bluuebunny/crossref_metadata_2025_split huggingface dataset:
c-AMP/MAPK dysregulation and its impact on survival and response to immunotherapy in advanced melanomas.
Authors: Al-Rohil Rami , Marks Etan , Vasudevaraja Varshini , Kelly Stephen , Snuderl Matija , Johnson Douglas Buckner , Jour George 
Published: May 2019

3086 Background: Immunotherapies blocking the interaction of CTLA-4 or Programmed Death 1 (PD-1) with their ligands are the standard of care for advanced MEL although many pts fail to benefit from immunotherapy. Herein, we seek to identify epigenetic and genetic signatures associated with lack of response in patients treated with immunotherapy . Methods: We performed whole exome sequencing of 580 cancer-related genes and whole-genome DNA methylation arrays targeting > 850k CpG sites covering promoters, enhancers, and transcription factor sites in 28 MEL samples from patients treated with PD-1 +/- CTLA-4 inhibitors. Findings were correlated with collected clinical history. Results: Findings are summarized in the table . Unsupervised clustering and multi-parametric analysis showed a distinct methylation signature independent of age, sex, stage, site of metastasis, or type of treatment (adj. p<0.01). Pathway analysis identified c-AMP/MAPK and PI3K-Akt signaling pathways (adj. p=2.10E-05 and 8.19E-06, respectively) enrichment in non-responders . This coincided with significant increase of mutational events in c -AMP/MAPK and PI3K-Akt pathways (p= 0.0001) including deleterious events affecting PDE4DIP (p=0.0002), a negative regulator of mTORC1, in non-responders. C-AMP/MAPK/PI3K genomic alterations were associated with a worse OS and PFS but not worse response rate (p=0.04, p=0.01, and p=0.20). PDE4DIP deleterious events were associated with decreased response rate, worse OS and PFS (p=0.002; p=0.002;p=0.00003). Conclusions: Convergent epigenetic dysregulation of cAMP/MAPK signaling and inactivation of PDE4DIP is associated with worse outcome and lack of response to immunotherapy, respectively. [Table: see text]
Preclinical testing of ultra-rapid FLASH total abdominal irradiation demonstrates survival benefit and decreased gastrointestinal toxicity compared to conventional external beam radiation.
Authors: Levy Karen , Rafat Marjan , Schueler Emil , Eggold Joshua Thomas , Wang Jinghui , Casey Keriann , Koong Albert , Maxim Peter , Loo Billy W. , Rankin Erinn 
Published: May 2019

3092 Background: Total abdominal irradiation (TAI) is not widely used in the treatment of ovarian cancer due to high abdominopelvic toxicity. Ultra-rapid FLASH irradiation has been shown to spare the lung, skin and brain from radiation toxicity in preclinical models. Conventional radiotherapy delivers a dose-rate of 3-4 Gy/minute, while our small animal FLASH system uses a linear accelerator to generate a dose-rate of 200 Gy/second. Our data demonstrates that use of FLASH-TAI in a preclinical model protects against death from irradiation and confers gastrointestinal (GI) protection when compared to conventional external beam irradiation. Ongoing studies are evaluating the potential for tumor control in an ID8 mouse model of ovarian cancer. Methods: Female C57BL/6 mice received TAI using FLASH and conventional (CONV) radiation at increasing doses: 8.5 Gy, 10.5 Gy and 12 Gy. Unirradiated controls and irradiated cohorts were analyzed at 5-days and 12 months post-irradiation. Normal tissue toxicity was determined by measuring total body weights, stool counts, laboratory analysis, histological analysis, immunohistochemistry, immunofluorescence microscopy and survival. Results: Solid stool production was preserved in FLASH mice, whereas a 50-63% decrease was observed in the CONV cohorts. Histology demonstrated that FLASH preserves small intestinal architecture. TUNEL analysis demonstrated an increase in apoptosis throughout the small intestine of only the CONV cohort. Exploratory necropsy of all surviving cohorts at 12 months post-irradiation was notable for secondary transmural proximal duodenal adenocarcinomas within the radiation field in 25% of only the aged CONV cohorts. There was no laboratory evidence of long-term hematopoietic, liver or kidney toxicity at 12 months. Survival analysis was notable for death of all 12 Gy CONV mice by 9 days post-irradiation whereas 75% of the 12 Gy FLASH mice were alive at 11 months. Conclusions: FLASH protects against death from TAI, improves small intestine epithelial integrity following TAI, protects against radiation-induced apoptosis and may protect from secondary gastrointestinal tumors in the radiation field. Our discovery that FLASH is a safe strategy to deliver effective doses of total abdominal radiation potentially identifies a new opportunity to utilize FLASH-TAI for treatment of ovarian peritoneal metastases.
