bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase I study of regorafenib and sildenafil in advanced solid tumors.
Authors: Poklepovic Andrew Stewart , Gordon Sarah W. , McGuire William P. , Thacker Leroy R. , Deng Xiaoyan , Tombes Mary Beth , Shrader Ellen , Ryan Alison A. , Kmieciak Maciej , Dent Paul 
Published: May 2020

3593 Background: Regorafenib (R) is an oral multikinase inhibitor with anti-angiogenic properties approved for use in several solid tumors. Sildenafil (S) is an oral phosphodiesterase-5 (PDE5) inhibitor that interacts synergistically with R in both short-term and colony formation assays to kill multiple cancer cell types. Mechanistic studies identified that PDE5 knockdown enhances R lethality, suggesting a direct target effect for S. Methods: A single-center, open-label, dose-escalation study was conducted in adults with advanced solid tumors. Patients (pts) took R (120 or 160 mg) and S (50 or 100 mg) once daily days 1 through 21 of each 28-day cycle. Pts remained on study treatment until progression or excessive toxicity, with response assessments every 8 wks. The maximum tolerated dose (MTD) was defined as the maximum tested dose with ≤1/6 pts experiencing dose-limiting toxicity (DLT), with Cycle 1 as the DLT observation period. Results: 32 pts were enrolled and 29 treated at 3 dose levels (DLs). Median duration of treatment was 8 (range 2 – 101) wks. One of 6 evaluable pts treated at DL2 (160 mg R + 50 mg S) experienced DLT (grade 4 lipase increase). One of 12 evaluable pts treated at DL3A (160 mg R + 100 mg S, the MTD) experienced DLT (grade 3 rash and grade 3 muscle pain). The toxicity profile was generally consistent with that seen in R monotherapy at FDA-approved doses. 10 pts had a best response of progressive disease (PD). 14 pts had a best response of stable disease (SD), 5 of whom had stable disease duration > 24 wks. 5 treated pts were not evaluable for response. Notably, 2 pts with ovarian cancer and 1 with cervical cancer had stable disease > 24 wks. Analyses of correlative studies to examine pharmacokinetics and drug combination pharmacodynamic effects are underway. Conclusions: The combination was well-tolerated. The recommended phase 2 dose is 160 mg R + 100 mg S. Objective responses were not observed, but prolonged stable disease was seen in a subset of pts. Encouraging disease control was seen in gynecologic cancers. Dosing up to 100 mg S is safe concurrently with standard doses of R, and may be considered as an adjunct to R in future trials. Evaluation of R+S in gynecologic cancers warrants further consideration. Clinical trial information: NCT02466802 . [Table: see text]
Myelodysplastic syndrome and acute myeloid leukemia as side effect of PARP inhibitors.
Authors: Master Samip R. , Mansour Richard P. 
Published: May 2020

3601 Background: Acute myeloid leukemia(AML) and myelodysplastic syndrome(MDS) have been rarely noted in patients on PARP inhibitors. The actual incidence is unknown and it has been put has warning/precaution of FDA label for olaparib, niraparib and rucaparib. Methods: The FDA has made the data on the adverse effects of various treatments available to the general public through the FDA Adverse Events Reports System (FAERS) public dashboard. We investigated the adverse events reported for PARP inhibitors like olaparib, niraparib and rucaparib for the years 2017-2019 to find out the number of patients who had acute leukemia or myelodysplastic syndrome reported while on those medications. Results: A total of 8151 adverse events were reported between 2017 and 2019 for olaparib, niraparib and rucaparib. Out of which, 6077 were serious and 1121 deaths were reported. There were 237 reports of AML and MDS, which compromise 2.9 % of total events reported. We also looked that cyclophosphamide data for comparison purposes during the same period. There were 29,162 adverse events reported for cyclophosphamide, out of which 963 i.e. 3.3% were AML and MDS. For olaparib, 2523 adverse events were reported and 173 (6.8%) were MDS/AML. For niraparib, 5496 adverse events were reported and 41(0.7%) were MDS/AML. For rucaparib, 153 adverse events were reported and 4 (2.6%) were MDS/AML. Conclusions: Based on this retrospective data, AML/MDS is an adverse event in pts of PARP inhibitors and needs to be monitored. Pts on olaparib seem to have high risk of AML/MDS compared to other two to PARP inhibitors.
Results of a phase Ib trial evaluating the safety and clinical activity of sapanisertib (TAK 228) in combination with serabelisib (TAK 117) and paclitaxel in patients with advanced ovarian, endometrial, or breast cancer.
Authors: Williams Casey B. , Williams Kirstin Anne , Krie Amy K. , De Pradip , Dey Nandini , Leyland-Jones Brian , Starks David , Rojas-Espaillat Luis Alexander 
Published: May 2020

