bluuebunny/crossref_metadata_2025_split huggingface dataset:
A phase I study of a novel MDM2-P53 antagonist APG-115 in Chinese patients with advanced soft tissue sarcomas.
Authors: Zhang Xing , Wen Xizhi , Yang Chen , Zeng Shan , Men Lichuang , Wang Hengbang , Ma Yuxiang , Zhang Yang , Peng Ruiqing , Weng Desheng , Zhang Li , Ji Jiao , Liu Wenqin , Liang Zhiyan , Huang Yingjie , Yang Dajun , Zhai Yifan 
Published: May 2019

3124 Background: APG-115 is a novel and orally active small-molecule MDM2 inhibitor. APG-115 alone or in combination with chemotherapeutic, targeted or IO agents have shown potent antitumor activities in multiple human xenograft tumor models and human cancer patient derived xenograft (PDX) models. Methods: The patients with advanced solid tumors were enrolled in this study in China (CTR20170975). The study objectives were to assess safety, pharmacokinetics (PK), pharmacodynamics (PD) and antitumor activity of APG-115. The patients received APG-115 (ranging 100–200 mg) orally QOD for first 21 days of a 28-day-cycle, until disease progression. Antitumor response assessment was performed every 8 weeks per RECIST v1.1. Archived tumor tissues were collected for analyses of MDM2 and TP53 before treatment. Results: As cut-off on Jan 4 2019, total 13 patients (9 soft tissue sarcomas (STSs), 2 adenoid cystic carcinomas (ACCs) and 2 osteosarcomas) were treated in 3 cohorts of APG-115 (100mg, 150mg, 200mg). The median number of prior systemic anticancer therapies was 2 (range 0-4). Two DLTs were observed in one patient at 200mg including thrombocytopenia and febrile neutropenia. The most common TEAEs (≥50% of pts) included: anemia, thrombocytopenia, vomiting, hypercholesterolaemia, and leukopenia. SAEs occurred in 7 patients (54%), four of which were treatment related. The most common Grade 3 or 4 TRAEs were anemia (38.5%), thrombocytopenia (38.5%), leukopenia (30.8%), and neutropenia (23.1%). One partial response was observed in a liposarcoma patient with MDM2-amplification and TP53-wild type at the 150mg cohort, 5 patients (3 STSs, 2 ACCs) had SD as the best overall response. PK analyses indicated an approximately dose proportional increase in Cmax and AUC0-t following a single or multiple oral administration across dose levels. Preliminary PD data showed that serum MIC-1 increase was exposure dependent within the dose range tested. Conclusions: Preliminary data suggested that APG-115 had promising anti-tumor activity in treatment of patients with MDM2-amplification and TP53-WT liposarcoma. Safety profile and PD effect were consistent with other MDM2 inhibitors. Dosing regimen optimization are ongoing. Clinical trial information: CTR20170975.
A dose escalation pharmacokinetic (PK) and pharmacodynamic (PD) study of mTORC1/2 inhibitor XP-105 (BI 860585) as monotherapy and in combination with exemestane or paclitaxel in patients (pts) with advanced solid tumors.
