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Purpose: The PARP inhibitor rucaparib is approved in the United States for patients with metastatic castration-resistant prostate cancer (mCRPC) and a deleterious germline and/or somatic BRCA1 or BRCA2 (BRCA) alteration. While sequencing of tumor tissue is considered the standard for identifying patients with BRCA alterations (BRCA+), plasma profiling may provide a minimally invasive option to select patients for rucaparib treatment. Here, we report clinical efficacy in patients with BRCA+ mCRPC identified through central plasma, central tissue, or local genomic testing and enrolled in TRITON2. Patients and Methods: Patients had progressed after next-generation androgen receptor–directed and taxane-based therapies for mCRPC and had BRCA alterations identified by central sequencing of plasma and/or tissue samples or local genomic testing. Concordance of plasma/tissue BRCA status and objective response rate and prostate-specific antigen (PSA) response rates were summarized. Results: TRITON2 enrolled 115 patients with BRCA+ identified by central plasma (n = 34), central tissue (n = 37), or local (n = 44) testing. Plasma/tissue concordance was determined in 38 patients with paired samples and was 47% in 19 patients with a somatic BRCA alteration. No statistically significant differences were observed between objective and PSA response rates to rucaparib across the 3 assay groups. Patients unable to provide tissue samples and tested solely by plasma assay responded at rates no different from patients identified as BRCA+ by tissue testing. Conclusions: Plasma, tissue, and local testing of mCRPC patients can be used to identify men with BRCA+ mCRPC who can benefit from treatment with the PARP inhibitor rucaparib.

Purpose: Comprehensive genomic profiling (CGP) is of increasing value for patients with metastatic castration-resistant prostate cancer (mCRPC). mCRPC tends to metastasize to bone, making tissue biopsies challenging to obtain. We hypothesized CGP of cell-free circulating tumor DNA (ctDNA) could offer a minimally invasive alternative to detect targetable genomic alterations (GA) that inform clinical care. Experimental Design: Using plasma from 3,334 patients with mCRPC (including 1,674 screening samples from TRITON2/3), we evaluated the landscape of GAs detected in ctDNA and assessed concordance with tissue-based CGP. Results: A total of 3,129 patients (94%) had detectable ctDNA with a median ctDNA fraction of 7.5%; BRCA1/2 was mutated in 295 (8.8%). In concordance analysis, 72 of 837 patients had BRCA1/2 mutations detected in tissue, 67 (93%) of which were also identified using ctDNA, including 100% of predicted germline variants. ctDNA harbored some BRCA1/2 alterations not identified by tissue testing, and ctDNA was enriched in therapy resistance alterations, as well as possible clonal hematopoiesis mutations (e.g., in ATM and CHEK2). Potential androgen receptor resistance alterations were detected in 940 of 2,213 patients (42%), including amplifications, polyclonal and compound mutations, rearrangements, and novel deletions in exon 8. Conclusions: Genomic analysis of ctDNA from patients with mCRPC recapitulates the genomic landscape detected in tissue biopsies, with a high level of agreement in detection of BRCA1/2 mutations, but more acquired resistance alterations detected in ctDNA. CGP of ctDNA is a compelling clinical complement to tissue CGP, with reflex to tissue CGP if negative for actionable variants. See related commentary by Hawkey and Armstrong, p. 2961

This retrospective celebrates The Clearing House centennial year of publishing and a reminiscence of what authors and readers valued in their teaching practice. The work here considers a 1974 artic...

18 Background: TRITON3 (NCT02975934) is a randomized, multicenter, open-label, phase 3 study of rucaparib vs physician’s choice (docetaxel [DTX], abiraterone [ABI] or enzalutamide [ENZ]) in patients (pts) with chemotherapy-naïve mCRPC with BRCA1/2 (BRCA) or ATM alterations. It was previously reported that rucaparib significantly improved the primary endpoint of radiographic progression-free survival (rPFS) vs physician’s choice in pts with BRCA or ATM alterations. We report here the interim overall survival (OS) and also report on efficacy of rucaparib compared individually with either DTX or ABI/ENZ. Methods: Pts had disease progression after 1 prior second-generation androgen pathway inhibitor therapy in any setting and were randomized 2:1 to rucaparib 600 mg BID or physician’s choice of DTX, ABI or ENZ. An ordered step-down multiple comparisons procedure was used to control the overall error rate. OS was a key secondary endpoint with rPFS as the primary endpoint tested first in the BRCA subgroup, then the intent-to-treat (ITT) population. Subgroup analyses based on physician’s choice were exploratory. Results: As of August 25, 2022, 302 pts with BRCA and 103 pts with ATM alterations were randomized. OS maturity was 54% in the BRCA subgroup and 59% in the ITT population. rPFS and OS are shown. The most frequent treatment-emergent adverse event (TEAE) in the rucaparib, DTX and ABI/ENZ groups was asthenia/fatigue (61.1%, 67.6% and 57.6%, respectively). The most frequent grade ≥3 TEAE in the rucaparib, DTX and ABI/ENZ groups was anemia (23.7%), neutropenia (14.1%), and hypertension (10.2%), respectively. Conclusions: Rucaparib significantly improved rPFS vs either DTX or ABI/ENZ; safety was consistent with prior reports. Interim OS results suggest a trend towards improvement for rucaparib vs DTX or ABI/ENZ in pts with mCRPC and BRCA alterations. Clinical trial information: NCT02975934 . [Table: see text]

Summary Rucaparib, a poly(ADP-ribose) polymerase inhibitor, is licensed for use in recurrent ovarian, fallopian tube, or primary peritoneal cancer. We characterized the absorption, distribution, metabolism, and elimination of rucaparib in 6 patients with advanced solid tumors following a single oral dose of [14C]-rucaparib 600 mg (≈140 μCi). Total radioactivity (TRA) in blood, plasma, urine, and feces was measured using liquid scintillation counting. Unchanged rucaparib concentrations in plasma were determined using validated liquid chromatography with tandem mass spectrometry. Maximum concentration (Cmax) of TRA and unchanged rucaparib in plasma was 880 ng Eq/mL and 428 ng/mL, respectively, at approximately 4 h post dose; terminal half-life was >25 h for both TRA and rucaparib. The plasma TRA-time profile was parallel to yet higher than that of rucaparib, suggesting the presence of metabolites in plasma. Mean blood:plasma ratio of radioactivity was 1.0 for Cmax and 0.8 for area under the concentration-time curve from time zero to infinity. Mean postdose recovery of TRA was 89.3% over 12 days (71.9% in feces; 17.4% in urine). Unchanged rucaparib and M324 (oxidative metabolite) were the major components in plasma, contributing to 64.0% and 18.6% of plasma radioactivity, respectively. Rucaparib and M324 were the major rucaparib-related components (each ≈7.6% of dose) in urine, whereas rucaparib was the predominant component (63.9% of dose) in feces. The high fecal recovery of unchanged rucaparib could be attributed to hepatic excretion and/or incomplete oral absorption. Overall, these data suggest that rucaparib is eliminated through multiple pathways, including metabolism and renal and biliary excretion. Electronic supplementary material The online version of this article (10.1007/s10637-019-00815-2) contains supplementary material, which is available to authorized users.

