was 1,000 mg/m 2 /d. I.v. belinostat displayed linear pharmacokinetics with respect to C max and AUC. The intermediate elimination half-life was 0.3 to 1.3 h and was independent of dose. Histone H4 hyperacetylation
was observed after each infusion and was sustained for 4 to 24 h in a dose-dependent manner. Increases in interleukin-6 levels
were detected following belinostat treatment. Stable disease was observed in a total of 18 (39%) patients, including 15 treated
for ≥4 cycles, and this was associated with caspase-dependent cleavage of cytokeratin-18. Of the 24 patients treated at the
maximum tolerated dose (1,000 mg/m 2 /d), 50% achieved stable disease.
Conclusions: I.v. belinostat is well tolerated, exhibits dose-dependent pharmacodynamic effects, and has promising antitumor activity.
To demonstrate the importance of using a combined genetic and functional approach to correctly interpret a genetic test for monogenic diabetes.
We identified three probands with a phenotype ...consistent with maturity-onset diabetes of the young (MODY) subtype GCK-MODY, in whom two potential pathogenic mutations were identified: R43H/G68D, E248 K/I225M, or G261R/D217N. Allele-specific PCR and cosegregation were used to determine phase. Single and double mutations were kinetically characterized.
The mutations occurred in cis (double mutants) in two probands and in trans in one proband. Functional studies of all double mutants revealed inactivating kinetics. The previously reported GCK-MODY mutations R43H and G68D were inherited from an affected father and unaffected mother, respectively. Both our functional and genetic studies support R43H as the cause of GCK-MODY and G68D as a neutral rare variant.
These data highlight the need for family/functional studies, even for previously reported pathogenic mutations.
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TPS9099
Background: The importance of intratumour heterogeneity (ITH) is increasingly recognised as a driver of cancer progression and survival outcome. However understanding how tumour ...clonal heterogeneity impacts upon therapeutic outcome is still an area of unmet clinical and scientific need. The TRACERx trial (NCT01888601), a prospective study of patients with radically resected primary non-small cell lung cancer (NSCLC), aims to define the evolutionary trajectories of lung cancer in both space and time through genetic analysis of multi-region and longitudinal tumour sampling. DARWIN II is an investigator initiated study for patients who are enrolled within the TRACERx trial, or who have multi-region sequencing of their primary disease, but subsequently relapse with metastatic disease. This study will examine the role of intra-tumour heterogeneity and predicted neo-antigens on the anti-tumour activity of anti-PDL1 immunotherapy. Methods: This multicentre non-randomised phase II molecularly stratified umbrella study will examine how clonal dominance and ITH influence outcomes after treatment, offering a unique opportunity to decipher mechanisms of resistance to immunotherapy with anti-PDL1. These data will help improve future study design by developing greater understanding of patient selection for immunotherapies in patients with NSCLC. The relationship between ITH and cfDNA/CTCs will also be explored in DARWIN II. The study arms: Arm 1: Patients either -1) without an actionable mutation and PDL1 positive or 2) without an actionable mutation and PDL1 negative following first line cytotoxic chemotherapy - Atezolizumab. Arm 2: BRAFV600 - Vemurafenib. Arm 3: ALK/RET gene rearrangement - Alectinib. Arm 4: Her2 Amplification - Trastuzumab Emtansine. Primary Outcome Measures: Progression free survival (PFS), defined as the period between the date of registration to the date of subsequent progression or death will be assessed according to: Neo-antigen burden, mutational burden, ITH as assessed using an ITH ratio index and genomic instability as assessed using a weighted genome instability index (wGII). Trial Sponsor: University College London. Clinical trial information: NCT02314481.