Authors: De Braud Filippo G. , Wu Wentao Jason 
Published: May 2019

3127 Background: Resistance to mTORC1 inhibition may develop through feedback loop leading to upregulation of mTORC2. XP-105, also known as BI 860585, is a potent dual mTORC1/2 inhibitor designed to overcome such resistance. This Phase 1 trial (NCT01938846) was performed to determine the MTD and activity of XP-105 alone or in combination with exemestane or paclitaxel in pts with advanced solid tumors. Methods: A 3+3 escalation design was used; Pts received XP-105 (5–300 mg/day) monotherapy or (40–220 mg/day) combined with fixed-dose exemestane 25 mg/day, or 80–160 mg/day combined with paclitaxel 60 or 80 mg/m2/week. A reduction of pAKT/total AKT ratio was used as a PD marker of target inhibition. Results: 90 pts were treated (41 with monotherapy, 25 and 24 in combination with exemestane, or paclitaxel respectively). XP-105 MTD was defined as 220 mg daily for monotherapy, and 160mg daily with exemestane 25 mg/d or paclitaxel 80 mg/m2/week. In the monotherapy arm, stable disease (SD) was reported in 8 pts (20%), with a median duration of 11 months. In the exemestane combination arm, 4 (16%) partial responses (PR) were reported. In the paclitaxel combination arm, 1 complete response (CR) and 4 PRs were reported (OR rate 21%). Disease control rate (CR/PR/SD) was 20%, 28%, and 58% in the monotherapy, XP-105/exemestane, and XP-105/paclitaxel arms, respectively. A sustained reduction in pAKT/total AKT to < 50% of baseline levels was observed with XP-105 ≥120mg daily. Overall, XP-105 was well tolerated; in the XP-105/paclitaxel combination the most frequent drug-related AEs were diarrhea and fatigue (58.3% each), hyperglycaemia (54.2%), anaemia (50%). Grade ≥3 AEs were hyperglycaemia, fatigue, diarrhea, anaemia, leukopenia. No PK interaction was observed. Conclusions: The MTD for XP-105 monotherapy and in combination with exemestane or paclitaxel was defined as 220 mg and 160mg once daily, respectively. Combination regimens showed higher activity as compared to monotherapy with durable OR in about 20% of pts. The observed safety profile of XP-105 compared favorably to those reported from other mTOR inhibitors. Clinical trial information: NCT01938846.
Cytoplasmic cyclin E independently predicts recurrence in older patients with primary breast cancer.
Authors: Johnston Simon , Parks Ruth , Syed Binafsha Manzoor , Green Andrew R. , Hunt Kelly , Keyomarsi Khandan , Ellis Ian O. , Cheung Kwok-Leung 
Published: May 2019

3128 Background: Primary breast cancer in the older ( > 70 years) population has distinct biological characteristics associated with favourable outcome, such as higher rate of estrogen receptor (ER) positivity. Due to comorbidities, older patients with primary breast cancer are more likely to die of non-breast cancer-related causes compared to their younger counterparts. Biomarkers that may influence treatment strategy therefore require interpretation in the specific biological and clinical context of older women. Cyclin E regulates cell cycle transition from G1 to S phase, and its deregulation is implicated in breast cancer pathogenesis. Tumour-specific isoforms of cyclin E localise to the cytoplasm. Expression of cytoplasmic cyclin E (c-cyclin E) is linked with poor clinical outcome. We now present multivariate analysis of breast cancer-specific survival (BCSS) by c-cyclin E and clinical markers of disease biology from a cohort of older women. The primary outcome, BCSS, excludes deaths from competing causes and is used as a surrogate for tumour biology. Methods: Between 1973 and 2010, 813 older women underwent initial surgery for early breast cancer and were followed up in a dedicated clinic in Nottingham. Excised tumours from 517 of these patients were successfully incorporated into a tissue microarray (TMA). Expression of c-cyclin E was assessed by IHC using an assay developed at MDACC, along with a panel of 24 biomarkers. Of these, ER, progesterone receptor (PR), human epidermal growth factor 2 (HER2) and Ki67 are in current clinical use and are analysed alongside c-cyclin E. Grade was assessed from the primary tumour. Multivariate analysis of BCSS was performed by Cox proportional hazard test. Results: In multivariate analysis alongside markers of disease biology currently used in the clinic (ER, PR, HER2, Ki67 and grade), c-cyclin E is the only factor that independently predicts BCSS in this cohort of older women (HR 5.0, 95% CI 2.1 – 12.0; p< 0.001). Conclusions: In the older population with primary breast cancer, c-cyclin E expression is the only independent biological marker of BCSS. Patients with low c-cyclin E expression are unlikely to die of breast cancer. These data have potential to influence treatment strategy in older patients. For example, patients with ER+, c-cyclin E negative disease plus multiple co-morbidities may be suitable for primary endocrine therapy. This hypothesis warrants prospective clinical evaluation.