This chapter explores the ubiquity of sound-from recording machines to DJ performances-to examine how a remix-based approach to sound in DH can provide tools for understanding sound as foundational to research and new knowledge creation. It examines how DJs remix archives and outline DJ methodology: an approach that mixes different sources to form new patterns of remixed thought. The chapter looks at sound studies and remix in relation to digital humanities, outlying exemplary work in the field before turning attention to the author's own work as a scholar and DJ working at the intersections of music, sound, and literature. It outlines some of the innovative and important cultural work being done at Vancouver Island University and at the Innovation Lab, including work with visiting poets, recording Indigenous elders, and three dimensional printing a sounding gramophone-an appropriate meeting of the past dialoguing with the present.

Background: Relapsed and refractory myeloid malignancies including myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) remain a clinical challenge due to high mortality, morbidity, and lack of effective therapeutic agents. PLX2853 is an orally available, non-benzodiazepine bromodomain and extraterminal domain (BET) inhibitor that exhibits low nanomolar potency and a modest preference for binding to the second of the double bromodomains of the BET proteins. By regulating genes (e.g., BCL2 and MYC) central to leukemic cell proliferation and survival, PLX2853 has demonstrated broad anti-leukemic activity both as a single agent and in combination with other agents in preclinical models. The pharmacokinetic (PK) profiles in patients with solid tumors revealed high peak plasma concentrations, a short terminal half-life (T 1/2 < 3 hour), and nearly complete elimination from the plasma by 9 hours post dose. This PK profile is hypothesized to improve tolerability by allowing transient target engagement followed by time for recovery after daily dosing. Methods: This is an open-label, Phase 1b dose-escalation study of PLX2853 as a single agent, administered with oral daily dosing for 21-day cycles in adult patients with relapsed or refractory (R/R) AML or high risk MDS. A modified continuous reassessment model with overdose control was used to guide dose escalation decisions and determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D). Primary objectives include safety and PK. Secondary objectives include measures of preliminary efficacy, and exploratory objectives include pharmacodynamic biomarker assessments. Results: Fourteen patients with R/R AML and 8 patients with high risk MDS (median age 69 years, range 47 - 79 years; median number of prior therapies 2, range 1-7) received PLX2853 in escalating doses from 20 to 180 mg QD. Through the data cut-off of 30 Jun 2021 (n=22), the most common treatment emergent adverse events (AEs) regardless of causality occurring in ≥20% of patients (n≥5) are: fatigue (n=14), nausea (n=13), decreased appetite (n=13), anemia (n=10), diarrhea (n=10), vomiting (n=9), hypokalemia (n=9), international normalized ratio increased (n=8), hyperglycemia (n=8), hypophosphatemia (n=8), peripheral edema (n=7), blood bilirubin increased (n=7), dyspnea (n=7), febrile neutropenia (n=6), constipation (n=6), sepsis (n=6), hypoalbuminemia (n=6), hyponatremia (n=6), insomnia (n=6), proteinuria (n=6), and hypertension (n=6). Two dose limiting toxicities (DLTs) were observed at the two highest doses: G3 and G4 hyperbilirubinemia at 180 mg QD and 140 mg QD respectively. The MTD is 140 mg QD and the RP2D, determined on the totality of data in this study and the companion phase 1 study in solid tumors (NCT03297424), is 80 mg QD. The median time to reach maximal PLX2853 plasma concentration (T max) is 1 hour, with no accumulation observed at steady state, consistent with the short T 1/2 (< 3 hours). Dose-dependent increases in exposures were observed across the dose range tested (20-180 mg daily). Fifteen of 22 patients completed at least 1 cycle of treatment. Median duration of treatment was 49 days (range 8 - 232 days). Best Overall Response: 1 patient with a confirmed marrow CR (MDS), 2 x partial remission (1 AML and 1 myeloid sarcoma), 12 x stable disease (7 AML and 5 MDS), 2 x progressive disease (1 AML and 1 MDS), and 5 x not evaluable (4 AML and 1 MDS). Conclusions: Daily dosing of PLX2853 was well tolerated as a monotherapy and showed early signs of clinical activity in some patients with relapsed or refractory AML or high risk MDS, with potential for combination with other agents. The RP2D is 80 mg QD continuous dosing. This clinical trial is registered at clinicaltrials.gov: NCT03787498. Disclosures Mims: Leukemia and Lymphoma Society's Beat AML clinical study: Consultancy, Research Funding; Aptevo: Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Glycomemetics: Research Funding; Kartos Pharmaceuticals: Research Funding; Xencor: Research Funding; Genentech: Consultancy; Abbvie: Consultancy; BMS: Consultancy; Kura Oncology: Consultancy; Syndax Pharmaceuticals: Consultancy; BMS: Consultancy; Jazz Pharmaceuticals: Consultancy; Aptevo: Research Funding. Solh: Jazz Pharmaceuticals: Consultancy; ADCT Therapeutics: Consultancy, Research Funding; Partner Therapeutics: Research Funding; BMS: Consultancy. Saultz: IKENA: Research Funding. Borate: Blueprint Medicine: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board; Jazz Pharma: Research Funding; Astellas: Membership on an entity's Board of Directors or advisory committees; incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding; Rampal: Membership on an entity's Board of Directors or advisory committees; Galecto, Inc.: Consultancy; Promedior: Consultancy. Pemmaraju: CareDx, Inc.: Consultancy; Dan's House of Hope: Membership on an entity's Board of Directors or advisory committees; Plexxicon: Other, Research Funding; Samus: Other, Research Funding; HemOnc Times/Oncology Times: Membership on an entity's Board of Directors or advisory committees; ASCO Leukemia Advisory Panel: Membership on an entity's Board of Directors or advisory committees; Roche Diagnostics: Consultancy; Novartis Pharmaceuticals: Consultancy, Other: Research Support, Research Funding; Affymetrix: Consultancy, Research Funding; LFB Biotechnologies: Consultancy; Stemline Therapeutics, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Sager Strong Foundation: Other; DAVA Oncology: Consultancy; Springer Science + Business Media: Other; Aptitude Health: Consultancy; MustangBio: Consultancy, Other; Incyte: Consultancy; Daiichi Sankyo, Inc.: Other, Research Funding; Celgene Corporation: Consultancy; Cellectis S.A. ADR: Other, Research Funding; Abbvie Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; ASH Communications Committee: Membership on an entity's Board of Directors or advisory committees; Protagonist Therapeutics, Inc.: Consultancy; Blueprint Medicines: Consultancy; Clearview Healthcare Partners: Consultancy; Bristol-Myers Squibb Co.: Consultancy; ImmunoGen, Inc: Consultancy; Pacylex Pharmaceuticals: Consultancy. Borthakur: Protagonist: Consultancy; Astex: Research Funding; Ryvu: Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; University of Texas MD Anderson Cancer Center: Current Employment; ArgenX: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy. Roboz: Actinium: Consultancy; Jasper Therapeutics: Consultancy; AbbVie: Consultancy; Mesoblast: Consultancy; Glaxo SmithKline: Consultancy; Helsinn: Consultancy; Blueprint Medicines: Consultancy; Janssen: Consultancy; Celgene: Consultancy; Amgen: Consultancy; Daiichi Sankyo: Consultancy; MEI Pharma - IDMC Chair: Consultancy; Jazz: Consultancy; Bayer: Consultancy; Agios: Consultancy; AstraZeneca: Consultancy; Astellas: Consultancy; Astex: Consultancy; Bristol Myers Squibb: Consultancy; Novartis: Consultancy; Janssen: Research Funding; Otsuka: Consultancy; Pfizer: Consultancy; Roche/Genentech: Consultancy. Powell: Plexxikon Inc.: Current Employment. Matusow: Plexxikon Inc.: Current Employment. Halladay: Plexxikon Inc.: Current Employment. Vali: Plexxikon Inc.: Current Employment. Hope: Plexxikon Inc.: Current Employment. Kundu: Daiichi Sankyo: Current Employment. Hsu: Daiichi Sankyo: Current Employment. Watkins: Plexxikon Inc.: Current Employment. Zhang: Plexxikon Inc.: Current Employment. Walling: Plexxikon Inc.: Consultancy; Aduro Biotech: Consultancy; Ambagon Therapeutics: Consultancy; Arch Oncology: Consultancy; CytomX: Consultancy; Flag Therapeutics: Consultancy; Harpoon Therapeutics: Consultancy; January Therapeutics: Consultancy; Myovant Sciences: Consultancy; Nurix Therapeutics: Consultancy; Propella Therapeutics: Consultancy; Prothena: Consultancy; Que Oncology: Consultancy; Shape Therapeutics: Consultancy; Aminex Therapeutics: Consultancy; Proximagen Neurosciences: Consultancy; Sesen Bio: Consultancy; Sunesis Pharmaceuticals: Consultancy; TRex BioSciences: Consultancy; Upsher-Smith: Consultancy; Nuvation Bio: Consultancy; Oryzon: Consultancy. Tsiatis: Plexxikon Inc.: Current Employment. DeZern: Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Taiho: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Title IX guidelines governing equal access to collide with state legislation around gender identity and multiple use bathrooms and changing facilities. This policy review of literature argues for a...

