In this first-in-human, Phase 1, open-label, multicenter study, we evaluated JNJ-64619178, a selective and potent PRMT5 inhibitor, in patients with advanced malignant solid tumors or non-Hodgkin ...lymphomas. The primary objective was to evaluate the safety and to identify a recommended Phase 2 dose (RP2D) of JNJ-64619178.
Adult patients with treatment-refractory advanced solid tumors or non-Hodgkin lymphomas and measurable disease received escalating doses of JNJ-64619178 following two schedules (Schedule A: 14 days on/7 days off; Schedule B: every day on a 21-day cycle). Safety, pharmacokinetics (PK), pharmacodynamics, and clinical activity were evaluated.
Ninety patients received JNJ-64619178. Thrombocytopenia was identified as the only dose-limiting toxicity. JNJ-64619178 showed dose-proportional PK and robust target engagement, as measured by plasma symmetric dimethylarginine, across all dose levels. The objective response rate was 5.6% (5 of 90). Patients with adenoid cystic carcinoma (ACC) had an ORR of 11.5% (3 of 26) and a median progression-free survival of 19.1 months.
JNJ-64619178 demonstrated manageable dose-dependent toxicity and preliminary evidence of antitumor activity in ACC and other tumor types. Plasma exposure was dose dependent, and target inhibition was maintained with intermittent and continuous dosing. Based on safety, clinical activity, PK, and PD findings, two provisional RP2Ds were selected: 1.5 mg intermittently and 1.0 mg once daily. Aside from ACC, clinical benefit was limited, and biomarkers to enrich for responsiveness to PRMT5 inhibition will be needed for further development.
Brigimadlin (BI 907828) is an oral MDM2-p53 antagonist that has shown encouraging antitumor activity in vivo. We present phase Ia results from an open-label, first-in-human, phase Ia/Ib study ...investigating brigimadlin in patients with advanced solid tumors (NCT03449381). Fifty-four patients received escalating doses of brigimadlin on day 1 of 21-day cycles (D1q3w) or days 1 and 8 of 28-day cycles (D1D8q4w). Based on dose-limiting toxicities during cycle 1, the maximum tolerated dose was selected as 60 mg for D1q3w and 45 mg for D1D8q4w. The most common treatment-related adverse events (TRAE) were nausea (74.1%) and vomiting (51.9%); the most common grade ≥3 TRAEs were thrombocytopenia (25.9%) and neutropenia (24.1%). As evidence of target engagement, time- and dose-dependent increases in growth differentiation factor 15 levels were seen. Preliminary efficacy was encouraging (11.1% overall response and 74.1% disease control rates), particularly in patients with well-differentiated or dedifferentiated liposarcoma (100% and 75% disease control rates, respectively).
We report phase Ia data indicating that the oral MDM2-p53 antagonist brigimadlin has a manageable safety profile and shows encouraging signs of efficacy in patients with solid tumors, particularly those with MDM2-amplified advanced/metastatic well-differentiated or dedifferentiated liposarcoma. Further clinical investigation of brigimadlin is ongoing. See related commentary by Italiano, p. 1765. This article is highlighted in the In This Issue feature, p. 1749.
Urothelial carcinoma remains a devastating disease with a poor prognosis. Though immune therapy with Bacillus Calmette–Guérin (BCG) has been used for localized bladder cancer for years, only ...immune-checkpoint blockade with antiprogrammed cell-death 1 (anti-PD-1) and antiprogrammed cell-death ligand 1 (anti-PD-L1) inhibitors have demonstrated improvement in survival of patients with metastatic disease. Anti-PD-L1 antibody, avelumab, was recently given United States Food and Drug Administration (FDA) accelerated approval for the treatment of recurrent/metastatic urothelial carcinoma after failure of first-line chemotherapy, marking the fifth immune checkpoint inhibitor to be given FDA approval for the treatment of metastatic urothelial cancer. The following manuscript will review avelumab, its pharmacology, and the clinical experience that has led to its approval, as well as future plans for clinical development of avelumab for the treatment or urothelial cancer.
