Pegbelfermin in Patients With Nonalcoholic Steatohepatitis and Stage 3 Fibrosis (FALCON 1): A Randomized Phase 2b Study.

BACKGROUND & AIMS: Pegbelfermin is a polyethlene glycol-conjugated analog of human fibroblast growth factor 21, a nonmitogenic hormone that regulates energy metabolism. This phase 2b study evaluated 48-week pegbelfermin treatment in patients with nonalcoholic steatohepatitis (NASH) and stage 3 (bridging) fibrosis. METHODS: The FALCON 1 study (NCT03486899) was a multicenter, randomized (1:1:1:1), double-blind, placebo-controlled study. Patients with biopsy-confirmed NASH and stage 3 fibrosis (N = 197) received weekly subcutaneous pegbelfermin (10, 20, or 40 mg) or placebo injections for 48 weeks. The week 24 primary endpoint was a ≥1-point decrease in fibrosis score without NASH worsening or NASH improvement without fibrosis worsening; pegbelfermin dose response was assessed using a Cochran-Armitage trend test across proportions (1-sided α = 0.05). Secondary/exploratory endpoints included histological and noninvasive measures of steatosis, fibrosis, and liver injury/inflammation. RESULTS: At week 24, the primary endpoint was met by 14% (placebo) vs 24%-31% (pegbelfermin arms); statistical significance was not reached due to lack of pegbelfermin dose response (P = .134). At weeks 24 and 48, more patients who received pegbelfermin had ≥30% relative reductions in hepatic fat fraction (magnetic resonance imaging-proton density fat fraction) vs placebo, although no differences reached statistical significance. In the pegbelfermin arms, improvements in liver fibrosis (magnetic resonance elastography and N-terminal type III collagen propeptide) and liver injury/inflammation (alanine aminotransferase, aspartate aminotransferase) were observed vs placebo. Adverse events occurred at similar frequencies across arms. No treatment-related serious adverse events were observed. CONCLUSIONS: The FALCON 1 study did not meet its primary endpoint; a ≥1-point decrease in fibrosis score without NASH worsening or NASH improvement without fibrosis worsening assessed via biopsy. Pegbelfermin was generally well tolerated during 48 weeks of treatment.

Pegbelfermin in Patients With Nonalcoholic Steatohepatitis and Compensated Cirrhosis (FALCON 2): A Randomized Phase 2b Study.

BACKGROUND & AIMS: Pegbelfermin is a polyethylene glycol-conjugated analog of human fibroblast growth factor 21, a nonmitogenic hormone that regulates energy metabolism. This phase 2b study evaluated 48-week pegbelfermin treatment in patients with nonalcoholic steatohepatitis (NASH) with compensated cirrhosis. METHODS: FALCON 2 (NCT03486912) was a randomized (1:1:1:1), double-blind, placebo-controlled study. Eligible adults had biopsy-confirmed NASH and stage 4 fibrosis. Pegbelfermin (10, 20, or 40 mg) or placebo was injected subcutaneously once weekly. The primary endpoint was 1 or more stages of improvement in the NASH Clinical Research Network fibrosis score without NASH worsening at week 48; pegbelfermin dose response was assessed using a Cochran-Armitage trend test across proportions (1-sided α = .05). Additional endpoints included histologic and noninvasive measures of steatosis, fibrosis, and liver injury/inflammation. RESULTS: Overall, 155 patients were randomized, and 154 patients received treatment. At week 48, 24% to 28% of the pegbelfermin arms had primary endpoint responses vs 31% of the placebo arm (P = .361). Nonalcoholic fatty liver disease activity score improvements were more frequent with pegbelfermin vs placebo and were driven primarily by reduced lobular inflammation. Numerically higher proportions of the pegbelfermin arms had liver stiffness (magnetic resonance elastography) and steatosis (magnetic resonance imaging-proton density fat fraction) improvements vs placebo; these differences were not statistically significant. Mean N-terminal type III collagen propeptide, alanine aminotransferase, and aspartate aminotransferase values were numerically lower in the 20- and/or 40-mg pegbelfermin arms compared with placebo. Serious adverse events were more frequent with pegbelfermin vs placebo, although none were treatment related. One patient (40-mg pegbelfermin) discontinued treatment because of a treatment-emergent adverse event (worsening ascites). CONCLUSIONS: FALCON 2 did not meet its primary endpoint of 1 or more stages of improvement in the NASH Clinical Research Network fibrosis without NASH worsening assessed via biopsy. Pegbelfermin generally was well tolerated in this advanced NASH population.