Background: Relapsed and refractory myeloid malignancies including myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) remain a clinical challenge due to high morbidity and mortality as well as a paucity of effective therapeutic agents. PLX2853 is an orally available, non-benzodiazepine bromodomain and extraterminal domain (BET) inhibitor that exhibits low nanomolar potency and a modest preference for binding to the second bromodomain (BD2) of the BET proteins. By regulating genes (e.g., MYC and BCL2) critical to leukemic cell growth and survival, PLX2853 has demonstrated broad anti-leukemic activity both as a single agent and in combination with other therapeutic agents in preclinical models. The pharmacokinetic (PK) profiles in patients with AML or MDS revealed high peak plasma concentrations, a short terminal half-life (T1/2 < 3 hour), and nearly complete elimination from the plasma by 9 hour post dose. This PK profile is hypothesized to enable improved tolerability by allowing transient target engagement followed by time for recovery after daily dosing. Methods: This is an open-label, Phase 1b (Ph1b) study of PLX2853 as a single oral agent administered daily for 21 day cycles in adult patients with relapsed or refractory AML or high risk MDS. A modified continuous reassessment model with escalation with overdose control is employed to determine the recommended phase 2 dose (RP2D). Primary objectives include safety and PK. Secondary objectives include measures of preliminary efficacy, and exploratory objectives include pharmacodynamics (PD) biomarker assessments. Enrollment through Cohort 5 (140 mg QD) is ongoing as of July 2020. Results: 9 subjects with relapsed or refractory AML and 7 subjects with high risk MDS (median age 65.7 years, range 47-77 years old; median number of prior therapies 2.3, range 1-5 prior therapies) have received PLX2853 in escalating doses from 20 to 140 mg QD. Through the data cut-off of 19 Jul 2020 (n=16), the most common treatment emergent adverse events (AEs) regardless of causality occurring in ≥20% of patients (n≥4) are: decreased appetite (n=9), (n=8), fatigue (N=8), hyperbilirubinemia (N=8), nausea (n=7), constipation (n=6), hypokalemia (n=6), leukopenia (n=6), vomiting (n=5), international normalised ratio increased (n=5), proteinuria (n=5), and dyspnea (n=5). Most were grade (G) 1-2. Treatment emergent AEs > G2 in > 1 patients are: anemia (n=7), leukopenia (n=5) hyperbilirubinemia (n=4), febrile neutropenia (n=4), sepsis (n=3), thrombocytopenia (n=3), hypertension (n=2), lymphocyte count decreased (n=3), and neutrophil count decreased (n=3). No dose limiting toxicity (DLT) has been observed. Following a daily dose of PLX2853 the median time to reach maximal plasma concentration (Tmax) is 1 hour, and no accumulation observed at steady state, which is consistent with the short T1/2 (< 3 hours). Dose-dependent increases in exposures were observed across the dose range tested (20-80 mg daily). Fifteen of 16 subjects have completed at least 1 cycle of treatment. The following best overall responses have been observed: 1 subject with a confirmed marrow complete remission, 1 subject with a partial remission (myeloid sarcoma), 10 subjects with stable disease, 1 subject with progressive disease, and 3 subjects not evaluable. Conclusions: In an ongoing Ph1b study of PLX2853, four cohorts have been completed with continuous, once daily dosing in patients with relapsed or refractory AML or high risk MDS, and no DLTs have been observed yet. As dose escalation continues, PK, PD, preliminary safety, and efficacy data will be reviewed further to determine the clinical significance of this BET inhibitor and identify the RP2D. This clinical trial is registered at clinicaltrials.gov: NCT03787498. Disclosures Mims: Agios: Consultancy; Kura Oncology: Membership on an entity's Board of Directors or advisory committees; Leukemia and Lymphoma Society: Other: Senior Medical Director for Beat AML Study; Novartis: Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees; Syndax Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Other: Data Safety Monitoring Board. Borate:Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz Pharmaceuticals: Research Funding; AbbVie: Other: Investigator in AbbVie-funded clinical trials; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees. Pemmaraju:Daiichi Sankyo: Research Funding; Novartis: Honoraria, Research Funding; Pacylex Pharmaceuticals: Consultancy; Cellectis: Research Funding; SagerStrong Foundation: Other: Grant Support; Celgene: Honoraria; Blueprint Medicines: Honoraria; MustangBio: Honoraria; DAVA Oncology: Honoraria; Roche Diagnostics: Honoraria; Samus Therapeutics: Research Funding; Affymetrix: Other: Grant Support, Research Funding; Incyte Corporation: Honoraria; Stemline Therapeutics: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Plexxikon: Research Funding; LFB Biotechnologies: Honoraria. Borthakur:BioTherix: Consultancy; BioLine Rx: Consultancy; Argenx: Consultancy; FTC Therapeutics: Consultancy; Curio Science LLC: Consultancy; Oncoceutics: Research Funding; Xbiotech USA: Research Funding; Polaris: Research Funding; BMS: Research Funding; Jannsen: Research Funding; BioLine Rx: Research Funding; Cyclacel: Research Funding; GSK: Research Funding; Abbvie: Research Funding; Novartis: Research Funding; Incyte: Research Funding; PTC Therapeutics: Research Funding; Nkarta Therapeutics: Consultancy; Treadwell Therapeutics: Consultancy; PTC Therapeutics: Consultancy; AstraZeneca: Research Funding. Roboz:Agios: Consultancy; Amphivena: Consultancy; MEI Pharma: Consultancy; Helsinn: Consultancy; Epizyme: Consultancy; Jasper Therapeutics: Consultancy; Cellectis: Research Funding; Trovagene: Consultancy; Takeda: Consultancy; Otsuka: Consultancy; Orsenix: Consultancy; AstraZeneca: Consultancy; Daiichi Sankyo: Consultancy; Astellas: Consultancy; Argenx: Consultancy; Actinium: Consultancy; Sandoz: Consultancy; Astex: Consultancy; Celgene: Consultancy; Janssen: Consultancy; Novartis: Consultancy; Pfizer: Consultancy; Abbvie: Consultancy; Array BioPharma: Consultancy; Bayer: Consultancy; Celltrion: Consultancy; Eisai: Consultancy; Jazz: Consultancy; Roche/Genentech: Consultancy. Powell:Plexxikon Inc.: Current Employment. Severson:Plexxikon Inc.: Current Employment. Matusow:Plexxikon Inc.: Current Employment. Halladay:Plexxikon Inc.: Current Employment. Hsu:Daiichi Sankyo Inc.: Current Employment. Watkins:Plexxikon Inc.: Current Employment. Zhang:Plexxikon Inc.: Current Employment. Walling:Plexxikon Inc.: Consultancy; Aduro Biotech: Consultancy; Arch Oncology: Consultancy; CytomX Therapeutics: Consultancy; Harpoon Therapeutics: Consultancy; ImmuNext: Consultancy; Myovant Sciences: Consultancy; Nurix Therapeutics: Consultancy; Que Oncology: Consultancy; Sesen Bio: Consultancy; Amgen: Consultancy; Aminex: Consultancy; Crown Bio: Consultancy; Leap Therapeutics: Consultancy; Prothena Corporation: Consultancy; Puma Biotechnology: Consultancy; Rhizen Pharmaceuticals: Consultancy; Shanghai Pharmaceuticals: Consultancy; Stealth Biotherapeutics: Consultancy; Sunesis Pharmaceuticals: Consultancy; Upsher-Smith Laboratories: Consultancy; Flag Therapeutics: Consultancy; January Therapeutics: Consultancy. Tsiatis:Plexxikon Inc.: Current Employment. DeZern:Celgene: Consultancy, Honoraria; Astex: Research Funding; Abbvie: Consultancy; MEI: Consultancy.