3604 Background: The link between taxane resistance and activation of PI3K/AKT/mTOR signaling suggests that by inhibiting this pathway in combination with anti-microtubule agents like paclitaxel may improve treatment outcomes in many malignancies. To investigate this further we combined the TORC 1/2 inhibitor sapanisertib (TAK-228), the PI3Kα isoform inhibitor serabelisib (TAK-117), and paclitaxel in a phase I trial to determine the safety, efficacy, and RP2D. Methods: Open label, cohort study using a traditional 3+3 dose escalation design with a maximum of 5 dosing cohorts. A dose expansion of cohort 4, the recommended RP2D, is planned for February 2020. Results: Enrollment to the DLT evaluation has been completed and the clinical results are summarized in Table. Sixteen patients have been enrolled; a majority were heavily pretreated and resistant to paclitaxel. Overall, the combination was safe and tolerable. One DLT occurred due to renal dysfunction in cohort 5. 360 adverse events have been reported, but only 28 (8%) grade 3 or 4 events. The most common events were leukopenia and non-febrile neutropenia. Two patients required dose reductions as a result of pneumonitis. The ORR is currently 46% in 13 evaluable patients. CBR is 69% and PFS is currently at 10 months. Two patients achieved a CR and three patients remain on treatment. Conclusions: The combination proved to be well tolerated in the doses and schedules used in cohorts 1-4 and exhibited very promising clinical activity in heavily pretreated patients. This regimen could prove to be a highly effective treatment option and a phase 2 study is warranted at the RP2D. Clinical trial information: NCT03154294 . [Table: see text]
Results of a completed first-in-human phase Ib dose-escalation study of oral CBL0137 in patients with advanced solid tumors.
Authors: Fedyanin Mikhail , Tryakin Alexey , Lisyanskaya Alla Sergeevna , Solovyeva Ekaterina , Fadeeva Natalia , Gladkov Oleg , Moiseyenko Vladimir , Cheporov Sergey V. , Shpigotskaya Polina , Purmal Andrei , Miller Langdon L. , Leonov Andrey , Zakurdaeva Kristina , Gurova Katerina , Gudkov Andrei , Tjulandin Sergei 
Published: May 2020

