Phase II Study of Arginine Deprivation Therapy With Pegargiminase in Patients With Relapsed Sensitive or Refractory Small-cell Lung Cancer.

BACKGROUND: Pre-clinical studies indicated that arginine-deprivation therapy using pegylated arginine deiminase (pegargiminase, ADI-PEG 20) may be effective in patients with argininosuccinate synthetase 1 (ASS1)-deficient small-cell lung cancer (SCLC). PATIENTS AND METHODS: Patients were enrolled into either a 'sensitive' disease cohort (≥ 90 days response to first-line chemotherapy) or a 'refractory' disease cohort (progression while on chemotherapy or < 90 days afterwards or ≥ third-line treatment). Patients received weekly intramuscular pegargiminase, 320 IU/m2 (36.8 mg/m2), until unacceptable toxicity or disease progression. The primary endpoint was tumor response assessed by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 with secondary endpoints including tolerability, pharmacodynamics, and immunogenicity. RESULTS: Between January 2011 and January 2014, 22 patients were enrolled: 9 in the sensitive disease cohort and 13 in the refractory disease cohort. At a pre-planned interim analysis, the best overall response observed was stable disease in 2 patients in each cohort (18.2%). Owing to the lack of response and slow accrual in the sensitive disease cohort, the study was terminated early. Pegargiminase treatment was well-tolerated with no unexpected adverse events or discontinuations. CONCLUSION: Although pegargiminase monotherapy in SCLC failed to meet its primary endpoint of RECIST-confirmed responses, more recent molecular stratification, including MYC status, may provide new opportunities moving forward

The SuperCam Instrument Suite on the Mars 2020 Rover: Science Objectives and Mast-Unit Description

On the NASA 2020 rover mission to Jezero crater, the remote determination of the texture, mineralogy and chemistry of rocks is essential to quickly and thoroughly characterize an area and to optimize the selection of samples for return to Earth. As part of the Perseverance payload, SuperCam is a suite of five techniques that provide critical and complementary observations via Laser-Induced Breakdown Spectroscopy (LIBS), Time-Resolved Raman and Luminescence (TRR/L), visible and near-infrared spectroscopy (VISIR), high-resolution color imaging (RMI), and acoustic recording (MIC). SuperCam operates at remote distances, primarily 2-7 m, while providing data at sub-mm to mm scales. We report on SuperCam's science objectives in the context of the Mars 2020 mission goals and ways the different techniques can address these questions. The instrument is made up of three separate subsystems: the Mast Unit is designed and built in France; the Body Unit is provided by the United States; the calibration target holder is contributed by Spain, and the targets themselves by the entire science team. This publication focuses on the design, development, and tests of the Mast Unit; companion papers describe the other units. The goal of this work is to provide an understanding of the technical choices made, the constraints that were imposed, and ultimately the validated performance of the flight model as it leaves Earth, and it will serve as the foundation for Mars operations and future processing of the data.In France was provided by the Centre National d'Etudes Spatiales (CNES). Human resources were provided in part by the Centre National de la Recherche Scientifique (CNRS) and universities. Funding was provided in the US by NASA's Mars Exploration Program. Some funding of data analyses at Los Alamos National Laboratory (LANL) was provided by laboratory-directed research and development funds

ATIM-38. PHASE 2 STUDY TO EVALUATE THE CLINICAL EFFICACY AND SAFETY OF MEDI4736 (DURVALUMAB, DURVA) + BEVACIZUMAB (BEV) IN BEV-NAÏVE PATIENTS WITH RECURRENT GLIOBLASTOMA (GBM)