The Cancer Molecular Screening and Therapeutics Program (MoST): Actionable mutation frequencies in a population with rare and less common cancers.
Authors: Thavaneswaran Subotheni , Ballinger Mandy L. , Grady John , Cowley Mark , Joshua Anthony , Sebastian Lucille , Collignon Emily , Silvestri Audrey , Kansara Maya , Pinese Mark , Sjoquist Katrin Marie , Hague Wendy , Lee Chee Khoon , Simes John , Thomas David Morgan 
Published: May 2019

3136 Background: Personalizing therapy will arguably have no greater impact than on patients (pts) with rare (< 6 per 100,000 population) or less common cancers (6-12/100,000). MoST combines a molecular screening platform and biomarker-driven treatments for pts with advanced cancer, with a particular focus on rare and less common cancers (RLC). Methods: Molecular screening was performed using in-house and commercial panels on archival tumor tissue. A Molecular Tumor Board by consensus reported on pathogenic variants with potential therapeutic actionability. Tiers of actionability were defined as: Tier 1–eligible for a MoST substudy; Tier 2–clinical evidence of efficacy in any cancer type, Tier 3—preclinical evidence. The clinical and molecular characteristics of the first 1,000 pts are presented here. Results: Pts were recruited from Sept 2016 to Dec 2018. A report was issued in 94% of cases in a median of 7.7 weeks from consent. In 6%, there was insufficient tissue. The median age at cancer diagnosis was 35 years (range 4-85 years), and 49% were male. Pts had a median of 2 lines of prior systemic therapy (0-11), and a median baseline ECOG performance status of 0 (range 0-3). 82% of pts had RLCs. A total of 2642 pathogenic variants were reported, of which 1144 (43%) were deemed therapeutically actionable. 651(57%) of actionable variants (AVs) occurred in RLC (Table). Most commonly, AVs were found in the cell cycle, homologous recombination repair (HR) and fibroblast growth factor (FGF) pathways. 559(66%) of pts had at least one AV identified, 30% tier 1, 63% tier 2 and 6% tier 3, including 66% of RLC. In 30% of cases, a tumor mutational burden >11 mutations/ megabase was reported. Conclusions: Here we report a high frequency of AVs in RLC, providing a rational basis for assessing the potential of personalized therapy in a population with a historically unmet need for effective treatment. Clinical trial information: ACTRN12616000908437. [Table: see text]
Effects of immune architecture on response to adjuvant capecitabine in triple-negative breast cancer (FinXX trial).
Authors: Chumsri Saranya , Asleh Karama , Brauer Heather Ann , Hinerfeld Douglas , Kachergus Jennifer M. , Lauttia Susanna , Lindman Henrik , Nielsen Torsten , Joensuu Heikki , Thompson E. Aubrey 
Published: May 2019

3142 Background: Recent studies have demonstrated a benefit of adjuvant capecitabine, particularly in triple negative breast cancer (TNBC) patients with residual disease after neoadjuvant chemotherapy. However, biomarkers to predict which patients are more likely to benefit from capecitabine are needed. Methods: The nanoString Breast Cancer 360 (BC360) and PanCancer Immunoncology (IO360) panels were used to quantify mRNA expression in TNBC samples in the FinXX trial. FinXX is a phase III trial which randomized high risk patients to receive either 3 cycles of docetaxel followed by 3 cycles of cyclophosphamide, epirubicin, and fluorouracil (Arm A: T+CEF) vs. 3 cycles of docetaxel plus capecitabine followed by 3 cycles of cyclophosphamide, epirubicin, and capecitabine (Arm B: TX+CEX). Gene signature scores were analyzed using prespecified algorithms developed by nanoString. Digital Spatial Profiling was carried out using GeoMX platform. Results: A total of 111 TNBC patients in FinXX trial were included (57 in Arm A and 54 