Abstract
Background
VISTA and PD-1/PD-L1 are independent immune checkpoints. Preclinical studies demonstrate synergism with dual blockade of these pathways. CA-170 is an oral agent targeting both ...VISTA and PD-L1. A Phase I dose escalation study (NCT02812875) has shown acceptable safety up to 2400 mg total daily dosage. Early results from current Phase II have been presented previously (Proc. SITC 2018; P715).
Methods
The current phase II randomized patients with multiple tumor types (Head & Neck Cancer, Squamous-NSCLC, Non-Squamous-NSCLC, MSI-H+ solid tumors and Hodgkin Lymphoma) to 400mg versus 800mg. Key eligibility included: age ≥ 18 years, ECOG ≤1, adequate organ function, no previous exposure to IO agents and 1-3 lines of prior therapy. Primary objective is response rate assessment by a central radiologist. Secondary endpoints include additional efficacy and safety endpoints.
Results
The study enrolled 62 IO-naïve patients over 8 months, from February through October 2018. Efficacy population included 15 non-squamous NSCLC patients, who had received a median of 2 lines of prior therapy. Additionally, median time from diagnosis was ∼ 14 months, and much higher than 8-9 months in earlier 2nd line IO antibody trials in NSCLC. Eight and seven patients, respectively, received 400 and 800 mg. Demographics and baseline characteristics of both groups are similar. While none of the non-squamous NSCLC patients achieved 30% cut-off for response by RECIST, six had tumor reductions, up to 20%. Analyzed by dose groups, CBR and median PFS were 75% and 19.5 weeks in the 400 mg group versus 50% and 7.9 weeks in the 800 mg group. Superior efficacy at 400mg was also observed in other tumor types. The AEs and SAEs have been as expected without any concerns or major events.
Conclusions
Excellent CBR and PFS have been observed at 400 mg. Superior effects at 400 mg versus 800 mg dosage may likely be due to a bell-shaped response curve, previously noted in pre-clinical studies with possible activation-induced T cell death at higher doses. CA-170 also appears to have significant safety benefit, compared to IO antibodies. These data position oral IO agents such as CA-170 for evaluation in adjuvant and/or maintenance settings in non-squamous NSCLC.
Legal entity responsible for the study
Aurigene Discovery Technologies Limited.
Funding
Aurigene Discovery Technologies Limited.
Disclosure
All authors have declared no conflicts of interest.
Abstract
Background
Patients with inflammatory bowel diseases (IBD) have lower bone mineral density (BMD). However, BMD does not reflect bone micro-structure/geometry, nor indicates the intrinsic ...properties of bone tissue. The trabecular bone score (TBS) delivers an indirect measurement of bone microarchitecture and predicts fracture risk independent of bone density. The aim of this study was to assess if patients with IBD present with lower TBS vs a healthy control (HC) population and to identify variables associated with lower TBS.
Methods
This prospective cohort study included patients with active Crohn’s disease (CD) or ulcerative colitis (UC) and a matched HC group. Patients with ostomies, short gut or known endocrine co-morbidities associated with low BMD, patients with osteoporosis on pharmacologic therapy were excluded. L1-L4 TBS and BMD parameters were determined by dual-energy X-ray absorptiometry (DXA) using a GE Lunar iDXA scan and TBS iNsight™ and GE enCORE™. Other collected variables included demographics, disease phenotype, laboratories (25-OH vitamin D 25OHD and parathyroid hormone levels PTH), disease activity (c-reactive protein CRP, simple endoscopic score SES-CD in CD, and endoscopic Mayo score EMS in UC). IBD severity was stratified based on endoscopy: mild (EMS=1 in UC or SES-CD=3–6), moderate (EMS=2 or SES-CD=7–15) and severe (EMS=3 or SES-CD>15). The primary outcome was the L1-L4 TBS. Secondary outcomes were left total and neck femoral BMD and the L1-L4 region BMD.