First-in-human imaging of nanoparticle entrapped docetaxel (CPC634) in patients with advanced solid tumors using 89Zr-Df-CPC634 PET/CT.
Authors: Miedema Iris H.C. , Zwezerijnen Gerben J.C. , Oprea-Lager Daniela E. , Verheul Henk M.W. , Vugts Danielle J. , Huisman Marc C. , Mathijssen Ron H.J. , Rijcken Cristianne J.F. , Hu Qizhi , Dongen G.a.M.S. van , Menke Catharina Wilhelmina 
Published: May 2019

3093 Background: CPC634 is a nanoparticle entrapping docetaxel designed to improve tumor accumulation and tolerability compared to conventionally administered docetaxel by taking advantage of the presumed enhanced permeability and retention (EPR) effect. In vivo imaging with zirconium-89 (89Zr)-desferal (Df)-CPC634 will provide valuable information on its biodistribution and will quantify tumor retention. Methods: Patients with solid tumors not amenable to standard therapy received 37 MBq, 0.1-2mg of 89Zr-Df-CPC634 tracer and whole body PET/CT scans were obtained at 2, 24 and 96h post-injection (p.i.). Patients were administered CPC634 (60mg/m2) two weeks later followed by a second tracer injection and scans at 24 and 96h p.i. Biodistribution was quantified by delineating organs of interest and calculating mean %ID/kg. Visual tumor retention was defined as focal uptake in tumor lesions exceeding local background and quantified as standardized uptake peak values (SUVpeak) in volumes of interest. Results: Five patients were included. Biodistribution of 89Zr-Df-CPC634 showed significant retention in healthy liver, and spleen compared to lung (respectively 2.54, 1.61 and 0.56 mean %ID/kg at 96h p.i.), supporting apparent opsonization of nanoparticles in cells of the reticuloendothelial system. Visual retention was observed in 16/37 evaluable tumor lesions with the highest intensity at 96h p.i, compatible with the assumed EPR effect. Tumor retention showed intra- and interpatient heterogeneity, with a mean %ID/kg of 3.43 [1.14-9.32]. Pre-administering unlabeled CPC634 did not change the mean tumor retention of 89Zr-Df-CPC634 (at 96h p.i. mean 3.50 %ID/kg [1.64-9.97]), however, four additional lesions were visible in comparison to tracer only. Conclusions: The biodistribution of 89Zr-Df-CPC634 was consistent with a prolonged exposure of nanoparticle containing docetaxel. 89Zr-Df-CPC634 showed high retention in tumors confirming the EPR effect of these nanoparticle in humans, and supporting their further development for tumor targeting of therapeutic agents. A Phase II efficacy study in platinum resistant ovarian cancer (NTC03742713) is currently ongoing. Clinical trial information: NCT03712423.
A first-in-human phase I/II trial of SRA737 (a Chk1 Inhibitor) in subjects with advanced cancer.