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Lidocaine is widely used as a local anaesthetic in the clinical practice to manage pre- and post-operative pain, skin burns, etc. However, the short duration of action (< 2 h) of ...marketed dosage forms limit their ability to meet clinical needs. Herein, we prepared a lidocaine-tPP(tri potassium phosphate)-complex loaded microemulsion to achieve greater penetration, followed by destabilization of microemulsion in the skin layer to precipitate oil-complex to produce a depot effect in the skin for prolonging the effects of anaesthesia. The lidocaine-tPP-complex-microemulsion was compared with lidocaine base loaded microemulsion, marketed ointment USP and lidocaine HCl. The pseudo ternary phase diagrams at three Smix ratios (1:2, 1:3 and 1:4; Pluronic F127: PEG 400) were constructed using Capmul MCM C8 EP as oil phase. The Smix at 1:4 ratio showed large microemulsion area in comparison to 1:2 and 1:6 ratio. The lidocaine base (LD-1:4-ME10O45SM and LD-1:4-ME20O45SM) and lidocaine-tPP-complex (LDC-1:4-ME10O45SM and LDC-1:4-ME20O45SM) loaded microemulsion batches (1:4 ratio) were thermodynamically stable. The ex vivo diffusion study showed sustained release up to 12 h with microemulsion batches, in comparison to lidocaine HCl (4 h) and ointment base (7 h). The selected LDC-1:4-ME20O45SM batch was non-irritating on the rabbit skin. In drug retention studies, LD-1:4-ME20O45SM and LDC-1:4-ME20O45SM batches showed 2.68- and 3.93-fold greater lidocaine retention in comparison to ointment USP. The radiant heat tail-flick test showed prolong local anaesthesia using LDC-1:4-ME20O45SM in comparison to ointment USP. The findings suggest that lidocaine-tPP-complex loaded microemulsion could be a potential strategy for providing prolong local anaesthesia.
In preparation for the operations of the ExoMars Rosalind Franklin rover, characterising its landing site in Oxia Planum is essential. Of particular interest is the extensive Clay-bearing Unit ...present at the site, a key target in the search for biosignatures. In this paper we provide a map based on variations in colour and spectral information within this unit, covering the 1σ landing envelope of the rover along with a 1 km buffer to account for minor shifts of the landing envelope ahead of launch (referred to going forward as the 1σ+ landing envelope). We used imagery from the Colour and Stereo Surface Imaging System (CaSSIS) and High Resolution Imaging Science Experiment (HiRISE) instruments, along with CaSSIS Band Ratio Composites with enhanced colour sensitivity to the presence of ferric (Fe3+) and ferrous (Fe2+) iron bearing materials. Our map is of a far higher resolution (map-scale 1:2000) than those previously available and, in contrast to previously available maps of this unit, differentiates between an Orange Subunit and a Blue Subunit which make up the Clay-bearing Unit. This mapping covered the ∼91% of the 1σ+ landing envelope where there was CaSSIS coverage and split the Clay-bearing Unit into three categories: one for each of the clay subunits, and another for exposures of the Clay-bearing Unit where either both subunits were too intermixed to reliably separate, or where it was difficult to determine which of the two were present.
The results from our mapping shows that at least ∼35% of the 1σ+ envelope is covered by exposures of the Clay-bearing Unit: ∼18% by the Orange Subunit, ∼9% the Blue Subunit, and ∼12% were classified as Indeterminate. The spread of these two subunits varied substantially over the 1σ+ landing envelope, with the south-east half of the landing envelope dominated by the Orange Subunit (∼70% exposures in this area belonging to the Orange Subunit, ∼10% to the Blue Subunit and ∼20% to the Indeterminate category), while the north-west has more sporadic exposures of the Clay-bearing Unit (∼22% Orange, ∼37% Blue and ∼41% Indeterminate). The colour distinction between the two subunits is thought to be due to constituent mineralogical differences rather than differences in dust coverage of the two subunits. The scale of the fracturing present in the two subunits has also been assessed in this study, via qualitative observations of the fracture length and quantitative mapping out of fracture networks. While there were differences in the scale of fracturing between the two subunits, these were not as great as had previously been identified.
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•CaSSIS and HiRISE used to map clay unit at Oxia Planum, landing site of ExoMars.•This map distinguishes between two subunits which make up the clay-bearing unit.•Band ratio CaSSIS imagery aided distinguishing subunits by their Fe3+/Fe2+ content.•Potential causes of clay-bearing unit variation were assessed.•Fracturing present within two subunits was generally found to be indistinguishable.
AZD9496 is an oral nonsteroidal, small-molecule inhibitor of estrogen receptor alpha (ERα) and a potent and selective antagonist and degrader of ERα. This first-in-human phase I study determined the ...safety and tolerability of ascending doses of oral AZD9496 in women with estrogen receptor (ER)
/HER2
advanced breast cancer, characterized its pharmacokinetic (PK) profile, and made preliminary assessment of antitumor activity.
