P863 KEYNOTE-022 parts 4 and 5: pembrolizumab plus trametinib for patients with solid tumors or BRAF wild-type melanoma

Background Pembrolizumab+dabrafenib+trametinib demonstrated promising antitumor activity and acceptable tolerability in BRAF-mutant melanoma in phase 1/2 KEYNOTE-022 parts 1 and 2 (NCT02130466). Pembrolizumab+dabrafenib+trametinib numerically prolonged PFS and DOR versus placebo+dabrafenib+trametinib but had a higher grade 3-5 TRAE rate in part 3. KEYNOTE-022 parts 4 and 5 evaluated pembrolizumab+trametinib. Methods In part 4 (open-label, 3+3 dose-finding) patients with advanced solid tumors (irrespective of BRAF status) or unresectable/metastatic BRAF wild-type melanoma received pembrolizumab 200 mg Q3W with trametinib as concurrent (2 or 4 weeks of trametinib run-in [1.5 or 2 mg QD], then pembrolizumab+trametinib [1.5 or 2 mg QD]) or intermittent dosing (2 weeks of trametinib run-in [1.5 or 2 mg QD], then pembrolizumab+trametinib [1.5 or 2 mg QD; 1 week off/2 weeks on]). Interim MTDs identified in part 4 were confirmed in part 5 using a modified toxicity probability interval design. The primary objectives were safety, tolerability, and ORR by investigator assessment per RECIST v1.1 of the maximum administered or tolerated dose (MAD/MTD) of pembrolizumab+trametinib. Safety was analyzed for all patients who received ≥1 dose of study drug; patients treated during the trametinib run-in who discontinued study before receiving pembrolizumab were included; patients who did not complete trametinib run-in or receive ≥66% of planned doses during the 6-week dose-limiting toxicity (DLT) evaluable period were not included for DLT evaluation. AEs were graded per NCI CTCAE v4. Results Of 42 enrolled patients, most were female (61.9%); median age was 55.0 years; 57.1% had received ≥2 prior lines of therapy. At database cutoff (June 26, 2019), median follow-up was 9.0 months (range, 1.4-25.6 months). Of 38 DLT-evaluable patients, 10 had DLTs (table 1). Dosing regimens were selected for confirmation in part 5 based on safety data. Any-grade TRAEs occurred in 39 (92.9%) patients; grade 3-4 TRAEs occurred in 19 (45.2%), none were grade 5. TRAEs led to discontinuation in 8 (19.0%) patients. Immune-mediated AEs occurred in 12 (28.6%) patients, most commonly severe skin reactions (n=6; 14.3%), pneumonitis (n=3; 7.1%), hypothyroidism (n=2; 4.8%). The MTD of concurrent pembrolizumab+trametinib was pembrolizumab 200 mg Q3W plus trametinib 1.5 mg with 2 weeks of trametinib run-in (ORR, 0/16; 0%) and the MTD of intermittent pembrolizumab+trametinib was pembrolizumab 200 mg Q3W plus trametinib 2 mg with 2 weeks of run-in (ORR, 4/15; 26.7%). Conclusions Both concurrent or intermittent pembrolizumab+trametinib dosing were feasible and the combination showed antitumor activity in patients with advanced solid tumors or advanced BRAF wild-type melanoma

A phase I study of the oral gamma secretase inhibitor R04929097 in combination with gemcitabine in patients with advanced solid tumors (PHL-078/CTEP 8575)