3607 Background: Curaxin CBL0137 is a novel compound with broad anticancer activity in animal models. The drug is a non-genotoxic DNA intercalator that interferes with histone/DNA binding causing decondensation of chromatin in tumor cells, functional inactivation of histone chaperone FACT, activation of p53 and IFN responses, and inhibition of pro-cancer transcriptional factors, MYC, NF-kB, HSF1, and HIF1a. Methods: The study enrolled adults with advanced chemorefractory solid tumors, ECOG PS ≤2, and adequate organ function. The primary objective was to find the maximum tolerated dose (MTD) and recommended dosing regimen (RDR). Secondary objectives were to evaluate CBL0137 safety, pharmacokinetics, and efficacy. CBL1037 was given orally once daily (QD) for the first 14 days of repeated 28-day cycles. A 3+3 dose escalation determined the MTD, defined as the highest dose at which ≤1 of 6 pts had Cycle 1 dose-limiting toxicity (DLT). Pharmacokinetics were assessed on Days 1 and 13. Efficacy was evaluated every 8 weeks. Results: 60 pts were enrolled (females/males [n]: 42/18; median [range] age 56 [25-76] years; ECOG PS [n] 0/1/2: 8/49/3); cancer types [n]: ovarian cancer [15], colorectal cancer [14], breast cancer [11], others [20]) over 16 dose levels ranging from 4 mg to 200 mg QD. Durations of therapy ranged from 6 to 342 days. Three DLTs were observed: prolongation of QTc Gr 3 (88 mg QD), neutropenia/thrombocytopenia Gr 4 (200 mg QD), and LV dysfunction Gr 3 (200 mg QD). Dose-dependent nausea/vomiting was observed and was Gr 2-4 at 200 mg QD. Gr 1/2 photosensitization occurred in 11 subjects across doses from 48 to 200 mg QD but was successfully managed with sun protection and resulted in no dose modifications or discontinuations. On Day 1, mean (range) plasma CBL0137 Tmax values were 5.1 (1-10) hrs. Generally linear increases in AUC occurred with increasing CBL0137 dose. Mean (range) t1/2 values were 25.6 (0.3-166) hrs, with minor dose dependency. Mean (range) Day 13/Day 1 Ctrough ratios showed 3.6 (1.7-7.2)-fold accumulations. Disease control was registered in 11 pts who had stable disease (SD). Target lesion regressions up to 21% were documented in 4 patients with breast cancer (2), sarcoma (1), and ovarian cancer (1). Pts with breast cancer (1) and sarcoma (1) had SD for > 36 weeks. Conclusions: The Phase 2 RDR for oral CBL0137 was established as 180 mg QD x 14 days in 28-day cycles based on bone marrow and gastrointestinal DLTs at 200 mg QD. CBL0137 showed a manageable safety profile with efficacy signals. Further study as a component of combinations is planned. Clinical trial information: 847 .
Identifying pan-cancer transcriptomic determinants of perineural and lymphovascular invasion using machine learning.
Authors: Guo Jimmy , Hoffman Hannah I. , Hwang Peter G , Kim Daniel Y , Alshalalfa Mohammed , Mahal Brandon Arvin Virgil , Hong Theodore S. , Hwang William L. 
Published: May 2020

3621 Background: Tumor invasion of nerves, blood vessels, and lymphatics are a primary means of local recurrence and escape from the local microenvironment, resulting in metastases and poor clinical outcomes. However, the genetic drivers that are most pertinent to these malignant processes are not well understood, and few therapeutics successfully target perineural invasion (PNI) and lympho-vascular invasion (LVI). Identifying genetic drivers and biomarkers can be valuable for therapeutic targeting and prognostication. Methods: We analyzed surgical pathology reports and bulk RNA-seq data of 1,624 patients across 12 cancer types from The Cancer Genome Atlas (TCGA). Differential gene expression analysis between patients with and without PNI/LVI was performed using DEseq2 in Python while adjusting for age, sex, race, and cancer type. Genes with an adjusted p-value < 0.001 were then used to derive parsimonious signatures using random forest classifier and recursive feature selection algorithms. Results: To assess whether these invasive histological phenotypes have clinical ramifications, we examined outcomes data and found that patients with PNI or LVI have reduced overall (OS) and disease-free survival (DFS) ( p < 0.05) relative to those without. In addition, patients with both PNI and LVI have the lowest DFS from our pan-cancer analysis, suggesting that each may have non-redundant contributions to poor outcomes. From the differential gene expression analysis, we identified a set of 621 and 606 genes that were highly associated with PNI and LVI, respectively (padj < 0.001). Many of these genes such as TEKT5 (padj = 3.18 x 10−64), which is canonically associated with ciliary and flagellar microtubules, and SCRIB (padj = 1.60 x 10−21), which helps establish apico-basal cell polarity, have not been described previously in relevance to PNI and LVI, and warrant further scientific and clinical investigation. These genes were ultimately condensed into a signature that optimizes for both model simplicity and goodness of fit with up to 90% accuracy as determined by trials on both a logistic regression and neural network model. Conclusions: We concluded from a pan-cancer analysis that PNI and LVI are associated with poor outcomes, and we were able to robustly identify sets of genes that characterize each invasive mechanism for further functional investigation.
Increased tumor purity and improved biomarker detection using precision needle punch enrichment of pathology specimen paraffin blocks: Method validation and implementation in a prospective clinical trial.
Authors: Killian Jonathan Keith , Wright Chris , Chan Lindsay , Danziger Natalie , Elvin Julia Andrea , Vergilio Jo-Anne , Lin Douglas I. , Williams Erik Abraham , Ramkissoon Shakti H. , Severson Eric Allan , Hemmerich Amanda , Duncan Daniel , Edgerly Claire I. , Tse Julie Y , McGregor Kimberly , Schrock Alexa Betzig , Alexander Brian Michael , Ross Jeffrey S. , Redman Mary Weber , Herbst Roy S. 
Published: May 2020