Authors: Plummer Elizabeth Ruth , Kristeleit Rebecca Sophie , Cojocaru Elena , Haris Noor Md , Carter Louise , Jones Robert Hugh , Blagden Sarah Patricia , Evans T.R. Jeffry , Arkenau Hendrik-Tobias , Sarker Debashis , Danson Sarah , Symeonides Stefan N. , Walter Harriet , Ocen Joanita , Randhawa Manreet , Kowalski Mark Marion , Verdon Ines , Dye Andrew , Banerji Udai 
Published: May 2019

3094 Background: SRA737 is a potent, highly selective and orally-bioavailable inhibitor of checkpoint kinase 1 (Chk1). SRA737-01 was designed to investigate the safety and tolerability of continuous, daily dosing with SRA737 and to evaluate preliminary efficacy in expansion cohorts of prospectively-selected genetically-defined subjects with advanced tumors. Methods: The escalation phase employed an accelerated titration design starting at 20 mg administered orally in 28-day cycles. Incremental 100% dose escalations in single-subject cohorts were followed by a rolling-6 design once SRA737-related ≥ Grade 2 toxicity was observed during Cycle 1. The expansion phase enrolled subjects prospectively selected by next-generation sequencing with: high grade serous ovarian, colorectal, metastatic castration-resistant prostate, non-small cell lung, and head and neck cancers. Results: In escalation, 18 subjects received SRA737 in 9 dose level cohorts, from 20 to 1300 mg QD; median treatment duration 62.5 days (range 1 to 226). Of these subjects, 3 experienced dose limiting toxicity (DLT; inability to receive 75% of the planned dose); 2 at 1300 mg QD due to gastrointestinal intolerability and 1 at 500 mg BID due to thrombocytopenia. The maximum tolerated dose (MTD) was established at 1000 mg QD or 500 mg BID. The Cmax and AUC0-24 at 1000 mg QD were 2391 ng/mL and 26795 ng∙h/mL respectively and the Cmin (411 ng/mL) exceeded that determined in preclinical models to be effective. Doses ≥ 300 mg QD also exceeded this level. Of 462 subjects prospectively screened for genetic alterations associated with Chk1 sensitivity, 93 were enrolled in expansion across all tumor types. Overall, the most commonly reported treatment-emergent adverse events were diarrhea (70%), nausea (64%), vomiting (51%), and fatigue (47%); the majority were of mild to moderate severity. Conclusions: In this first-in-human trial of SRA737 monotherapy, the MTD was 1000 mg/day and based on overall tolerability and PK, the recommended Phase 2 dose is 800 mg/day. The successful enrollment of prospectively-selected genetically-defined subjects will allow response data to be correlated with genomic profiles hypothesized to confer sensitivity to Chk1 inhibition. Clinical trial information: NCT02797964.
A randomized phase 0 trial of the mitochondrial inhibitor ME344 or placebo added to the antiangiogenic (Aa) bevacizumab in early HER2-negative breast cancer (E-HERNEBC).
Authors: Quintela-Fandino Miguel , Morales Serafin , Salgado Alfonso Cortes , Manso Luis , Apala Juan V , Cortes Javier , Guerra Juan Antonio , Caleiras Eduardo , Mulero Francisca , Mouron Silvana Andrea 
Published: May 2019

3100 Background: We have shown that when Aas induce vascular normalization (VN), tumors escape upregulating mitochondrial metabolism. Mitochondrial inhibition with ME344 induced synergy with various Aas. We also found that VN could be traced by showing a 10% decrease in tumor FDG-PET SUV from day (d) 0 to d8 of Aa. We studied the activity of adding ME344 or placebo to Bev (Ki67 decrease) in E-HERNEBC in a phase 0 randomized trial. As a secondary objective we measured the activity of the combination in patients (Pts) showing VN according to FDG-PET. Methods: Untreated E-HERNEBC Pts with T > 1cm, any N, M0 underwent a baseline FDG-PET (d1) and received a single dose of Bev (15mg/kg) prior to randomization (1:1) to arm A (FDG-PET on d8 followed by ME344 10 mg/kg IV on d8, d15 and d21) or Arm B (FDG-PET on d8 followed by placebo on d8, d15 and d21). Tumors were biopsied on d0 and 28. A 40 Pts sample size was powered to detect a 30% relative difference between arms in digitally acquired Ki67 decrease from d0 to d28 (alpha 0.05, beta 0.2). Results: Arm A: 20 Pts; Arm B: 21 Pts. Baseline characteristics were in arm A vs B: age 58.4(41.5-75.3) vs 53.6(39-82.8); T1(30%)/T2(60%)/T3(10%) vs T1(52%)/T2(48%)/T3(0%); N0(80%)/N1(20%) vs N0(81%)/N1(19%); ER+(75%)/TNBC(25%) vs ER+(71.4%)/TNBC(28.6%); Ki67 31.6% (3.6%-70%) vs 25.2% (1.2% - 81.5%). PET-SUV decreased > 10% from d0 to d8 in 6/20 (arm A) and 6/21 (arm B) Pts. Two G3 adverse events (blood pressure) were reported (1/arm) and deemed related to Bev. Results of the primary endpoint: table. Conclusions: ME344 showed significant biologic activity, enhancing the effect in Ki67 decrease vs placebo when added to Bev in E-HERNEBC. The activity was greater in TNBC. A trend for greater activity in patients experiencing VN according to FDG-PET was observed. Clinical trial information: NCT02806817. [Table: see text]
A phase I dose-escalation study of two cycles carboplatin-olaparib followed by olaparib monotherapy in patients with advanced cancer.