Vocalizations are widely used for communication between animals. Mice use a large repertoire of ultrasonic vocalizations (USVs) in different social contexts. During social interaction recognizing the partner's sex is important, however, previous research remained inconclusive whether individual USVs contain this information. Using deep neural networks (DNNs) to classify the sex of the emitting mouse from the spectrogram we obtain unprecedented performance (77%, vs. SVM: 56%, Regression: 51%). Performance was even higher (85%) if the DNN could also use each mouse's individual properties during training, which may, however, be of limited practical value. Splitting estimation into two DNNs and using 24 extracted features per USV, spectrogram-to-features and features-to-sex (60%) failed to reach single-step performance. Extending the features by each USVs spectral line, frequency and time marginal in a semi-convolutional DNN resulted in a performance mid-way (64%). Analyzing the network structure suggests an increase in sparsity of activation and correlation with sex, specifically in the fully-connected layers. A detailed analysis of the USV structure, reveals a subset of male vocalizations characterized by a few acoustic features, while the majority of sex differences appear to rely on a complex combination of many features. The same network architecture was also able to achieve above-chance classification for cortexless mice, which were considered indistinguishable before. In summary, spectrotemporal differences between male and female USVs allow at least their partial classification, which enables sexual recognition between mice and automated attribution of USVs during analysis of social interactions., Author summary Many animals communicate by producing sounds, so-called vocalizations. Mice use many different kinds of vocalizations in different social contexts. During social interaction recognizing the partner's sex is important and female mice appear to know the difference between male and female vocalizations. However, previous research had suggested that male and female vocalizations are very similar. We here show for the first time that the emitter's sex can be guessed from the vocalization alone, even single ones. The full spectrogram was the best basis for this, while reduced representations (e.g. basic properties of the vocalization) were less informative. We therefore conclude that while the information about the emitter's sex is present in the vocalization, both mice and our analysis must rely on complex properties to determine it. This novel insight is enabled by the use of recent machine learning techniques. In contrast, we show directly that a number of more basic techniques fail in this challenge. In summary, differences in the vocalizations between male and female mice allow to guess the emitter's sex, which enables sexual recognition between mice and automated analysis. This is important in studying social interactions between mice and how speech is produced and analyzed in the brain.