Abstract BACKGROUND Durva is a human IgG1 mAb against PD-L1. Blockade of PD-1/PD-L1 has shown benefit among solid tumors; data implicate PD-1/PD-L1 signaling as a significant contributor to immunosuppression in GBM. BEV is an approved angiogenesis inhibitor for recurrent GBM; angiogenesis inhibition may promote antitumor benefit of immunotherapies. A review showed that lower dose BEV resulted in longer PFS/OS than the standard. METHODS Ongoing Phase 2 open-label study (NCT02336165) evaluates safety and efficacy of durva (10mg/kg Q2W) in 5 GBM cohorts. Results are presented for Cohorts B2 (durva + BEV 10mg/kg Q2W) and B3 (durva +BEV 3mg/kg Q2W) in BEV-naïve recurrent GBM. Primary efficacy endpoint for Cohorts B2/B3 is 6-month progression-free survival (PFS6), by modified RANO per investigator assessment; secondary endpoints include safety/tolerability. Comparative benchmark for BEV in recurrent GBM is PFS6 of 42%. The null hypothesis (PFS6 ≤42%) was tested in Intent-to-Treat (ITT) population against the alternative hypothesis (PFS6 ≥62%). ITT includes patients receiving any dose of durva and having at least baseline and 1 post-baseline tumor assessment. Durva alone in Cohort B of this study demonstrated PFS6 of 20% (90% CI: 9.7, 33.0). RESULTS As of 02Apr2018, 33 patients were treated in each cohort (B2, male: 54.5%, median age: 57.0 [40–74] years; B3, male: 60.6%, median age: 54.0 [23–73] years). Most common treatment-related adverse events (TRAEs, in ≥4 [12.1%] patients in either cohort): fatigue, dysphonia, increased ALT, AST, amylase, or lipase, diarrhea, hypertension, arthralgia, headache, and proteinuria. Incidences of TRAEs by maximum CTCAE grade (Gr) ≥3 for Cohorts B2/B3 were Gr3: 24.2/6.1%; Gr4: 0/6.1%; and Gr5: 0/0%. Kaplan-Meier estimate for PFS6 (n=33 each): B2, 15.2% (80% CI: 8.2, 24.0); B3, 21.1% (80% CI: 12.4, 31.4); 3 patients in each cohort showed partial response. CONCLUSIONS The addition of durva to BEV did not improve on the outcome of durva alone

ATIM-12. PHASE 2 STUDY TO EVALUATE THE CLINICAL EFFICACY AND SAFETY OF MEDI4736 (DURVALUMAB [DUR]) IN PATIENTS WITH BEVACIZUMAB (BEV)-REFRACTORY RECURRENT GLIOBLASTOMA (GBM)

Abstract BACKGROUND GBM patients who progress on BEV, an approved angiogenesis inhibitor for recurrent GBM, have a dismal outcome with a median survival of &lt; 6&nbsp;months. DUR is a human IgG1 monoclonal Ab against PD-L1. METHODS This ongoing Phase 2 open-label study (NCT02336165) evaluates safety and efficacy of DUR (10&nbsp;mg/kg every 2 weeks [Q2W]) in 5 GBM cohorts. Results are presented for Cohort C (DUR + continuing BEV 10&nbsp;mg/kg Q2W in BEV-refractory recurrent GBM). The primary efficacy endpoint for Cohort C is overall survival at 6&nbsp;months (OS-6), based on modified RANO criteria by investigator assessment; secondary endpoints include safety/tolerability and progression-free survival (PFS). The Intent-to-treat population includes patients receiving any dose of DUR and having at least baseline and 1 post-baseline tumor assessment. RESULTS First patient treated: 24 Mar 2015; data cutoff: 15 Mar 2017. Cohort C completed enrollment of 22 patients (male: 63.6%; mean age: 54.8 [37–77] years; baseline ECOG PS0: 27.3%, PS1: 68.2%; baseline measurable lesions: 81.8%). Treatment-emergent adverse events (TEAEs) occurred in 19 (86.4%) patients and most commonly included neurologic events associated with GBM. Treatment-related AEs (TRAEs) occurred in 10 (45.5%) patients, and incidences by maximum CTCAE grade (Gr) were Gr1: 5 (22.7%); Gr2: 4 (18.2%); Gr3: 1 (4.5%; fatigue); and Gr4/5: 0 patients. Most common TRAEs (≥2 [9.1%] patients) were fatigue, increased ALT, constipation, and headache. All patients (n=22) were evaluable for efficacy: OS range, 0.9 - 51.6 weeks; 8 patients (36%) had OS ≥ 22 weeks; PFS range, 0.9 -24.4 weeks; 11 patients (50%) had PFS ≥ 8 weeks; 3 patients were still alive at cutoff date; OS-6 to follow. CONCLUSIONS DUR + continuing BEV therapy appears to be well tolerated and shows preliminary activity in BEV-refractory recurrent GBM. Further studies are warranted