in Arm B) with 10.2 years median follow up. There were 7 cancer- and immune-related gene signatures identified by BC360 and IO360 panels that were significantly associated with improved recurrent free survival favoring an addition of capecitabine. These include cytotoxic cell signature (HR 0.37, 95%CI 0.15-0.92, p 0.03), endothelial signature (HR 0.18, 95%CI 0.04-0.83, p 0.03), mast cell signature (HR 0.43, 95%CI 0.21-0.88, p 0.02), PDL2 gene (HR 0.29, 95%CI 0.09-0.99, p 0.05), immunoproteasome (HR 0.34, 95%CI 0.13-0.89, p 0.02), exhausted CD8 (HR 0.29, 95%CI 0.09-0.97, p 0.04), and PD1 (HR 0.44, 95%CI 0.20-1.02, p 0.05). Conclusions: Analysis of RNA abundance signatures strongly suggests that there are important immune features that are associated with benefit from capecitabine in TNBC. However, analysis of RNA extracted from whole tumor sections lacks spatial discrimination. We anticipate that a more detailed, spatially-defined analysis of protein abundance, using the novel NanoString GeoMX platform, will provide more insights and define specific immune features associated with improved outcome. Additional results of GeoMX will be reported at the meeting. Clinical trial information: NCT00114816.
Three versus six months adjuvant FOLFOX or CAPOX for high risk stage II and stage III colon cancer patients: The efficacy results of Hellenic Oncology Research Group (HORG) participation to the International Duration Evaluation of Adjuvant chemotherapy (IDEA) project.
Authors: Sougklakos Ioannis , Boukovinas Ioannis , Xynogalos Spyros , Kakolyris Stylianos , Ziras Nikolaos , Vaslamatzis Michael , Athanasiadis Athanasios , Ardavanis Alexandros , Androulakis Nikolaos E. M. , Christopoulou Athina , Makrantonakis Paris , Bompolaki Iliada , Christofyllakis Charalampos , Kentepozidis Nikolaos K. , Emmanouilides Christos E. , Kouroussis Charalambos , Prinarakis Efthimios , Kalisperi Ageliki , Mavroudis Dimitrios , Georgoulias Vassilis 
Published: May 2019

3500 Background: The IDEA aimed to investigate whether a 3-month (3M) of oxaliplatin/fluoropyrimidines-based adjuvant chemotherapy (CT) is non-inferior to the 6-month (6M) in 3-year disease free survival (DFS) in stage high risk stage II and in stage III colon cancer (CC). Methods: HORG-IDEA randomized patients between 3M and 6M of CT with FOLFOX4 or CAPOX with primary end point the 3 years DFS (3yDFS). Results: In total 1121 patients, 413 with high risk stage and 708 with stage IIICC, were randomized between May 2009 and October 2015. The median follow-up was 67 (38-126) months. There were 79 DFS events (43 in 3M and 38 in 6M arm) in high risk stage II patients leading to 3yDFS rate of 82.7 and 83.4% for 3M and 6M, respectively (HR: 1.05; 95%CI: 0.68-1.63, p = 0.829). Similarly, 214 DFS events (161 in 3M and 153 in 6M arm) has been recorded in stage III patients, leading to a 3yDFS rate of 72.9% in the 3M vs. 74.1% in the 6M (HR = 1.06; 95%CI: 0.81–1.42, p = 0.622). For high risk stage II patients receiving FOLFOX4, 3yDFS rate was 76.7% in the 3M vs.79.3% in the 6M (HR = 1.21; 95%CI: 0.54–2.70 p = 0.641). For high risk stage II patients receiving CAPOX 3-year DFS rate was 85.4% in the 3M vs. 83.8% in the 6M (HR = 0.99; 95%CI: 0.59–1.67 p = 0.968). For stage III CC patients receiving mFOLFOX6, 3-year DFS rate was 71.5% in the 3M vs.77.3% in the 6M (HR = 1.18; 95%CI: 0.74–1.86 p = 0.479). For stage III CC patients receiving CAPOX 3-year DFS rate was 74.5% in the 3M vs. 74.7% in the 6M (HR = 0.99; 95%CI: 0.70–1.44 p = 0.991). Conclusions: The results of the HORG-IDEA study are in line with those of the global IDEA project, indicating that 3yDFS is depended on the administered adjuvant regimen, and the choice of regimen and duration should be personalized. Clinical trial information: NCT01308086.