Forty-five patients received AZD9496 20 mg once daily (QD) to 600 mg twice daily (BID) in a dose-escalation, dose-expansion "rolling 6" design. Safety, tolerability, and PK activity in each cohort were reviewed before escalating to the next dose. PK was determined by mass spectrometry. Adverse events (AEs) were graded according to the Common Terminology Criteria for Adverse Events (CTCAE) v4.0. Objective tumor response was evaluated by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1.
Most common causally related AEs were diarrhea (35.6%), fatigue (31.1%), and nausea (22.2%), and seven patients had grade ≥3 AEs. Three patients experienced a dose-limiting toxicity: one each at 150 mg BID (abnormal hepatic function), 400 mg BID (diarrhea and elevated liver function tests), and 600 mg BID (diarrhea), and all were reversible. The maximum tolerated dose was not reached. Partial response was confirmed in one patient, who also had decreased tumor marker Ca15.3. Four patients had stable disease at 12 months' follow-up.
AZD9496 is well tolerated with an acceptable safety profile, showing evidence of prolonged disease stabilization in heavily pretreated patients with ER
/HER2
advanced breast cancer.
.
The habitable zone high in the atmosphere of Venus, defined here by the combination of high temperature and acidity, lies between 51 and 62km altitude and overlaps with the cloud layers. Here we ...study the hazard posed to this potential aerial biosphere by the ionising radiation of penetrating galactic cosmic rays (GCR) or extreme solar particle events (SPE) such as the 1859 Carrington Event and 775 AD event, modelled on the spectral shapes of the February 1956, August 1972 or October 1989 SPEs. Display omitted
•Venus aerial habitable zone defined as 62–51km altitude by acidity–heat combination.•Modelled radiation exposure from cosmic rays and extreme solar particle events of 1859 Carrington Event and 775 AD event.•Ionising radiation at top of habitable zone enhanced around 50,000× by modelled 775 AD event.•But total absorbed dose unlikely to pose survival hazard to venusian aerial life.•Companion paper models solar ultraviolet radiation penetration through habitable zone.
While the present-day surface of Venus is certainly incompatible with terrestrial biology, the planet may have possessed oceans in the past and provided conditions suitable for the origin of life. Venusian life may persist today high in the atmosphere where the temperature and pH regime is tolerable to terrestrial extremophile microbes: an aerial habitable zone. Here we argue that on the basis of the combined biological hazard of high temperature and high acidity this habitable zone lies between 51km (65°C) and 62km (−20°C) altitude. Compared to Earth, this potential venusian biosphere may be exposed to substantially more comic ionising radiation: Venus has no protective magnetic field, orbits closer to the Sun, and the entire habitable region lies high in the atmosphere – if this narrow band is sterilised there is no reservoir of deeper life that can recolonise afterwards. Here we model the propagation of particle radiation through the venusian atmosphere, considering both the background flux of high-energy galactic cosmic rays and the transient but exceptionally high-fluence bursts of extreme solar particle events (SPE), such as the Carrington Event of 1859 and that inferred for AD 775. We calculate the altitude profiles of both energy deposition into the atmosphere and the absorbed radiation dose to assess this astrophysical threat to the potential high-altitude venusian biosphere. We find that at the top of the habitable zone (62km altitude; 190g/cm2 shielding depth) the radiation dose from the modelled Carrington Event with a hard spectrum (matched to the February 1956 SPE) is over 18,000 times higher than the background from GCR, and 50,000 times higher for the modelled 775 AD event. However, even though the flux of ionising radiation can be sterilizing high in the atmosphere, the total dose delivered at the top of the habitable zone by a worst-case SPE like the 775 AD event is 0.09Gy, which is not likely to present a significant survival challenge. Nonetheless, the extreme ionisation could force atmospheric chemistry that may perturb a venusian biosphere in other ways. The energy deposition profiles presented here are also applicable to modelling efforts to understand how fundamental planetary atmospheric processes such as atmospheric chemistry, cloud microphysics and atmospheric electrical systems are affected by extreme solar particle events. The companion paper to this study, Constraints on a potential aerial biosphere on Venus: II. Solar ultraviolet radiation (Patel et al., in preparation), considers the threat posed by penetration of solar UV radiation. The results of these twin studies are based on Venus but are also applicable to extrasolar terrestrial planets near the inner edge of the circumstellar habitable zone.
Background
Microsatellite‐stable (MSS) colorectal cancer (CRC) tends to be poorly immunogenic, with limited treatment options. In MSS CRC xenograft models, trifluridine/tipiracil (FTD/TPI) plus ...programed death 1 inhibitors resulted in synergistic antitumor activity and increased tumor immunogenicity. This phase 2 study evaluated FTD/TPI plus nivolumab in patients with MSS metastatic CRC.