3622 Background: While many sequencing assays may be geared for short variants (SV), more complex biomarkers such as genomic loss of heterozygosity (gLOH) score, also referred to as homologous recombination deficiency (HRD) score, require higher tumor purity for confident detection. Practical methods to increase tumor nuclei percentage (TN%) from pathology specimens are needed to achieve biomarker results to maximize patient matching to approved therapies and/or clinical trial enrollment. Methods: Tumor purity of specimens was determined by the computational analysis pipeline component of the FDA-approved NGS assay, FoundationOneCDx. In the validation study, specimen purities for each tissue block were compared following either no enrichment (UnE, n=46), pathologist-directed enrichment by straight razor blade (RBE, n=30) or precision needle punch (NPE, n=47). Post-enrichment H&E slides confirmed target region sampled for the NPE arm. Based upon validation data, the needle punch process was implemented for the Lung-MAP prospective clinical trial (LM-NPE). TN% was compared between the first 55 tested LM-NPE specimens and the validation study to assess performance on real-world samples outside of a controlled validation experiment. Results: The mean computational TN% in the 4 groups were: UnE: 33%; RBE: 30%; NPE: 52%; and LM-NPE: 48%. In the validation study, NPE had significantly higher purity than both UnE and RBE (p<0.001); in the trial arm, LM-NPE performed equivalently to NPE (p=0.344). Based upon a 30% tumor purity cutoff, gLOH could be determined for 52% UnE, 50% RBE, 89% NPE and 71% LM-NPE. Comparing NPE and LM-NPE groups reveals no statistical difference in Pass/Fail rates for gLOH determination (p=0.883; Fisher’s Test). Conclusions: Precision needle punch cores from tissue blocks have elevated tumor purity, and consequently, a greater number of successful gLOH determinations. Moreover, this process is rapid and inexpensive. Precision punches may constitute best practice with respect to enriching tumor cells from low-purity specimens for biomarker detection in a routine laboratory specimen-processing setting. [Table: see text]
Survival associated with mutations in SWI/SNF chromatin remodeling complex genes.
Authors: Hassett Michael J. , Tramontano Angela , Zhang Zilu , Kehl Kenneth L. , Schrag Deborah 
Published: May 2020

3643 Background: The SWI/SNF (SWitch/Sucrose NonFermentable) chromatin remodeling complex (CRC) - a combinatorial assembly of products from multiple genes - alters histone/DNA interactions and thereby impacts transcription, DNA replication/repair, and cell division. Studies suggest that over 20% of human cancers contain mutations in at least one SWI/SNF gene, implying that it is the most highly mutated CRC in human cancer. To address existing knowledge gaps, we sought to evaluate the association between SWI/SNF mutations and overall survival (OS). Methods: We identified adult cancer patients who consented to have OncoPanel testing (Dana-Farber/Brigham & Women’s Hospital’s next generation sequencing platform) from June 2013-August 2019. These data were merged with institutional electronic health records and National Death Index vital status. We determined mutation frequency and co-occurrence for the nine SWI/SNF genes included in OncoPanel (ARID1A, ARID1B, ARID2, BCL11B, PBRM1, SMARCA4, SMARCB1, SMARCE1, and SS18). We assessed the association between mutation and OS (from time of OncoPanel testing) for cancers with at least 500 analyzed and 20 mutated cases, controlling for age and TP53 status. Exploratory analyses were conducted using cBioPortal and SAS (no multiple comparison adjustment). Results: Among 25,434 samples from 24,648 patients, a mutation in at least one evaluated SWI/SNF gene was identified in 26% of cases (ARID1A 10.5%, ARID1B 7.2%, SMARCA4 5.5%, PBRM1 4.9%, ARID2 4.8%, BCL11B 3.5%, SMARCE1 1.1%, SMARCB1 1.0%, and SS18 0.7%). The most frequently mutated cancers included small bowel (52%), endometrial (49%), ampullary (48%) and bladder (45%). Co-occurrence was common (30 of 36 potential gene-pairs), with the largest associations (odds ratio; all P < .05) seen for SMARCB1:BCL11B (4.19), ARID1B:BCL11B (3.87), ARID2:BCL11B (3.85), and SMARCA4:BCL11B (3.78). Associations between having a mutation and OS were seen for the following cancers/genes (odds ratio; all P < .05): ARID1A (colorectal 0.72, pancreatic 1.46), ARID1B (melanoma 0.32), SMARCA4 (esophagogastric 1.48, non-small cell lung 1.89, ovarian 0.43), SMARCB1 (non-small cell lung 2.04), and SS18 (soft tissue sarcoma 2.06). Conclusions: Mutations in SWI/SNF genes are widespread, with mutation rates varying by cancer type. Co-occurrence was common, especially with BCL11B. Associations with OS were both favorable and unfavorable, with variability seen by gene and cancer type. Future research should explore the mechanisms by which mutations in SWI/SNF genes influence treatment response/OS.
Tailored treatment strategy for locally advanced rectal carcinoma: Five-year results of the French phase II, randomized, multicenter GRECCAR4 trial.
Authors: Rouanet Philippe 
Published: May 2020