Results
A total of 141 patients were included (115 IBD and 26 HC). Patients with IBD had significantly lower TBS, femoral and L1-L4 BMD and Z-Scores when compared to controls (Figure 1). Endoscopic disease activity was not associated with TBS (Figure 2) or total/neck femur and L1-L4 BMD and Z-scores (p>0.05 for all). When stratifying levels by 25OHD quartiles, patients with 25OHD ≥28 ng/mL (the highest 50th percentile of the study population) had significantly higher TBS Z-scores when compared to those with 25OHD ≤28 ng/mL (0.3 -0.2 – 1.1 vs -0.1 -1.1 – 0.5, p=0.002). No associations were seen between TBS Z-scores and use of steroids, gender, type of IBD (UC vs CD), smoking status or when comparing females 50 years or older vs the rest of the group (p>0.05 for all). Moreover, there were no differences in TBS between patients who did or did not engage in resistance exercises (p=0.22) and/or regular aerobic exercises (RAPA ≥6) (p=0.84).
Conclusion
Patients with IBD present with lower TBS Z-scores when compared to HC and there is no correlation with disease activity. The only variable associated with lower TBS was a 25OHD <28 ng/mL. Further studies looking at the implications of these findings are warranted.
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FIGURE 2
This multicenter, double-blind, randomized study compared the efficacy, pharmacokinetics (PKs)/pharmacodynamics (PDs), safety and immunogenicity profile of RTXM83 vs. reference rituximab ...(R-rituximab), both with CHOP, as first-line treatment of diffuse large B-cell lymphoma (DLBCL). A total of 272 patients <65 years of age, with good prognosis (136 per arm) were randomized (1:1) to receive six cycles of either RTXM83 or R-rituximab. The primary efficacy endpoint was achieved (overall response rate of 83.6% for RTXM83 and 82.9% for R-rituximab) with a difference 0.7% between arms (95%CI: -8.77% to 10.17%) fulfilling the predefined non-inferiority margin (-13%). Similar number of patients reported at least one adverse event (AE) (131 per arm) or one serious AE (47 with RTXM83 and 45 with R-rituximab). Anti-drug antibody development was comparable between the arms. PK/PD secondary endpoint results support similarity between the compounds. RTXM83 exhibits non-inferior efficacy and similar safety/immunogenicity to R-rituximab, being an accessible alternative for the treatment of patients with previously untreated DLBCL.
C3 glomerulopathy has recently been described as a distinct entity. The underlying mechanism is unregulated activation of the alternate pathway of the complement system. The most common presentation ...is with an acute nephritic syndrome. The diagnosis is made on immunofluoroscence by the presence of isolated or dominant C3 staining. In this retrospective study, renal biopsy data were collected from 2010 to 2013 patients with C3 glomerulopathy identified and their clinical and biochemical parameters analyzed. Out of 514 biopsies available for analysis, the incidence of C3 glomerulopathy was 1.16% (n = 6). The mean age of the presentation was 26 years and the average estimated glomerular filtration rate was 30.65 ml/min/1.73 m(2). The most common histopathological pattern was membranoproliferative glomerulonephritis (n = 4).
The self-assembly of 3-hydroxyphenalenone (3-HPLN) on the Ag(111) surface has been studied with scanning tunneling microscopy and first-principles computations. The prochiral 3-HPLN molecule forms ...zipper-like chains when deposited on the Ag(111) surface, representing a 2D analog of their arrangement in bulk crystals. Upon annealing, local chiral trimer motifs form and serve as building blocks in extended 2D supramolecular networks not observed in 3D crystals. The extended network is porous and is held together via weak van der Waals interactions. The dispersion forces between trimers suggest that their handedness is overall racemic, but the asymmetric packing of 3-HPLN trimers around the pores leads to a chiral network. The offset alignment of neighboring 3-HPLN molecules in the unit cell resembles the offset between neighboring particles that are seen in the most efficient packings of rounded triangles. Computations illustrate that charge is transferred from the Ag(111) surface to the lowest unoccupied orbital of 3-HPLN, and a number of networks (including a honeycomb, as well as an alternative close-packed arrangement) are investigated.