Methods
This single‐arm, safety lead‐in study used a Simon's two‐stage design (enrolling 6 patients in the safety lead‐in, proceeding to stage 2 if ≥2 of the first 15 patients achieved a partial or complete response per immune‐related response criteria irRC within 6 months). Patients with histologically proven MSS mCRC, and disease progression after ≥2 prior chemotherapy regimens received FTD/TPI (35 mg/m2 twice daily; days 1–5 and 8–12 every 28 days) plus nivolumab (3 mg/kg every 2 weeks).
Results
Between August 2016 and January 2017, 18 patients (50% men; median age 56.5 years) were enrolled; 72% had colon cancer and 56% had KRAS mutations. All patients received treatment (median, 2.5 cycles range, 1–8). No dose‐limiting toxicities were observed in the study. The most frequent adverse events (AEs) of any cause and grade were nausea (67%), diarrhea (61%), and neutropenia (50%); 13 patients (72%) experienced grade ≥3 AEs. No patients discontinued treatment because of AEs. No patient achieved a tumor response (either per Response Evaluation Criteria in Solid Tumors RECIST or irRC), and the study did not progress to the second stage. Stable disease was achieved in 8 patients per irRC and in 10 patients per RECIST. Median progression‐free survival was 2.2 months (95% CI, 1.8–6.0 months) per irRC and 2.8 months (95% CI, 1.8–5.1 months) per RECIST.
Conclusion
Patients with refractory MSS metastatic CRC failed to experience clinical benefit with FTD/TPI plus nivolumab, although safety data in this population indicated tolerability and feasibility of this combination.
Trial registration number
NCT02860546.
This phase 2 study utilized a Simon’s 2‐stage design to evaluate the combination of trifluridine/tipiracil (FTD/TPI) and nivolumab in patients with microsatellite‐stable (MSS) metastatic colorectal cancer (mCRC). Among 18 patients enrolled in the first stage, no clinical responses were observed with FTD/TPI plus nivolumab, and therefore, the study did not progress to the second stage. Patients with refractory MSS mCRC failed to experience clinical benefit with the FTD/TPI plus nivolumab combination, although safety data indicated that this combination was tolerable in these patients.
History and Applications of Dust Devil Studies Lorenz, Ralph D.; Balme, Matthew R.; Gu, Zhaolin ...
Space Science Reviews,
11/2016, Letnik:
203, Številka:
1-4
Journal Article, Book Review
Recenzirano
Odprti dostop
Studies of dust devils, and their impact on society, are reviewed. Dust devils have been noted since antiquity, and have been documented in many countries, as well as on the planet Mars. As ...time-variable vortex entities, they have become a cultural motif. Three major stimuli of dust devil research are identified, nuclear testing, terrestrial climate studies, and perhaps most significantly, Mars research. Dust devils present an occasional safety hazard to light structures and have caused several deaths.
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•Tailored microemulsion-gel for depot effect to treat psoriasis.•Target to improve permeability and cyclosporine retention using microemulsion.•Topical cyclosporine delivery will ...avoid systemic immunosuppression side effects.
Psoriasis is a widespread chronic disease affecting 1–3 % of total population. In major cases (>80 %), it is treated by topical application of corticosteroids. However, the topical route is very challenging due to physico-chemical nature of diseased stratum corneum and so no single treatment works for every patient. The oral route showed severe side effects due to systemic immunosuppression, which can be avoided by topical route. The aim of the research work was to investigate cyclosporine loaded microemulsion based gel for effective cyclosporine permeation and retention in the skin tissue for psoriasis treatment. The pseudo ternary phase diagram at three Smix ratios (2:1, 1:1, and 1:2; Tween 80: isopropyl alcohol) were constructed using isopropyl myristate as oil phase. The Smix at 2:1 ratio showed large microemulsion area. The transmission electron microscope images showed spherical non-aggregated oil globules with the size < 50 nm. The selected microemulsion (Cy-2-ME12O55SM) was incorporated in Carbopol 940 gel for topical application. The ex vivo diffusion study showed improved permeation (>24 h) with microemulsion-gel in comparison to cyclosporine suspension. The microemulsion-gel was non-irritating on the rabbit skin. In drug retention studies, microemulsion-gel showed high drug retention (trapping, 38.92 %) in the skin tissue, which was due to destabilization of microemulsion after penetration in the skin layer causing precipitation of cyclosporine. The depot effect due to cyclosporine precipitates could be helpful for sustained effect of cyclosporine for the effective treatment of psoriasis.
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