PURPOSE: To establish the recommended phase II dose of the oral γ-secretase inhibitor RO4929097 (RO) in combination with gemcitabine; secondary objectives include the evaluation of safety, tolerability, pharmacokinetics, biomarkers of Notch signaling and preliminary anti-tumor activity. METHODS: Patients with advanced solid tumors were enrolled in cohorts of escalating RO dose levels (DLs). Tested RO DLs were 20 mg, 30 mg, 45 mg and 90 mg. RO was administered orally, once daily on days 1-3, 8-10, 15-17, 22-24. Gemcitabine was administered at 1,000 mg/m(2) on d1, 8, and 15 in 28 d cycles. Dose limiting toxicities (DLTs) were assessed by CTCAE v4. Serial plasma was collected for RO (total and unbound) and gemcitabine pharmacokinetic analysis. Biomarkers of Notch signaling were assessed by immunohistochemistry in archival tissue. Antitumor activity was evaluated (RECIST 1.1). RESULTS: A total of 18 patients were enrolled to establish the recommended phase II dose. Of these, 3 patients received 20 mg RO, 7 patients received 30 mg RO, 6 patients received 45 mg RO and 2 patients received 90 mg RO. DLTs were grade 3 transaminitis (30 mg RO), grade 3 transaminitis and maculopapular rash (45 mg RO), and grade 3 transaminitis and failure to receive 75 % of planned RO doses secondary to prolonged neutropenia (90 mg); all were reversible. The maximum tolerated dose was exceeded at 90 mg RO. Pharmacokinetic analysis of both total and free RO confirmed the presence of autoinduction at 45 and 90 mg. Median levels of Notch3 staining were higher in individuals who received fewer than 4 cycles (p = 0.029). Circulating angiogenic factor levels did not correlate with time to progression or ≥ grade 3 adverse events. Best response (RECIST 1.1) was partial response (nasopharyngeal cancer) and stable disease > 4 months was observed in 3 patients (pancreas, tracheal, and breast primary cancers). CONCLUSIONS: RO and gemcitabine can be safely combined. The recommended phase II dose of RO was 30 mg in combination with gemcitabine 1,000 mg/m(2). Although RO exposure was limited by the presence of autoinduction, RO levels achieved exceeded the area under the concentration-time curve for 0-24 h (AUC(0-24)) predicted for efficacy in preclinical models using daily dosing. Evidence of clinical antitumor activity and prolonged stable disease were identified

Serendipitous discovery of a dying Giant Radio Galaxy associated with NGC 1534, using the Murchison Widefield Array

This article has been accepted for publication in Monthly Notices of the Royal Astronomical Society. © 2015 The Authors. Published by Oxford University Press on behalf of the Royal Astronomical Society.Recent observations with the Murchison Widefield Array at 185~MHz have serendipitously unveiled a heretofore unknown giant and relatively nearby ($z = 0.0178$) radio galaxy associated with NGC\,1534. The diffuse emission presented here is the first indication that NGC\,1534 is one of a rare class of objects (along with NGC\,5128 and NGC\,612) in which a galaxy with a prominent dust lane hosts radio emission on scales of $\sim$700\,kpc. We present details of the radio emission along with a detailed comparison with other radio galaxies with disks. NGC1534 is the lowest surface brightness radio galaxy known with an estimated scaled 1.4-GHz surface brightness of just 0.2\,mJy\,arcmin$^{-2}$. The radio lobes have one of the steepest spectral indices yet observed: $\alpha=-2.1\pm0.1$, and the core to lobe luminosity ratio is $Peer reviewe

Serendipitous discovery of a dying Giant Radio Galaxy associated with NGC 1534, using the murchison widefield array

Recent observations with the Murchison Widefield Array at 185 MHz have serendipitously unveiled a heretofore unknown giant and relatively nearby (z=0.0178) radio galaxy associated with NGC 1534. The diffuse emission presented here is the first indication that NGC 1534 is one of a rare class of objects (along with NGC 5128 and NGC 612) in which a galaxy with a prominent dust lane hosts radio emission on scales of ~700 kpc. We present details of the radio emission along with a detailed comparison with other radio galaxies with discs. NGC 1534 is the lowest surface brightness radio galaxy known with an estimated scaled 1.4-GHz surface brightness of just 0.2 mJy arcmin-2. The radio lobes have one of the steepest spectral indices yet observed: α = -2.1 ± 0.1, and the core to lobe luminosity ratio is <0.1 per cent. We estimate the space density of this low brightness (dying) phase of radio galaxy evolution as 7 × 10-7 Mpc-3 and argue that normal AGN cannot spend more than 6 per cent of their lifetime in this phase if they all go through the same cycle

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Characterization of the interaction of Escherichia coli O157:H7 intimin with a human colonic epithelial cell line, HCT-8