Phase I/II study to evaluate systemic durvalumab + intraperitoneal (IP) ONCOS-102 in patients with peritoneal disease who have epithelial ovarian (OC) or metastatic colorectal cancer (CRC): Interim phase I clinical and translational results

3017 Background: Metastasis to the peritoneal cavity is associated with end-stage disease in many cancers, including OC and CRC, both of which exhibit poor responses to checkpoint inhibitors. Locoregional treatment with oncolytic viruses may be used to improve the efficacy of checkpoint inhibitors at both treated and distant tumor sites. This study evaluates the combination of IP-administered ONCOS-102, an oncolytic adenovirus encoding for granulocyte macrophage colony stimulating factor (GMCSF), with systemic durvalumab, an anti PD-L1 antibody, in patients with peritoneal disease who have histologically confirmed OC or metastatic CRC and have failed prior standard therapies. Methods: This ongoing Phase 1/2, open-label study (NCT02963831) evaluates safety and antitumor/biologic activity of durvalumab (1500 mg IV, every 4 weeks x 12) + ONCOS-102 (IP, weekly x 6); cyclophosphamide is given pre first ONCOS-102 dose. Phase 1 uses a 3+3 design to evaluate the ONCOS-102 dose (1 or 3 x 1011 VP) to be given with durvalumab. Phase 2 evaluates the activity of the combination using Simon’s 2-stage MINIMAX design. Safety, response rate by RECIST 1.1, and immunological effects in tumors were evaluated for Phase 1; the current abstract reports on the phase 1 results. Results: Enrollment opened 7 Sep 2017; data cutoff, 1 Nov 2019. There were 17 patients treated in Phase 1: 8 CRC, 9 ovarian; 94% female; median age, 56 [37-77] years; ECOG PS0, 47%; ECOG PS1, 53%. There were no DLTs. Grade 3 treatment-related AEs included hypokalemia (n = 2); anemia, myocarditis, increased GGT, and influenza like illness (n = 1 each). There were 4 deaths due to PD. One patient had durable confirmed partial response and remains on treatment > 1 year; 4 patients had stable disease as best overall response. Two patients remained on treatment at data cutoff. Analysis of pre- and on-treatment tumor biopsies revealed changes in the tumor-infiltrating immune cells and PD-L1 expression, including an increase in tumor-infiltrating CD8 T cells in 5 of 11 evaluable patients. Conclusions: Combination of durvalumab and IP ONCOS-102 was safe, and no DLTs were observed. Preliminary analyses demonstrate evidence of biologic and clinical activity. Phase 2 enrollment is ongoing. Clinical trial information: NCT02963831

Differential saliva-induced breakdown of starch filled protein gels in relation to sensory perception

In this study, the differential breakdown of protein gels containing four types of high and low cross-linked starch granules were studied. Susceptibility to saliva-induced breakdown of starch granules and the consequences of these for overall breakdown of the gel matrix were captured using a multiple extrusion cell (MEC). Gels filled with two types of starch were used for sensorial evaluation by a QDA panel and the mechanical impact of the starch granules on these latter gels was characterized using uniaxial compression measurements. These data were used to better understand differences in sensory mouth feel attributes. MEC measurements indicated that the low cross-linked starches were more susceptible to saliva-induced breakdown compared to their highly cross-linked counterparts. The sensory space of starch filled gels was divided into three dimensions. Protein content of the gel matrix determined one dimension, resulting in high sensory ratings for separating and slippery mouth feel. The distinction into the two other dimensions, one being dominated by grainy/spreadable/sticky and the other by crumbly/crumbly effort, originates mainly from different starch types used: larger starch granules from the low cross-linked potato starch were perceived as more grainy and gels filled with these granules were more spreadable with a lower rating for crumbly and crumbly effort. Surprisingly, in most cases ratings for firm for both starch types were more or less comparable, indicating that these granules behave as inert fillers in a rather similar way, as also suggested by compression measurements. This work indicates that low cross-linked potato starch displays a higher susceptibility for digestion by amylase present in saliva. This is possibly the reason for the larger spreadability and lower rating for crumbly effort of the gel containing this type of starch