Pembrolizumab for previously treated advanced anal squamous cell carcinoma: results from the non-randomised, multicohort, multicentre, phase 2 KEYNOTE-158 study.

BACKGROUND: Outcomes in advanced anal squamous cell carcinoma are poor, with few treatment options and controlled clinical trials. We evaluated the efficacy and safety of pembrolizumab in patients with advanced anal squamous cell carcinoma (cohort A) from the phase 2 KEYNOTE-158 study. METHODS: Eligible patients enrolled in the ongoing non-randomised, multicohort, multicentre, phase 2 KEYNOTE-158 study, which was done across 38 centres worldwide, were aged 18 years or older; had histologically or cytologically confirmed advanced or metastatic anal squamous cell carcinoma; had previous failure of or intolerance to standard therapy or no standard therapy options; and had a PD-L1-evaluable tissue sample. Patients received pembrolizumab 200 mg intravenously every 3 weeks for 2 years, or until disease progression, unacceptable toxicity, investigator's decision to withdraw the patient from the study, or withdrawal of patient consent. The primary endpoint was objective response, as assessed by Response Evaluation Criteria in Solid Tumors version 1.1. Efficacy and safety analyses included all patients who received at least one dose of pembrolizumab. The trial is registered with ClinicalTrials.gov, NCT02628067. FINDINGS: Between March 3, 2016, and July 23, 2018, 163 patients were screened, of whom 112 were enrolled and treated in the anal cancer cohort. 91 (81%) patients were female, 104 (93%) had M1 disease, and 75 (67%) had PD-L1-positive tumours. The median time from first dose to data cutoff (June 27, 2019) was 34·7 months (IQR 32·5-36·4). 12 (11%, 95% CI 6-18) patients had an objective response, including 11 (15%, 8-25) of 75 patients with PD-L1-positive tumours and one (3%; 0-17) of 30 patients with PD-L1-negative tumours. 68 (61%) patients had treatment-related adverse events (20 [18%] patients had grade 3-4 adverse events), the most common of which were fatigue (17 patients), diarrhoea (13), hypothyroidism (13), and nausea (13). Serious treatment-related adverse events occurred in 12 (11%) patients. 25 (22%) patients had immune-mediated adverse events, and one (1%) had an infusion reaction. There were no treatment-related deaths. INTERPRETATION: Pembrolizumab monotherapy is a possible treatment option with a favourable benefit-risk ratio for patients with previously treated advanced anal squamous cell carcinoma who have no alternative satisfactory treatment options. FUNDING: Merck Sharp & Dohme.

Efficacy and safety of pembrolizumab in patients with advanced mesothelioma in the open-label, single-arm, phase 2 KEYNOTE-158 study.

BACKGROUND: Malignant pleural mesothelioma (MPM) has few treatment options. Pembrolizumab showed preliminary clinical benefit in programmed death ligand 1 (PD-L1)-positive MPM. We evaluated the efficacy and safety of pembrolizumab monotherapy in patients with previously treated MPM irrespective of PD-L1 status in the KEYNOTE-158 study. METHODS: The ongoing open-label, multicohort, single-arm, phase 2 KEYNOTE-158 study enrolled eligible adults (≥18 years) with MPM who had progression on or intolerance to standard therapy, Eastern Cooperative Oncology Group performance status 0-1, and biomarker-evaluable tumour samples. Individuals were enrolled from 35 academic facilities and community-based institutions across 14 countries in Australia, North America, Europe, and Asia. Participants received pembrolizumab 200 mg intravenously every 3 weeks for up to 35 cycles. The primary efficacy endpoint was objective response per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, based on radiological imaging every 9 weeks for the first year of the study and every 12 weeks thereafter and assessed by independent central review. Efficacy and safety were analysed in all patients who received at least one dose of pembrolizumab. This trial is registered with ClinicalTrials.gov, NCT02628067. FINDINGS: Patients were enrolled in the MPM cohort between Feb 9, 2016, and Aug 16, 2016. As of June 27, 2019, 118 patients had been enrolled and received at least one dose of pembrolizumab. Ten (8% [95% CI 4-15]) patients had an objective response. Median duration of objective response was 14·3 months (range 4·0 to 33·9+), and 60% of objective responses were ongoing at 12 months. Objective responses were observed in six (8%) of 77 patients with PD-L1-positive MPM (median response duration 17·7 months [range 5·8 to 33·9+]) and four (13%) of 31 patients with PD-L1-negative MPM (10·2 months [4·0-16·6]). Median overall survival was 10·0 months (95% CI 7·6-13·4) and median progression-free survival was 2·1 months (2·1-3·9). Treatment-related adverse events occurred in 82 (69%) of 118 patients and serious adverse events that were considered to be treatment-related occurred in 14 (12%) of 118 patients. 19 (16%) patients had grade 3-4 treatment-related events, and most common of these were colitis (three patients), hyponatraemia (three), and pneumonitis (two). One patient died from treatment-related apnoea. By the end of the trial, 113 (96%) patients had discontinued pembrolizumab and progressive disease was the most common reason for discontinuation. INTERPRETATION: Pembrolizumab showed durable antitumour activity and manageable toxicity in patients with advanced MPM, regardless of PD-L1 status. Our data support the programmed death 1 (PD-1) and PD-L1 pathway as a potential therapeutic target in some patients with previously treated mesothelioma but biomarkers that can effectively identify such patients are yet to be elucidated. FUNDING: Merck Sharp & Dohme Corp, a subsidiary of Merck & Co, Inc, Kenilworth, NJ, USA.