•3-HPLN forms locally chiral trimers on the Ag(111) surface upon annealing.•The trimers self-assemble into networks which are chiral at the space group level.•Two trimers form an asymmetric unit cell which results in the porous chiral network.•Rotational entropy may be important in promoting the asymmetric packing.
Abstract Objectives Various drugs are effective in the management of painful diabetic neuropathy, but none is completely satisfactory. The objective of this study is to test the effectiveness and ...safety aspect of glyceryl trinitrate (GTN) in the management of painful diabetic neuropathy as a nitric oxide (NO) donor with local vasodilating properties in spray form. Design Randomized double blind placebo controlled cross-over study. Methods Fifty patients with painful diabetic neuropathy (type 2) were screened consecutively, out of which two were excluded (1 with HbA1 c > 11 and one withdrew his consent). The remaining 48 were given either drug (group A) or placebo (group B) in the first phase. After thorough clinical assessment in the first phase, quantitative assessment of pain was done by McGill Pain Questionnaire, Visual Analogue Score, Present Pain Intensity and 11 point Lickerts Scale, at the beginning and after 4 weeks, followed by 2 weeks wash out period and thereafter receiving 4 weeks of cross-over regimen. Adverse drug effects were assessed periodically. Results Of the 48 patients, five dropped out, two in group A and three in group B. Both groups A and B experienced significant improvement in pain score in their drug phase of trial, when compared to placebo phase of other group ( p < 0.001). After crossing over the treatment arm, patients of group B observed significant improvement in all pain scores compared to group A ( p < 0.001). The numbers needed to treat (NNT) calculated on VAS as pain parameters came out to be 4. The drug was well tolerated by all the patients except palpitation and headache for some days in five patients. Conclusion GTN spray, a well tolerated drug, provides significant improvement in painful diabetic neuropathy. These data provide a basis for future trials for longer duration in a larger group of patients.
We report recurrent hypokalemic periodic quadriparesis in a 30-year-old woman. Patient had also symptoms of multiple large and small joint pain, recurrent oral ulceration, photosensitivity and hair ...loss that were persisting since last 6 months and investigations revealed systemic lupus erythematosus (SLE) with distal tubular acidosis. Our patient was successfully treated with oral potassium chloride, sodium bicarbonate, hydroxychloroquine and a short course of steroids. Thus, tubular dysfunction should be carefully assessed in patients with SLE.
Background: Various drugs are effective in the management of painful diabetic neuropathy, but none is completely satisfactory. We previously found sodium valproate to be effective and safe in a ...short-term study. Aim: To test the effectiveness and safety of sodium valproate in the management of painful diabetic neuropathy over 3 months. Design: Randomized double-blind placebo-controlled study. Methods: Consecutive attending patients with type 2 diabetes mellitus with painful neuropathy were asked to participate in the trial: 48 agreed. Five were excluded: three with HbA1c > 11, one with too low a pain level and one who withdrew consent. The remaining 43 were given either drug (group A) or placebo (group B). Each patient was assessed clinically. Quantitative assessment of pain was done by McGill Pain Questionnaire, Visual Analogue Score and Present Pain Intensity, at the beginning of the study, after 1 month and after 3 months. Motor and sensory nerve conduction velocities were measured initially and after 3 months. Liver function tests and other adverse drug-related effects were assessed periodically. Results: Of the 43 patients, four dropped out: one in group A and three in group B. There was significant improvement in pain score in group A, compared to group B, at 3 months (p < 0.001). Changes in electrophysiological data were not significant. The drug was well-tolerated by all patients, except one, who had raised serum AST and ALT levels after 1 month of treatment, and whose treatment was discontinued. Discussion: Sodium valproate is well-tolerated, and provides significant subjective improvement in painful diabetic neuropathy.
The life of distribution transformers depends on creep phenomenon of winding conductors especially in power deficient areas and poor power distribution networks. The creep strain in winding ...conductors more than the specified clearance between adjacent windings causes fault hence failure of the distribution transformer. In this paper, the creep life of both aluminum and copper wound distribution transformers is calculated using experimental creep results of winding conductors. The effect of frequent switching is also calculated and observed experimentally on the creep life of the distribution transformers.
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