Updated results of TRIBE2, a phase III, randomized strategy study by GONO in the first- and second-line treatment of unresectable mCRC.
Authors: Cremolini Chiara , Antoniotti Carlotta , Lonardi Sara , Rossini Daniele , Pietrantonio Filippo , Cordio Stefano Sergio , Bergamo Francesca , Marmorino Federica , Maiello Evaristo , Passardi Alessandro , Masi Gianluca , Tamburini Emiliano , Santini Daniele , Grande Roberta , Zaniboni Alberto , Granetto Cristina , Murgioni Sabina , Aprile Giuseppe , Boni Luca , Falcone Alfredo 
Published: May 2019

3508 Background: In the phase III TRIBE study FOLFOXIRI/bev significantly improved Response Rate (RR), PFS and OS when compared with FOLFIRI/bev as initial treatment of mCRC. However, the actual advantage by the triplet could be lower when compared with a pre-planned sequential strategy of doublets (FOLFOX, FOLFIRI). TRIBE2 (NCT02339116) is a phase III trial in which unresectable mCRC pts were randomized 1:1 to FOLFOX/bev followed by FOLFIRI/bev after PD (arm A) or FOLFOXIRI/bev followed by the reintroduction of the same regimen after PD (arm B). A pre-planned interim analysis showed a significant advantage for arm B in terms of PFS2, primary endpoint of the study, defined as the time from randomization to PD on any treatment given after first PD or death (PD2). Methods: The study had 80% power to detect a HR for PFS2 of 0.77 in favor of arm B with an overall 2-sided-α error of 0.05 (0.0131 and 0.0455 for the interim and final analyses, planned at 303 and 466 PFS2 events, respectively). Secondary endpoints included RR, 1st-PFS, i.e. the time from randomization to the first evidence of PD or death (PD1), 2nd-PFS, i.e. the time from PD1 to PD2, and OS. Results: From February 2015 to May 2017, 679 pts (arm A/B: 340/339) were enrolled in 58 Italian sites. Main pts’ characteristics were (arm A/B): right side 38%/38%, synchronous mets 89%/89%, RAS mutant 65%/63%, BRAF mutant 10%/10%. At a median follow up of 30.6 mos, 514 (arm A/B: 272/242) PD2, 594 (arm A/B: 303/291) PD1 and 408 (arm A/B: 217/191) OS events were collected. A significant advantage by upfront FOLFOXIRI/bev was confirmed in terms of PFS2 (19.1 vs 16.4 mos, HR 0.74, 95%CI 0.62-0.88, p<0.001), RR (62% vs 50%, OR 1.61, 95%CI 1.19-2.18, p=0.002) and 1st-PFS (12.0 vs 9.8 mos, HR 0.75, 95%CI 0.63-0.88, p<0.001). A significant OS benefit for pts in arm B was also observed (27.6 vs 22.6 mos, HR: 0.81, 95%CI: 0.67-0.98, p=0.033). Out of 594 pts with a PD1 event, 470 (79%, arm A/B: 251/219) received a treatment after PD. In the per-protocol analysis (N=323), pts in arm B showed significantly longer 2nd-PFS (6.5 vs 5.8 mos, HR 0.76, 95%CI 0.59-0.97, p=0.024). Conclusion: Upfront FOLFOXIRI/bev followed by the pre-planned reintroduction of the same agents after PD provided a statistically significant and clinically relevant PFS2 and OS benefit when compared with the pre-planned sequential administration of FOLFOX/bev and FOLFIRI/bev in unresectable mCRC patients. A median OS of 27.6 mos was reached despite the high percentage of pts with poor prognostic features ( RAS and BRAF mutations, right side, synchronous mets). Clinical trial information: NCT02339116.