Efficacy, Safety and Steroid-sparing Effect of Topical Cyclosporine A 0.05% for Vernal Keratoconjunctivitis in Indian Children.

PURPOSE: To evaluate the efficacy, safety, and steroid-sparing effect of topical cyclosporine A (Cs A) 0.05% in patients with moderate to severe steroid dependent vernal keratoconjunctivitis (VKC). METHODS: A prospective, comparative, placebo controlled study was carried out on 68 VKC patients, with 34 patients treated with topical Cs A 0.05% and the remaining 34 with topical carboxymethyl cellulose 0.5% (placebo). Both groups also received topical loteprednol etabonate 0.5%. Symptom (itching, photophobia, tearing, and discharge) score, sign (tarsal and limbal papillae, corneal involvement, and conjunctival hyperemia) score, and drug score (steroid drop usage/day/eye) were recorded at baseline and each follow-up visit. The intraocular pressure (IOP) measurement and evaluation of any ocular side effects were carried out. RESULTS: Significant reduction in symptom score and sign score was seen in both groups. Cs A group significantly showed more reduction in symptom (P < 0.0001 in all follow-up visits) and sign (P < 0.0001 in all follow-up visits) scores compared to the placebo group. At day 7, mean steroid usage reduced from 4 to 3.44 ± 0.5 and 3.79 ± 0.4 in Cs A and placebo groups, respectively (P < 0.0001). Steroid drops completely stopped in 21 patients at day 60 in the Cs A group compared to none in the placebo group. No significant rise in IOP or any side effects were noted in either group. CONCLUSION: Topical Cs A 0.05% is effective and safe in patients with moderate to severe VKC with good steroid-sparing effect.

Pembrolizumab in Relapsed or Refractory Primary Mediastinal Large B-Cell Lymphoma.

PURPOSE: Patients with relapsed or refractory primary mediastinal large B-cell lymphoma (rrPMBCL) have a poor prognosis, and their treatment represents an urgent and unmet need. Because PMBCL is associated with genetic aberrations at 9p24 and overexpression of programmed cell death-1 (PD-1) ligands (PD-L1), it is hypothesized to be susceptible to PD-1 blockade. METHODS: In the phase IB KEYNOTE-013 (ClinicalTrials.gov identifier: NCT01953692) and phase II KEYNOTE-170 (ClinicalTrials.gov identifier: NCT02576990) studies, adults with rrPMBCL received pembrolizumab for up to 2 years or until disease progression or unacceptable toxicity. The primary end points were safety and objective response rate in KEYNOTE-013 and objective response rate in KEYNOTE-170. Secondary end points included duration of response, progression-free survival, overall survival, and safety. Exploratory end points included association between biomarkers and pembrolizumab activity. RESULTS: The objective response rate was 48% (7 complete responses; 33%) among 21 patients in KEYNOTE-013 and 45% (7 complete responses; 13%) among 53 patients in KEYNOTE-170. After a median follow-up time of 29.1 months in KEYNOTE-013 and 12.5 months in KEYNOTE-170, the median duration of response was not reached in either study. No patient with complete response experienced progression, including 2 patients with complete response for at least 1 year off therapy. Treatment-related adverse events occurred in 24% of patients in KEYNOTE-013 and 23% of patients in KEYNOTE-170. There were no treatment-related deaths. Among 42 evaluable patients, the magnitude of the 9p24 gene abnormality was associated with PD-L1 expression, which was itself significantly associated with progression-free survival. CONCLUSION: Pembrolizumab is associated with high response rate, durable activity, and a manageable safety profile in patients with rrPMBCL.