Authors: Geenen Jill J.J. , Dackus Gwen , Schouten Philip C. , Pluim Dick , Marchetti Serena , Sonke Gabe S. , Huitema Alwin , Beijnen Jos H. , Schellens Jan H. M. , Linn Sabine C. 
Published: May 2019

3118 Background: The PARP-inhibitor olaparib has single-agent activity in BRCA mutated breast and ovarian cancer. Preclinical studies show synergistic effects when combining PARP-inhibitors and platinum drugs in BRCA1/2 mutated cancer cell models. A formulation change from olaparib capsules to tablets initiated a new dose finding study of olaparib tablets BID continuously with carboplatin. Methods: Patients were included in a 3+3 dose-escalation schedule in the following dose-levels: olaparib 25mg BID and carboplatin AUC 3 d1/d22, olaparib 25mg BID and carboplatin AUC 4 d1/d22, olaparib 50mg BID and carboplatin AUC4 d1/d22, olaparib 75mg and carboplatin AUC 4 d1/d22 and olaparib 100mg BID and carboplatin AUC 4 d1/d22. After two cycles patients continued olaparib 300mg BID as monotherapy. Primary objective was to assess the Maximum Tolerable Dose (MTD). Secondary objectives were to investigate the preliminary response rate, pharmacodynamics and systemic exposure. Results: In total 24 patients were included with breast cancer (n = 18), ovarian cancer (n = 3), melanoma (n = 1), colorectal cancer (n = 1) and esophageal cancer (n = 1). Nineteen out of 24 patients had a germline BRCA mutation (79%). Most common AEs were nausea (46%), fatigue (33%) and platelet count decrease (33%). The majority of AEs (83%) were grade 1/2 in severity. Because two dose-limiting toxicities (consisting of ≥ 7 days dose delay of cycle 2 or missing ≥ 5 doses of olaparib due to hematologic toxicity) occurred in dose-level 4, dose-level 3 (olaparib 75mg and carboplatin AUC 4; n = 6 patients) was determined to be the MTD. Fourteen out of 24 patients (56%) had a partial response as best response, according to RECIST 1.1. Systemic exposure of the olaparib tablet formulation appeared comparable to the previous capsule formulation with an olaparib tablet AUC0-14 of 16.3 μg/ml*h at MTD. PARP activity in PBMCs was decreased by 98.7% ± 0.14% at day eight compared to day one for dose-level 3. Conclusions: Olaparib tablets 75mg BID and carboplatin AUC 4 for two cycles preceding olaparib monotherapy is a feasible and tolerable treatment schedule with encouraging clinical antitumor activity. Clinical trial information: NCT02418624.
Pharmacodynamics of PI3K, MEK, and AKT inhibitors through isoform-specific measurements of MEK, ERK, AKT, and ribosomal protein S6 in needle biopsies.