CCTG CO.26: Updated analysis and impact of plasma-detected microsatellite stability (MSS) and tumor mutation burden (TMB) in a phase II trial of durvalumab (D) plus tremelimumab (T) and best supportive care (BSC) versus BSC alone in patients (pts) with refractory metastatic colorectal carcinoma (rmCRC).
Authors: Chen Eric Xueyu , Jonker Derek J. , Loree Jonathan M. , Kennecke Hagen F. , Berry Scott R. , Couture Felix , Ahmad Chaudhary E. , Goffin John R. , Kavan Petr , Harb Mohammed , Colwell Bruce , Samimi Setareh , Samson Benoit , Abbas Tahir , Aucoin Nathalie , Aubin Francine , Koski Sheryl L. , Wei Alice Chia-chi , Tu Dongsheng , O'Callaghan Christopher J. 
Published: May 2019

3512 Background: Targeting both PD-L1 and CTLA-4 may be synergistic immunotherapy approaches. CO.26 evaluated if dual inhibition leads to improved pt survival vs BSC alone in rmCRC. Methods: rmCRC pts were randomized 2:1 to D+T vs BSC. Treatment consisted of D (1500 mg) D1 q 28 days and T (75 mg) D1 for first 4 cycles, and supportive measures. Primary endpoint was overall survival (OS). Two-sided p < 0.10 was considered statistically significant. Cell-free (cf)DNA sequencing for MSI and TMB used GuardantOMNI panel and baseline plasma. Results: From 08/2016-06/2017, 180 pts were enrolled. Pt characteristics were balanced between arms. At median follow-up of 15.2 months (mos), median OS was 6.6 mos for D+T and 4.1 mos for BSC (p = 0.07; Hazard ratio (HR): 0.72, 90% confidence interval (CI): 0.54 – 0.97). Progression free survival (PFS) was 1.8 mos vs 1.9 mos, respectively (HR 1.01, 90% CI 0.76 – 1.34). Disease control rate (DCR) was 22.6% for D+T and 6.6% for BSC (p = 0.006). cfDNA analysis was successful in 168/169 pts (99.4%). Two pts were MSI-high. In 166 MSS pts, OS HR was 0.66 (p=0.024; 90% CI 0.49-0.89). Excluding the MSI-H cases (TMB of 74.7 and 247.1 mts/Mb), mean TMB was 20.4 ± 16.3 mts/Mb (range: 0.96 – 114.0). In MSS pts, a pre-specified cutpoint of 20 mts/Mb stratified pts into high and low TMB groups but was not predictive for OS , PFS, or DCR (interaction p-values > 0.7). Using a minimum p-value approach, pts with TMB >28 mts/Mb (21% of MSS pts) had the greatest OS benefit (HR 0.34, 90% CI 0.18-0.63) for D+T (interaction p = 0.07). High TMB was associated with a trend in worse prognosis for OS in the BSC arm using both 20 mts/Mb (HR 1.26, 90% CI 0.76-2.12) and 28 mts/Mb (HR 2.59 90% CI 1.46-4.62) cutpoints. Conclusions: D+T significantly prolonged OS in pts with rmCRC. High TMB may select a group of MSS pts who benefit from D+T. Plasma TMB appeared prognostic in the BSC arm. This is the first study showing combined PD-L1 and CTLA-4 inhibition prolongs survival in pts with MSS rmCRC. Updated results based on deaths in more than 90% of pts will be presented. Clinical trial information: NCT02870920.