A Phase Ib Dose-Escalation Study of Encorafenib and Cetuximab with or without Alpelisib in Metastatic BRAF-Mutant Colorectal Cancer.

Preclinical evidence suggests that concomitant BRAF and EGFR inhibition leads to sustained suppression of MAPK signaling and suppressed tumor growth in BRAFV600E colorectal cancer models. Patients with refractory BRAFV600-mutant metastatic CRC (mCRC) were treated with a selective RAF kinase inhibitor (encorafenib) plus a monoclonal antibody targeting EGFR (cetuximab), with (n = 28) or without (n = 26) a PI3Kα inhibitor (alpelisib). The primary objective was to determine the maximum tolerated dose (MTD) or a recommended phase II dose. Dose-limiting toxicities were reported in 3 patients receiving dual treatment and 2 patients receiving triple treatment. The MTD was not reached for either group and the phase II doses were selected as 200 mg encorafenib (both groups) and 300 mg alpelisib. Combinations of cetuximab and encorafenib showed promising clinical activity and tolerability in patients with BRAF-mutant mCRC; confirmed overall response rates of 19% and 18% were observed and median progression-free survival was 3.7 and 4.2 months for the dual- and triple-therapy groups, respectively.Significance: Herein, we demonstrate that dual- (encorafenib plus cetuximab) and triple- (encorafenib plus cetuximab and alpelisib) combination treatments are tolerable and provide promising clinical activity in the difficult-to-treat patient population with BRAF-mutant mCRC. Cancer Discov; 7(6); 610-9. ©2017 AACR.See related commentary by Sundar et al., p. 558This article is highlighted in the In This Issue feature, p. 539.

A note on posterior predictive checks to assess model fit for incomplete data.

We examine two posterior predictive distribution based approaches to assess model fit for incomplete longitudinal data. The first approach assesses fit based on replicated complete data as advocated in Gelman et al. (2005). The second approach assesses fit based on replicated observed data. Differences between the two approaches are discussed and an analytic example is presented for illustration and understanding. Both checks are applied to data from a longitudinal clinical trial. The proposed checks can easily be implemented in standard software like (Win)BUGS/JAGS/Stan. Copyright © 2016 John Wiley & Sons, Ltd.

Frontal osteomyelitis presenting as upper eyelid ectropion: A cautionary tale.

Frontal osteomyelitis is a rare clinical entity that can occur as sequelae to frontal sinusitis, head trauma, as a postoperative complication following sinus surgery or due to haematogenous spread. It usually presents with a soft, fluctuant forehead swelling with pain and fever. Cicatricial ectropion is an extremely rare feature of frontal osteomyelitis. We present a young male patient presenting with cicatricial ectropion that occurred as the sole manifestation of an underlying frontal osteomyelitis. Extensive Medline search did not find any such reported case. We feel that frontal osteomyelitis should be kept in mind as a possible etiology when considering the differential diagnosis of cicatricial ectropion.

Bayesian model selection for incomplete data using the posterior predictive distribution.

We explore the use of a posterior predictive loss criterion for model selection for incomplete longitudinal data. We begin by identifying a property that most model selection criteria for incomplete data should consider. We then show that a straightforward extension of the Gelfand and Ghosh (1998, Biometrika, 85, 1-11) criterion to incomplete data has two problems. First, it introduces an extra term (in addition to the goodness of fit and penalty terms) that compromises the criterion. Second, it does not satisfy the aforementioned property. We propose an alternative and explore its properties via simulations and on a real dataset and compare it to the deviance information criterion (DIC). In general, the DIC outperforms the posterior predictive criterion, but the latter criterion appears to work well overall and is very easy to compute unlike the DIC in certain classes of models for missing data.

Peripapillary nerve fibre layer thickness and macular thickness in children with anisometropic amblyopia attending a referral centre in Eastern India.