Authors: Herrick William , Kilpatrick Casey , Esposito Dominic , Stotler Howard , Hollingshead Melinda G. , Doroshow James H. , Parchment Ralph E. , Srivastava Apurva K. 
Published: May 2019

3134 Background: The success of drugs targeting the MAPK or PI3K pathways in cancer has been slowed by insufficient pathway suppression or onset of resistance through rebound or cross-pathway activation. Isoform-specific measurement of key signaling molecules and a pathway convergence marker ribosomal protein S6 (RPS6), may provide valuable pharmacodynamic (PD) evidence to assess drug effectiveness. Methods: We developed Luminex multiplex assays to measure total and phosphorylated forms of RPS6, ERK1, ERK2, MEK1, MEK2, AKT1, AKT2, and AKT3 from a single tumor biopsy. Fit-for-purpose validation was performed with three drugs currently in clinical trials. A SW620 (KRAS G12V) model was tested with selumetinib (NSC741078, 20 mg/kg), MK2206 (NSC756656, 24 mg/kg), and two PTEN-null models (PC3 & HCC70) with AZD8186 (NSC777572, 25 & 50 mg/kg). Tumors were collected at multiple timepoints after single and repeated dosing, processed by a validated method (PMID 27001313) and data analyzed relative to vehicle control (n = 4-5/grp). Results: The multiplexed assays demonstrated satisfactory analytical performance. Treatment of the SW620 model with a single dose of selumetinib suppressed pERK1/2 ( > 90%), MEK1/2 (50%) and pRPS6 (40-60%) up to 4 h (last time point tested) which was reversed by 24 h. AKT inhibitor, MK2206, suppressed pAKT1/2 (75%) and pAKT3 (50%) 2 h post-dose with reversal at 24 h but did not significantly suppress pRPS6, implying limited downstream modulation. Dosing selumetinib for 21 days had no added effect on pERK isoforms. In both PTEN-null models, AZD8186 suppressed all pAKT isoforms by 40-75% up to 4 h post-dose. The pAKT remained suppressed at 7 h in HCC70 but both pAKT and pRPS6 rebounded by 7 h in PC3. The basal pERK1/2 levels were low and unaffected by AZD8186 in PC3 and HCC70. Conclusions: We established the fitness of PD assays to provide critical evidence regarding the duration of on-target effects, timeline of biomarker reversal and effectiveness of pathway suppression for three distinct classes of drugs. The PD assays are ready for an ongoing clinical trial of AZD8186 and to support clinical development of FGFR inhibitors. Funded by NCI Contract HHSN261200800001E.
Mutation and treatment profiles of patients with concurrent EGFR and ALK actionable mutations (muts).
Authors: Zhao Jun , Liu Caixia , Liu Hui , He Yong , Rao Liqiang , Hao Jiqing , Liu Xiang , Xie Zefeng , Chen Rongrong , Xia Xuefeng 
Published: May 2019

3138 Background: Actionable muts in EGFR and ALK define two molecular subtypes sensitive to EGFR-TKIs and ALK-TKIs, respectively. Although generally mutually exclusive, they did co-exist in some cases. However, when and how do they co-exist are not well understood. Methods: Pts with concurrent actionable muts in ALK and EGFR were selected from our database. Their mutation profiles and treatment histories were analyzed. PFS was estimated using Kaplan-Meier method. Results: Among 341 ALK-positive ( ALK-pos) and 3804 EGFR-positive ( EGFR-pos) pts, 9 (2.6% of ALK-pos, 0.2% of EGFR-pos) had concurrent EGFR and ALK actionable muts, including 3 EX19Indel + EML4-ALK, 2 EX19Indel + STRN-ALK, 2 L858R + L1152R, 1 L858R + EML4-ALK, and 1 G719C + S768I + STRN-ALK. All 9 pts had lung cancer. One pt with EX19Indel + EML4-ALK was treatment naïve. The other 8 pts have taken ≥ 1 EGFR-TKIs. The mPFS of these pts on first-generation EGFR-TKIs was 22 mo (95% CI: 11 - NR). Except for 1 pt who progressed on Gefitinib and subsequently on Osimertinib had a T790M+C797G, the other 7 EGFR-TKI resistance pts had no common known resistance muts. 3 pts ordered NGS tests before