PURPOSE BRCA1 or BRCA2 ( BRCA) alterations are common in men with metastatic castration-resistant prostate cancer (mCRPC) and may confer sensitivity to poly(ADP-ribose) polymerase inhibitors. We present results from patients with mCRPC associated with a BRCA alteration treated with rucaparib 600 mg twice daily in the phase II TRITON2 study. METHODS We enrolled patients who progressed after one to two lines of next-generation androgen receptor–directed therapy and one taxane-based chemotherapy for mCRPC. Efficacy and safety populations included patients with a deleterious BRCA alteration who received ≥ 1 dose of rucaparib. Key efficacy end points were objective response rate (ORR; per RECIST/Prostate Cancer Clinical Trials Working Group 3 in patients with measurable disease as assessed by blinded, independent radiology review and by investigators) and locally assessed prostate-specific antigen (PSA) response (≥ 50% decrease from baseline) rate. RESULTS Efficacy and safety populations included 115 patients with a BRCA alteration with or without measurable disease. Confirmed ORRs per independent radiology review and investigator assessment were 43.5% (95% CI, 31.0% to 56.7%; 27 of 62 patients) and 50.8% (95% CI, 38.1% to 63.4%; 33 of 65 patients), respectively. The confirmed PSA response rate was 54.8% (95% CI, 45.2% to 64.1%; 63 of 115 patients). ORRs were similar for patients with a germline or somatic BRCA alteration and for patients with a BRCA1 or BRCA2 alteration, while a higher PSA response rate was observed in patients with a BRCA2 alteration. The most frequent grade ≥ 3 treatment-emergent adverse event was anemia (25.2%; 29 of 115 patients). CONCLUSION Rucaparib has antitumor activity in patients with mCRPC and a deleterious BRCA alteration, but with a manageable safety profile consistent with that reported in other solid tumor types.

3018 Background: PLX2853 is a potent, orally active small molecule BET inhibitor. Its unique pharmacokinetic (PK) profile is associated with less thrombocytopenia and improved tolerability by allowing transient target engagement with a prolonged pharmacodynamic (PD) response and time for recovery after dosing. Methods: We conducted a first-in-human 3+3 Ph1b/2a study of PLX2853 in adults with relapsed or refractory solid tumors and lymphoma to determine the safety, PK and recommended phase II dose (RP2D) (NCT03297424). Secondary endpoints included efficacy and PD. Results: As of 2 February 2021, 44 subjects (median age 65, range 39 - 84) received PLX2853 in escalating doses from 5mg to 120mg QD and 40mg to 60mg BID. Ovarian cancer (n = 11), uveal melanoma, colorectal, and prostate (n = 5 each) were the most represented tumor types. Adverse events (AE) occurring in ≥15% of subjects included nausea (41%), decrease appetite (39%), fatigue (27%), vomiting (25%), diarrhea (25%), dysgeusia (25%), dehydration (23%), anemia (20%), dry mouth (18%), dizziness (16%), abdominal pain (16%), and pyrexia (16%). Thrombocytopenia occurred in 11% of subjects. Most AEs ( > 85%) were grades (G) 1-2. Of all AEs, 40% were related. There were 5 treatment-related serious AEs in 2 subjects (n = 1 G4 thrombocytopenia, G4 ischemic stroke, G3 subarachnoid hemorrhage [SAH], and G3 thromboembolic event; n = 1 G3 vomiting). Dose-limiting toxicities were observed at 120mg QD (G4 thrombocytopenia, G4 ischemic stroke, G3 thromboembolic event, and G3 SAH; asymptomatic G4 thrombocytopenia), 60mg BID (G3 thrombocytopenia with recovery > 7 days), and 40mg BID (dose reduction for transient G3 fatigue). PLX2853 systemic exposure was dose-proportional up to 120mg with a short terminal half-life ( < 3.5 hr). Plasma concentrations were above the IC90 in the MYC-responsive reporter assay for 9 hr at 80mg or higher doses. RNA-seq analyses of peripheral blood mononuclear cells showed a dose-dependent modulation of BET target gene expression. One complete response (ongoing 9+ months) was seen in a patient with DLBCL, two patients had partial responses (1 uveal melanoma, 1 primary peritoneal cancer), and 14 patients had stable disease. The median PFS was 82.5 days (range: 51 – 209 days). Conclusions: PLX2853 shows encouraging signs of clinical activity and is well tolerated at the anticipated RP2D of 80 mg/day. PLX2853 is being evaluated as monotherapy and in combination. Clinical trial information: NCT03297424.