The maintenance of normal cellular growth and differentiation depends on the co-ordinated and precise regulation of gene expression. In cancer cells, epigenetic mechanisms, including DNA methylation ...and histone modifications, interact to repress transcription of genes which are crucial for suppression of tumour growth and sensitivity to cytotoxic therapies. Pharmacological reactivation of genes silenced in this way may lead to tumour growth delay and reversal of cytotoxic drug resistance. The work of this thesis has focused on the pharmacodynamic characterisation and optimisation of the use of the main epigenetic therapies currently undergoing clinical evaluation: the histone deacetylase inhibitors (HDACi) and the nucleoside DNA methyltransferase inhibitor decitabine (DAC). Information regarding isoform selectivity of the hydroxamic acid HDACi might offer mechanistic clues as well as allowing targeting of these drugs to appropriate tumour types. Semi-quantitative RT-PCR analysis of the expression of HDACs 1 to 11 identified correlations between HDAC7 expression and sensitivity to oxamflatin (p=0.004) and trichostatin A (p=0.009) and between HDAC2 expression and LAQ824 sensitivity (p=0.008). No other correlations were observed between the levels of expression of HDAC isoforms in a cell line (or group of cell lines clustered by HDAC expression) and that cell line or cluster's sensitivity to hydroxamate HDACi. These results suggest that whilst the hydroxamic acid HDACi might have some isoform selectivity, the overall picture is of pan-HDAC inhibition. Two hydroxamate HDACi of different in vitro potency, LAQ824 and PXD101, were characterised in terms of their effects on histone acetylation and protein expression as well as anti-tumour efficacy in preclinical models. LAQ824, the more potent HDACi in vitro, proved more toxic in vivo than PXD101 and, unlike PXD101, lacked a clear dose response relationship for both histone acetylation and anti-tumour efficacy. A phase 1 clinical trial of PXD101 demonstrated that PXD101 is safe and tolerable when administered to patients at doses which induce a biological response. Histone hyperacetylation was clearly demonstrated even at the starting dose of PXD101 (150mg/m2). The maximum tolerated dose was 1000mg/m2, the dose limiting toxicities being fatigue and atrial fibrillation. Correlative studies performed during this trial have shown that markers of drug-target interaction developed using pre-clinical models can predict biological effects in humans. Reversal of the epigenetic silencing caused by DNA methylation can be achieved both in vitro and in vivo by treatment with decitabine (DAC). Several studies have shown that reversal of methylation of key genes by DAC treatment in vitro can be enhanced by subsequent addition of an HDAC inhibitor. The use of an HDAC inhibitor in combination with a hypomethylating agent may therefore have therapeutic potential. The work of this project has shown for the first time in vivo that the addition of an HDACi to low, demethylating doses of DAC in human tumour xenografts can lead to enhanced gene expression. Depending on the time-point studied, the combination of DAC and an HDACi is up to 2-fold more effective than DAC alone in inducing re-expression of the epigenetically silenced gene MLH1 in human tumour xenografts without evidence of toxicity to the mice. MLH1 re-expression leads to reversal of the drug resistant phenotype. In addition to restoring drug sensitivity, adding DAC to a 5 day schedule of PXD101 led to enhanced reduction of tumour volume in xenografts compared with either drug alone. The maximum doses of DAC (3 x 5mg/kg) and PXD101 (40mg/kg) used in combination experiments were well below the equivalent maximum tolerated doses in humans. Combining these drugs in cancer patients might therefore be feasible. The A2780 ovarian cancer cell line and its cisplatin resistant derivative A2780/cp70 were used as a model of drug resistance associated with epigenetic silencing. Microarray studies of A2780/cp70 treated with DAC and/or PXD101 were compared with studies of untreated cells and the cisplatin sensitive parent line. A group of 45 genes was identified which appear to account for chemosensitivity. Further validation of these genes and investigation of their functions may permit new insight into mechanisms of drug resistance and may lead to the development of biomarkers which could be used in future trials of combined epigenetic therapies.
We have recently completed a 64-night spectroscopic monitoring campaign at the Lick Observatory 3 m Shane telescope with the aim of measuring the masses of the black holes in 12 nearby (z < 0.05) ...Seyfert 1 galaxies with expected masses in the range {approx}10{sup 6}-10{sup 7} M{sub sun} and also the well-studied nearby active galactic nucleus (AGN) NGC 5548. Nine of the objects in the sample (including NGC 5548) showed optical variability of sufficient strength during the monitoring campaign to allow for a time lag to be measured between the continuum fluctuations and the response to these fluctuations in the broad H{beta} emission, which we have previously reported. We present here the light curves for the H{alpha}, H{gamma}, He II {lambda}4686, and He I {lambda}5876 emission lines and the time lags for the emission-line responses relative to changes in the continuum flux. Combining each emission-line time lag with the measured width of the line in the variable part of the spectrum, we determine a virial mass of the central supermassive black hole from several independent emission lines. We find that the masses are generally consistent within the uncertainties. The time-lag response as a function of velocity across the Balmer line profiles is examined for six of the AGNs. We find similar responses across all three Balmer lines for Arp 151, which shows a strongly asymmetric profile, and for SBS 1116+583A and NGC 6814, which show a symmetric response about zero velocity. For the other three AGNs, the data quality is somewhat lower and the velocity-resolved time-lag response is less clear. Finally, we compare several trends seen in the data set against the predictions from photoionization calculations as presented by Korista and Goad. We confirm several of their predictions, including an increase in responsivity and a decrease in the mean time lag as the excitation and ionization level for the species increases. Specifically, we find the time lags of the optical recombination lines to have weighted mean ratios of {tau}(H{alpha}):{tau}(H{beta}):{tau}(H{gamma}):{tau}(He I):{tau}(He II) = 1.54:1.00:0.61:0.36:0.25. Further confirmation of photoionization predictions for broad-line gas behavior will require additional monitoring programs for these AGNs while they are in different luminosity states.
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