taking EGFR-TKIs. None of them had ALK muts at that time. Later, 1 pt (19Indel) gained an STRN-ALK after 15 mo on Osimertinib, 1 pt (L858R) gained an EML4-ALK after 5 mo on Gefitinib, and 1 pt (L858R) gained an L1152R after 10 mo on Afatinib. Therefore, ALK muts were likely developed as resistance mechanisms during EGFR-TKIs therapies in these 3 pts. Unfortunately, with no information on ALK status before EGFR-TKI therapies, we can not tell if the ALK muts were also developed during and conferred resistance to EGFR-TKI therapies in the other 5 pts. Both STRN-ALK and ALK L1152R were recorded 4 times in our database, and they concurred with EGFR actionable muts in 3 and 2 of the 4 records, respectively. Conclusions: ALK and EGFR actionable muts concurred at a relatively low frequency in our pts. In some cases, ALK muts were developed during EGFR-TKI therapies. Developed either together or sequentially, some combinations of EGFR and ALK muts, such as L858R with L1152R and EX19Indel with ALK fusion, may form more easily or may be preferable than other combinations for the development or evoluation of tumors.
Validation of the Immunoscore prognostic value in stage III colon cancer patients treated with oxaliplatin in the prospective IDEA France cohort study (PRODIGE-GERCOR).
Authors: Pages Franck , Andre Thierry , Taieb Julien , Vernerey Dewi , Henriques Julie , Borg Christophe , Marliot Florence , Ben Jannet Rim , Louvet Christophe , Mineur Laurent , Bennouna Jaafar , Desrame Jérôme , Faroux Roger , Duval Alex , Laurent-Puig Pierre , Svrcek Magali , Hermitte Fabienne , Catteau Aurelie , Galon Jerome , Emile Jean-François 
Published: May 2019

3513 Background: The Immunoscore (IS), which has been shown to prognostically classify Stage I-III colon cancer (CC) patients, was assessed in the IDEA France cohort study evaluating 3 versus 6 months of oxaliplatin-based adjuvant chemotherapy in Stage III CC patients. Methods: Densities of CD3+ and cytotoxic CD8+ T cells in the tumor and invasive margin of each patient were quantified by digital pathology and converted to IS using pre-defined published cut-off. The performance of IS to predict disease-free survival (DFS) was assessed in the modified intention-to-treat population, in each study arm, and was adjusted with relevant clinical features in multivariable Cox models. Harrell’s C-statistics was used to investigate the IS performance. Results: 1322 patients were included; 82 were excluded due to pre-analytical non-conformity. IS was successfully analyzed in 1062 (85.6%) eligible patients. In a 2-category IS analysis, Low and (Int+High) IS were observed in n=599 (43.6%) and n=463 (56.4%) patients, respectively. IS was significantly correlated with T stage, T/N stage (T1-3 and N1 versus T4 and/or N2), and microsatellite instability status. The study met its primary objective of validating that Low IS identifies patients with higher-risk of relapse or death [HR=1.54; 95%CI 1.24-1.93, p=0.0001]. The 3-year DFS rates were 66.80% [95%CI 62.23-70.95] and 77.14% [95%CI 73.50-80.35] for Low IS and (Int+High) IS, respectively. In multivariable analysis, IS remained independently associated with DFS (p<0.0012) when combined with T/N stage. The addition of IS to the T/N stage significantly improved the model discrimination capacity [bootstrap C index mean difference, 0.022; 95%CI 0.005-0.04]. In addition, IS in 3 categories (Low, Int, High) and as a continuous variable were also both significantly associated with DFS (all p<0.001). In univariable analysis, IS was also associated with DFS in 6 months arm (p<0.0001); a similar trend was observed in 3 months arm (p=0.09). Conclusions: IS was confirmed as a prognostic factor of DFS in Stage III CC patients in the prospective IDEA France cohort study. Clinical trial information: NCT03422601.