25 Background: Comprehensive genomic profiling (CGP) by next-generation sequencing (NGS) of circulating tumor DNA (ctDNA) from plasma provides a minimally invasive method to identify targetable genomic alterations (GAs) and resistance mechanisms in patients with metastatic castration-resistant prostate cancer (mCRPC). The circulating tumor fraction in patients with mCRPC and the clinical validity of GAs detected in plasma remain unknown. We evaluated the landscape of GAs using ctDNA-based CGP and assessed concordance with tissue-based CGP. Methods: Plasma from 3,334 patients with advanced prostate cancer (including 1,674 mCRPC screening samples from the TRITON2/3 trials and 1,660 samples from routine clinical CGP) was analyzed using hybrid-capture-based gene panel NGS assays. Results were compared with CGP of 2,006 metastatic prostate cancer tissue biopsies. Concordance was evaluated in 837 patients with both tissue (archival or contemporaneous) and plasma NGS results. Results: 3,127 patients [94%] had detectable ctDNA. BRCA1/2 were mutated in 295 patients [8.8%]. In concordance analysis, 72/837 [8.6%] patients had BRCA1/2 mutations detected in tissue, 67 [93%] of whom were also identified by ctDNA, and 20 patients were identified using ctDNA but not tissue [23% of all patients identified using ctDNA]. ctDNA detected subclonal BRCA1/2 reversions in 10 of 1,660 [0.6%] routine clinical CGP samples. AR alterations, including amplifications and hotspot mutations, which were detected in 940/2,213 patients [42%]. Rare AR compound mutations, rearrangements, and novel in-frame deletions were identified. Altered pathways included PI3K/AKT/mTOR [14%], WNT/β-catenin [17%], and RAS/RAF/MEK [5%]. Microsatellite instability was detected in 31/2,213 patients [1.4%]. Conclusions: In the largest study of mCRPC plasma samples conducted to date, CGP of ctDNA recapitulated the genomic landscape detected in tissue biopsies, with a high level of agreement in detection of BRCA1/2 alterations. It also identified patients who may have gained somatic BRCA1/2 alterations since archival tissue was collected. ctDNA detected more acquired resistance GAs than tissue, including novel AR-activating variants. The large percentage of patients with rich genomic signal from ctDNA, and the sensitive, specific detection of BRCA1/2 alterations position liquid biopsy as a compelling clinical complement to tissue CGP for patients with mCRPC.

This phase I study (CO-338-044; NCT02740712), conducted in patients with advanced solid tumors, evaluated the effect of the poly(ADP-ribose) polymerase (PARP) inhibitor rucaparib on the pharmacokinetics (PK) of caffeine 200 mg, warfarin 10 mg, omeprazole 40 mg, and midazolam 2 mg (cytochrome P450 (CYP) 1A2, CYP2C9, CYP2C19, and CYP3A substrates; dosed as a cocktail) and digoxin 0.25 mg (P-glycoprotein (P-gp) substrate; dosed separately) without rucaparib and following oral rucaparib 600 mg b.i.d. Geometric mean (GM) ratios (90% confidence interval (CI)) of area under the concentration-time curve (AUC) from time zero to last quantifiable measurement with and without rucaparib were: caffeine, 2.26 (1.93-2.65); S-warfarin, 1.49 (1.40-1.58); omeprazole, 1.55 (1.32-1.83); midazolam, 1.39 (1.14-1.68); and digoxin, 1.20 (1.12-1.29). There was limited effect on peak concentration of the substrates (GM ratios, 0.99-1.13). At steady state, rucaparib 600 mg b.i.d. moderately inhibited CYP1A2, weakly inhibited CYP2C9, CYP2C19, and CYP3A, and marginally increased digoxin exposure.

Vocalizations are a widespread means of communication in the animal kingdom. Mice use a large repertoire of ultrasonic vocalizations (USVs) in different social contexts, for instance courtship, territorial dispute, dominance and mother-pup interaction. Previous studies have pointed to differences in the USVs in different context, sexes, strains and individuals, however, in many cases the outcomes of the analyses remained inconclusive.We here provide a more general approach to automatically classify USVs using deep neural networks (DNN). We classified the sex of the emitting mouse (C57Bl/6) based on the vocalization’s spectrogram, reaching unprecedented performance (~84% correct) in comparison with other techniques (Support Vector Machines: 64%, Ridge regression: 52%). Vocalization characteristics of individual mice only contribute mildly, and sex-only classification reaches ~78%. The performance can only partially be explained by a set of classical shape features, with duration, volume and bandwidth being the most useful predictors. Splitting estimation into two DNNs, from spectrograms to features (57-82%) and features to sex (67%) does not reach the single-step performance.In summary, the emitter’s sex can be successfully predicted from their spectrograms using DNNs, excelling over other classification techniques. In contrast to previous research, this suggests that male and female vocalizations differ in their spectrotemporal structure, recognizable even in single vocalizations.

The phase 1‐2 study CO‐338‐010 (Study 10; NCT01482715) is evaluating single‐agent rucaparib, a poly(ADP‐ribose) polymerase inhibitor, administered orally to patients with an advanced solid tumor. In the dose escalation phase (Part 1), we characterized the single‐dose and steady‐state pharmacokinetic profiles of rucaparib administered once daily (QD; dose range, 40‐500 mg; n = 16) or twice daily (BID; dose range, 240‐840 mg; n = 30). Across all dosing schedules examined, the plasma exposure of rucaparib was approximately dose proportional; half‐life was approximately 17 hours, and median time to maximum concentration (tmax) ranged from 1.5 to 6.0 hours after a single dose and 1.5 to 4.0 hours following repeated dosing. The steady‐state accumulation ratio ranged from 1.60 to 2.33 following QD dosing and 1.47 to 5.44 following BID dosing. No effect of food on rucaparib pharmacokinetics was observed with a single dose of 40 mg (n = 3) or 300 mg (n = 6). In a phase 2 portion of the study (Part 3), the pharmacokinetic profile of rucaparib was further evaluated at the recommended phase 2 dose of 600 mg BID (n = 26). The mean (coefficient of variation) steady‐state maximum concentration (Cmax) and area under the concentration‐time curve from time zero to 12 hours (AUC0‐12h) were 1940 ng/mL (54%) and 16 900 ng ⋅ h/mL (54%), respectively. A high‐fat meal moderately increased rucaparib exposure. The fed‐to‐fasted geometric mean ratios (90% confidence interval [CI]) for AUC0‐24h and Cmax were 138% (117%‐162%) and 120% (99.1%‐146%); the median (90%CI) tmax delay was 2.5 (0.5‐4.4) hours.