grantor: University of TorontoIntimin, the outer membrane protein encoded by the ' eaeA' gene, is essential for the production of attaching and effacing (A/E) lesions caused by enterohemorrhagic and enteropathogenic 'Escherichia coli' (EHEC and EPEC). Previous adherence assays utilized the cloned 3-kb EHEC 'eaeA' gene on a relatively large fragment of DNA (6.1-kb, Louie et al., 1993). Thus, it was unknown whether specific virulence genes downstream were required for intracellular processing, surface expression, or maintaining the proper conformation of intimin in the membrane. The studies presented here utilized the cloned 'eaeA' gene on a 3.5-kb fragment of DNA, in plasmid pMH34. In 'E. coli' JM101, pMH34 can be induced to express a much larger quantity of intimin than wild-type EHEC and EPEC strains. A method of preincubating HCT-8 cells with EHEC or EPEC 'eaeA' mutants was developed. By this method, it was determined that intimin alone, on the surface of JM101(pMH34), is functional for the production of A/E lesions when prior signaling is provided. Furthermore, the signaling functions of EHEC and EPEC are functionally homologous, and contribute to the latent period in A/E lesion formation. Secondly, intimin alone does not function as an initial adhesin in the context of the bacterial outer membrane. Metabolic labeling of bacteria for adherence assays indicated that the intimin specified by pMH34 provided only a three-fold increase in adherence to HCT-8 cells, compared to JM101 alone. Lastly, the polarized, human colonic epithelial cell line, HCT-8, was shown to be a relevant model of EHEC infection.M.Sc

Cobimetinib- and vemurafenib-induced granulomatous dermatitis and erythema induratum: A case report

Metastatic melanoma is an aggressive malignancy. Survival can be increased with the combination of BRAF and MEK inhibition. BRAF inhibitor-induced cutaneous toxicities can be attenuated with MEK inhibition. Here, we describe the first reported case of a patient with metastatic melanoma who developed granulomatous dermatitis and erythema induratum when treated with combination BRAF (vemurafenib) and MEK inhibitor (cobimetinib) therapy and discuss the clinical features and management of dermatologic side-effects secondary to BRAF +/– MEK inhibition

Chronic immune-related adverse events in patients with cancer receiving immune checkpoint inhibitors: a systematic review

Immune-related adverse events (irAEs) are toxicities resulting from use of immune checkpoint inhibitors (ICIs). These side effects persist in some patients despite withholding therapy and using immunosuppressive and immune-modulating agents. Little is known about chronic irAEs and they are felt to be rare. We performed a systematic review to characterize non-endocrine chronic irAEs reported in the literature and describe their management. Ovid MEDLINE and Embase databases were searched for reports of adult patients with solid cancers treated with ICIs who experienced chronic (&gt;12 weeks) non-endocrine irAEs. Patient, treatment and toxicity data were collected. Of 6843 articles identified, 229 studies including 323 patients met our inclusion criteria. The median age was 65 (IQR 56–72) and 58% were male. Most patients (75%) had metastatic disease and the primary cancer site was melanoma in 43% and non-small cell lung cancer in 31% of patients. The most common ICIs delivered were pembrolizumab (24%) and nivolumab (37%). The chronic irAEs experienced were rheumatological in 20% of patients, followed by neurological in 19%, gastrointestinal in 16% and dermatological in 14%. The irAE persisted for a median (range) of 180 (84–2370) days and 30% of patients had ongoing symptoms or treatment. More than half (52%) of patients had chronic irAEs that persisted for &gt;6 months. The ICI was permanently discontinued in 60% of patients and 76% required oral and/or intravenous steroids. This is the first systematic review to assess and report on moderate/severe chronic non-endocrine irAEs after treatment with ICI in the literature. These toxicities persisted for months-years and the majority required discontinuation of therapy and initiation of immunosuppression. Further research is needed to better understand chronic irAEs, which hold potential substantial clinical significance considering the expanded use of ICIs and their integration into the (neo)adjuvant settings

Runs of homozygosity and a cluster of vulvar cancer in young Australian Aboriginal women

Objective A cluster of vulvar cancer exists in young Aboriginal women living in remote communities in Arnhem Land, Australia. A genetic case–control study was undertaken involving 30 cases of invasive vulvar cancer and its precursor lesion, high-grade vulvar intraepithelial neoplasia (VIN), and 61 controls, matched for age and community of residence. It was hypothesized that this small, isolated population may exhibit increased autozygosity, implicating recessive effects as a possible mechanism for increased susceptibility to vulvar cancer. Methods Genotyping data from saliva samples were used to identify runs of homozygosity (ROH) in order to calculate estimates of genome-wide homozygosity. Results No evidence of an effect of genome-wide homozygosity on vulvar cancer and VIN in East Arnhem women was found, nor was any individual ROH found to be significantly associated with case status. This study found further evidence supporting an association between previous diagnosis of CIN and diagnosis of vulvar cancer or VIN, but found no association with any other medical history variable. Conclusions These findings do not eliminate the possibility of genetic risk factors being involved in this cancer cluster, but rather suggest that alternative analytical strategies and genetic models should be explored