To study the macular thickness and peripapillary nerve fibre layer thickness in children with anisometropic amblyopia, a prospective non-randomised case series study was undertaken among 39 children (25 boys and 14 girls) aged between 5 and 16 years. This study was carried out between January 2010 and April 2011. The peripapillary retinal nerve fibre layer (RNFL) thickness and macular layer thickness was measured using optical coherence tomography (OCT), the RNFL thickness and the macular layer thickness of the amblyopic eye was assessed and compared to the normal eye of the same subject. It was found that macular layer thickness in the amblyopic eye was greater than that of the macular thickness in the normal eye. The mean macular layer thickness in the amblyopic eyes was 229.589 microm with a standard deviation of -+/- 31.9149 microm. The mean macular layer thickness in the normal eyes of these children was 206.8717 microm with a standard deviation of +/- 28.490 microm, the p-value was 0.00141 which is much lesser than 0.005 and hence is strongly statistically significant. However the mean RNFL thickness in the amblyopic eye was 104.454 microm with a standard deviation of +/- 22.244 microm. The mean RNFL thickness of the normal eye was 108.2746 microm with a SD of +/- 19.370 microm. The p-value in this case being 0.4246 which is statistically insignificant. It is conducted that macular layer thickness is raised in the amblyopic eye of children with anisometropic amblyopia though the RNFL thickness is not.

Microparticulated anti-HIV vaginal gel: in vitro-in vivo drug release and vaginal irritation study.

The aim of this study was to develop and evaluate a Zidovudine (AZT)-loaded microparticulated bioadhesive vaginal gel (MBVG) in order to obtain a controlled releasing, safe gel delivery system. AZT microparticles (ZMPs) were evaluated for encapsulation efficiency, drug loading, surface morphology and in vitro drug release profiles and drug release mechanism and optimized. The optimized ZMPs were then encompassed in bioadhesive gel using different bioadhesive polymers and evaluated for the drug encapsulation efficiency, drug loading, in vitro and in vivo drug release profiles, drug release mechanism and vaginal irritancy study. From the dissolution data of ZMP4 and MBVG4 showed a zero-order diffusion pattern and Fickian diffusion case I transport mechanism in 24 and 36 h, respectively. On the basis of a pharmacokinetic study of MBVG4 (containing ZMP: Carbopol 1:4), it was found to have better bioavailability, larger AUC and T(max) in comparison to an oral pure suspension of AZT.

Study of alkaline phosphatase activity and DNA content of pterygium tissue showing its degenerative character.

A prospective, non-randomised, interventional case series study was designed among 127 specimens obtained from 100 consecutive patients presenting with primary pterygium attending the outpatient department of a teaching hospital in Kolkata, West Bengal between September 2009 and August 2010. After harvesting the pterygium it was transported in 10% formol saline for staining, fixing and embedding prior to evaluation of tissue alkaline phosphatase level and estimation of DNA content in nucleus of cells in pterygium tissue. The main outcome was to measure alkaline phosphatase activity and DNA content in pterygium tissue and normal bulbar conjunctiva along with histopathological staining and to see if any correlation exists between alkaline phosphatase activity and DNA content of pterygium tissue in different stages of evolution as suggested by histological staining. The elastic proliferation and hyaline degeneration are prominent in well developed pterygium. The alkaline phosphatase activity in all cases of pterygium is maximum and the DNA content of the cells of the pterygium tissue is diminished as compared to normal bulbar conjunctiva. Histopathological changes as evident from epithelial cell changes from cylindrical to flat cells with cyst formation in basal layers, the disappearance of nuclei in the submucosa coupled with increase in hyaline content of the tissue all point towards degenerative changes. Biochemically too there is a decrease in DNA content in the nuclei of the cells in pterygium, histochemically there is an increase in the alkaline phosphatase activity, all these changes point to pterygium being a degenerative tissue.

Photodynamic therapy for circumscribed choroidal haemangioma: a case report.

Choroidal haemangioma is a benign tumour with visual acuity diminution due to subretinal fluid accumulation. There are many modalities of treatment of this visually disabling syndrome, some of them being argon laser photocoagulation, cryotherapy, external beam irradiation, proton beam radiotherapy, episcleral plaque radiotherapy and transpupillary thermotherapy. Another new modality of treatment with remarkable success rate is photodynamic therapy. In this modality a photosensitiser is injected intravenously followed by irradiation of a specific wave length for a specified time period. The photosensitiser concentrates within the vascular channels and after irradiation these channels are irreversibly obliterated. A 62 years old female patient of choroidal haemangioma, who presented in eye outpatient department was treated with the standard protocol used for photodynamic therapy. On follow-up of this patient it was found that there was improvement in the visual acuity from 6/12 in the left eye (affected eye) to 6/9. Not only was there an improvement in the visual acuity but there was anatomical improvement too as was evident by regressed cystoid macular oedema and circumscribed choroidal haemangioma. After six months of follow-up there was no leakage of dye with digital fluorescein angiography and indocyanine green.