Background: PLX2853 is an orally available, non-benzodiazepine BET (bromodomain and extraterminal domain) inhibitor that exhibits low nanomolar potency and a modest preference for binding to the second bromodomain (BD2) of the BET proteins. By regulating genes (e.g. MYC and BCL2) critical to leukemic cell growth and survival, PLX2853 demonstrated broad anti-leukemic activity both as a single agent and in combination with other therapeutic agents in preclinical models. The pharmacokinetic (PK) profile in solid tumor patients revealed a short half-life (< 3 hour) enabling high peak plasma concentrations and nearly complete elimination from the plasma 9 hour post dose. Since strong and prolonged suppression of BET proteins have often untoward effects in normal tissues, the PLX2853 PK profile is hypothesized to be associated with improved tolerability by allowing transient target engagement followed by time for recovery after daily dosing. Methods: We are conducting an open-label, Phase 1b (Ph1b) study of PLX2853 as a single oral agent administered daily in adult patients with relapsed or refractory acute myeloid leukemia (AML) or high risk myelodysplastic syndrome (MDS) using a modified continuous reassessment model (mCRM) with escalation with overdose control (EWOC) to determine the recommended phase 2 dose (RP2D). Up to 36 patients are expected to enroll. The dosing cycle and dose limiting toxicity window (DLT) is 21 days. Primary objectives include safety and PK. Secondary objectives include measures of preliminary efficacy, and exploratory objectives include pharmacodynamics (PD) biomarker assessments in various tissues. Enrollment through Cohort 2 (40 mg QD) is ongoing as of July 2019. Results: Five subjects with relapsed or refractory AML (median age 65 years) have received PLX2853 in escalating doses from 20 to 40 mg QD. Among these first 5 patients treated, the most common treatment emergent adverse events (AEs) regardless of causality in > 1 patient: decreased appetite (n=3), nausea (n=2), diarrhea (n=2), peripheral edema (n=2), cough (n=2), oropharyngeal pain (n=2), blood bilirubin increase (n=2), anemia (n=2), febrile neutropenia (n=2), fatigue (n=2), bacteremia (n=2), headache (n=2), dyspnea (n=2), and hypertension (n=2). Most were grade (G) 1-2. Treatment emergent AEs > G2 in > 1 patient included: anemia (n=2), febrile neutropenia (n=2) and hypertension (n=2). No treatment-related serious AEs or DLTs have been observed. Following a 20 mg daily dose of PLX2853, median time to reach maximal plasma concentrations (Tmax) is 1 hour and the absorption half-life (T1/2) is < 3 hours. Conclusions: In an ongoing Ph1b study, PLX2853 has now completed its first dosing cohort for patients with relapsed or refractory AML or high risk MDS, and no DLT has been observed yet. As dose escalation continues, PK, PD, preliminary safety and efficacy data will be assessed further to determine the clinical significance of target engagement. This clinical trial is registered at clinicaltrials.gov: NCT03787498. Disclosures Pemmaraju: mustangbio: Consultancy, Research Funding; abbvie: Consultancy, Honoraria, Research Funding; samus: Research Funding; celgene: Consultancy, Honoraria; cellectis: Research Funding; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; novartis: Consultancy, Research Funding; plexxikon: Research Funding; Daiichi-Sankyo: Research Funding; sagerstrong: Research Funding; affymetrix: Research Funding; incyte: Consultancy, Research Funding. Borate:Novartis: Consultancy; Takeda: Consultancy; Pfizer: Consultancy; Daiichi Sankyo: Consultancy; AbbVie: Consultancy. Solh:ADC Therapeutics: Research Funding; Amgen: Speakers Bureau; Celgene: Speakers Bureau. Borthakur:Polaris: Research Funding; Arvinas: Research Funding; Agensys: Research Funding; Tetralogic Pharmaceuticals: Research Funding; Cantargia AB: Research Funding; Argenx: Membership on an entity's Board of Directors or advisory committees; BioLine Rx: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncoceutics, Inc.: Research Funding; Eli Lilly and Co.: Research Funding; BMS: Research Funding; AstraZeneca: Research Funding; Bayer Healthcare AG: Research Funding; Novartis: Research Funding; FTC Therapeutics: Membership on an entity's Board of Directors or advisory committees; AbbVie: Research Funding; Strategia Therapeutics: Research Funding; Cyclacel: Research Funding; Xbiotech USA: Research Funding; Eisai: Research Funding; Merck: Research Funding; BioTheryX: Membership on an entity's Board of Directors or advisory committees; Oncoceutics: Research Funding; NKarta: Consultancy; Incyte: Research Funding; Janssen: Research Funding; GSK: Research Funding; PTC Therapeutics: Consultancy. DeZern:Astex Pharmaceuticals, Inc.: Consultancy; Celgene: Consultancy. Zhang:Plexxikon Inc.: Employment. Powell:Plexxikon Inc.: Employment. Severson:Plexxikon Inc.: Employment. Inokuchi:Plexxikon Inc.: Employment. Matusow:Plexxikon Inc.: Employment. Halladay:Plexxikon Inc.: Employment. Hsu:Daiichi Sankyo, Inc.: Employment. Watkins:Plexxikon Inc.: Employment. Walling:Myovant Sciences: Consultancy; Nurix: Consultancy; Aduro Biotech: Consultancy; Plexxikon: Consultancy; CytomyX: Consultancy; Flag Therapeutics: Consultancy; Aminex: Consultancy; Immunext: Consultancy; SensenBio: Consultancy; Harpoon Therapeutics: Consultancy. Tsiatis:Plexxikon Inc.: Employment. Mims:PTC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Astellas Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Agios Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees.

Background: The phase 2 TRITON2 (NCT02952534) study is evaluating the poly(ADP-ribose) polymerase inhibitor rucaparib in mCRPC patients with a deleterious germline or somatic mutation in BRCA1, BRCA2, ATM, or 1 of 12 other DNA damage repair (DDR) genes who have progressed on prior androgen receptor-directed therapy and 1 taxane-based therapy. Here we present results from central genomic screening of plasma and tissue samples for TRITON2. Methods: Plasma samples were profiled for genomic alterations (GAs) in 70 genes and tumor tissue FFPE samples for GAs in 395 genes by Foundation Medicine, Inc., using next-generation sequencing (NGS) assays. Deleterious alterations included frameshift, nonsense, and deleterious missense mutations, protein-truncating rearrangements, and (for tissue samples) homozygous loss. Tissue samples included both archival and more recent specimens, whereas plasma samples were collected at the time of disease progression on prior therapy. Results: As of July 2, 2018, 359 plasma samples from patients with mCRPC were screened for deleterious GAs in a DDR gene. Of the plasma samples, 96% (343/359) were successfully sequenced for a comprehensive genomic profile. The most commonly altered genes were AR (49%) and TP53 (48%). Deleterious GAs were detected in BRCA1 (2%), BRCA2 (10%), ATM (15%), CDK12 (6%), or other DDR genes (6%). GAs in the MAPK pathway were observed in 5% of plasma samples. Additionally, 738 tissue samples from primary prostate cancer tumors (78%) or metastases (22%) were profiled. Only 66% of tissue samples (487/738) were sequenced successfully, highlighting the challenges associated with NGS of predominantly archival prostate tissues (median sample age, 2.5 years [range, 4 days to 21 years]). The most commonly altered genes were TP53 (38%), PTEN (33%), ERG-TEMPRSS2 fusions (28%), AR (15%), and MYC (9%). Deleterious GAs were observed in BRCA1(2%), BRCA2 (9%), ATM (7%), CDK12 (7%), or other DDR genes (5%), as well as in the PI3K/AKT (41%), Wnt (11%), MAPK (5%), and mismatch repair (3%) pathways. Further, GAs in the DDR, PI3K/AKT, and Wnt pathways were observed at a higher rate in metastatic (42%, 40%, and 15%, respectively) than in primary prostate tissues (32%, 34%, and 12%, respectively). Updated and expanded genomic analyses and plasma-tissue concordance analyses will be presented. Conclusions: Genomic NGS profiling of plasma and FFPE tumor tissue samples successfully identified patients with GAs in a DDR gene for the evaluation of rucaparib in mCRPC. The plasma assay is convenient for patients and has a low NGS failure rate, whereas the tumor tissue assay has a higher failure rate but can detect more alteration types. Taken together, these data highlight the strengths and limitations of tissue and plasma testing to identify GAs for targeted therapies in mCRPC. Citation Format: Foad Green, Jeremy D. Shapiro, Ray McDermott, Josep Maria Piulats, Alison Reid, Peter Ostler, Jingsong Zhang, David Campbell, Dominique Spaeth, Ivor Percent, Arif Hussain, Andrew D. Simmons, Tony Golsorkhi, Simon P. Watkins, Andrea Loehr, Simon Chowdhury, Wassim Abida. Comprehensive genomic profiling of >1000 plasma and tumor tissue samples from metastatic castration-resistant prostate cancer (mCRPC) patients gives insight into targeted treatment strategies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 727.

5031 Background: The phase 2 TRITON2 study (NCT02952534) is evaluating the PARP inhibitor rucaparib in patients with mCRPC who have a deleterious germline or somatic alteration in BRCA ( BRCA1 or BRCA2) or 1 of 13 other DNA damage repair genes. Here we present analyses of tumor genomics and baseline clinical characteristics in mCRPC patients with a deleterious alteration in BRCA. Methods: Plasma (baseline) and tissue (archival or baseline) samples from patients with a deleterious alteration in BRCA were analyzed using Foundation Medicine next-generation sequencing assays. The alterations and zygosity of the alterations that were detected, as well as the somatic/germline status from Color Genomics testing, were summarized. Associations between genomic alterations, DNA yield, allele frequency, and baseline clinical characteristics were investigated. Results: Results are shown in the Table for a cohort of 40 BRCA2 and 5 BRCA1 patients enrolled in TRITON2 (Abida W et al. Presented at ESMO 2018. Abst 793PD). A biallelic alteration was observed in 21 of the 22 BRCA2 patients (95%) for whom alteration zygosity could be determined. Among the 5 BRCA1 patients, 1 alteration was monoallelic and 4 were of unknown zygosity. Co-occurring alterations in cancer-related or DNA damage repair genes were observed in many patients with BRCA alterations. At baseline, cell-free DNA (cfDNA) yield correlated positively with the sum of target lesions (STL; P= 0.04), but not with prostate-specific antigen (PSA) levels ( P= 0.86). No correlation was observed between allele frequency of the BRCA alteration baseline STL ( P= 0.68) or PSA levels ( P= 0.97). Conclusions: Patients with a BRCA mutation enrolled in TRITON2 demonstrate a profile of genomic alterations consistent with that of prior studies of patients with mCRPC. Plasma cfDNA profiling showed a correlation between baseline cfDNA yield and measurable tumor burden, but not baseline PSA. Clinical trial information: NCT02952534. [Table: see text]

This work emphasises the modelling capabilities of the unsteady flamelet/reaction progress variable approach to implement diesel spray flames for capturing the auto-ignition and flame lift-off phenomena. The droplet size distribution based on the moment scheme characterises the poly-disperse spray model [1] employed in this work. The flamelet progress variable solutions embedded in a Reynolds-averaged Navier–Stokes (RANS) framework, together with the probability density function (PDF) approach, signify the turbulence–chemistry interaction. All thermochemical scalars are represented as a function of mean mixture fraction, mixture fraction variance, reaction progress variable and scalar dissipation rate. Mixture fraction is assumed to follow a beta-PDF distribution, because the reaction progress variable and scalar dissipation rate distributions are assumed to be a delta-PDF. In order to assess the capability of this developed model, the predicted results are compared with experimental data [2] . The developed model gives a reasonably good overall prediction performance in terms of auto-ignition, flame development and flame lift-off length. The flame temperature distributions are comparable with the formations of luminous flames. The predicted flame growth rate is consistent with the experimental results but there is a small over-prediction. Therefore, the present approach can accurately and efficiently capture the auto-ignition and flame lift-off phenomena of diesel spray flame.

Throughout the decades of educational reform cycles, the value of homework has proven either meaningful or meaningless depending on the reforming framework. Questions about homework as simply busy work or knowledge work, mere content distraction or content extension, ambivalence toward importance, or discipline of character all cloud any conclusions about homework, good or bad. Our research is a case study of one rural, high school that has created a No Excuses Homework expectation that is embedded in the school's culture. Focus groups of faculty and students, interviews with both the principal and assistant principal, combined with quantitative data reveal a cultural shift within the organization. Three themes emerge as contributors to a cultural transformation around homework expectations: initial and ongoing professional development exploring the creation of meaningful homework assignments and consistent quality expectations, continuous support for students and parents in meaningful homework s...

Middle and secondary schools have increasingly offered distance-learning classes as a means of meeting diverse student needs and curriculum requirements while using instructional and budget resources efficiently. Little emphasis has been placed on the readiness of students to participate and succeed in these less conventional learning environments. The ill-prepared and apprehensive student may be prone to academic dishonesty. This investigation seeks to synthesize how pedagogical efforts to foster the development of self-regulated learning skills may reduce instances of cheating and plagiarism in online classes.