4014 Background: Preoperative radiochemotherapy and total mesorectal excision are the standard-of-care for locally-advanced rectal carcinoma, but some patients are over- or undertreated. Our phase II study assessed the feasibility of tailored radiochemotherapy, based on tumor response to induction high-dose chemotherapy (FOLFIRINOX). Methods: We enrolled 206 patients; good responders after chemotherapy (≥75% tumor volume reduction) were randomly assigned to immediate surgery (arm A) or standard radiochemotherapy (Cap 50: 50 Gy and oral capecitabine daily) plus surgery (arm B). Poor responders were randomly assigned to Cap 50 (arm C) or intensive radiochemotherapy (Cap 60 (60 Gy irradiation), arm D) before surgery. Results: After induction treatment, 194 patients were classified as good (n=30, 15%) or poor (n=164, 85%) responders, and included in arms A and B (16 and 14 patients) or C and D (113 and 51 patients). The primary objective was obtained: (90% CI) R0 resection rates in the four arms respectively were 100% (74–100), 100% (85–100), 83% (72–91), and 88% (77–95). At 5 years: overall survival 90% (CI: 47.3-98.5), 93.3% (CI: 61.3-99.0), 84.3% (CI: 71.0-91.8), 86.1% (CI: 71.6-93.5); disease-free survival 80% (CI: 40.9-94.6), 89.5% (CI: 64.1-97.3), 72.9% (CI: 58.5-82.9), 72.8% (CI: 57.7-83.2); local recurrence 0, 0, 2.1% (CI: 0.3-13.9), 9.3% (CI: 3.6-23.0); metastasis 20% (CI: 5.4-59.1), 10.5% (CI: 2.7-35.9), 18% (CI: 31.8-94.6), 18.8% (CI: 10.2-33.0). Late morbidity and quality of life evaluations showed no significant difference between arms. Conclusions: Tailoring preoperative radiochemotherapy based on induction treatment response is safe and promising. Early tumoral response to induction chemotherapy can discriminate tumor prognosis. Clinical trial information: NCT01333709 .
Pre- versus postoperative CAPOX plus bevacizumab (CAPOX-Bev) for resectable liver metastases from colorectal cancer (CLM): A randomized phase II/III trial (HiSCO-01).
Authors: Takakura Yuji , Shinozaki Katsunori , Ikeda Satoshi , Egi Hiroyuki , Hirata Yuzo , Shimomura Manabu , Oshiro Takafumi , Hinoi Takao , Sumitani Daisuke , Nakahara Masahiro , Yoshimitsu Masanori , Honmyo Naruhiko , Kobayashi Tsuyoshi , Ohdan Hideki 
Published: May 2020

4021 Background: The role of neoadjuvant chemotherapy, particularly for those with initially resectable CLM, is controversial. And the optimal regimen and duration to be used in the neoadjuvant setting is not established. We conducted prospective, multicenter, randomized phase II/III study to assess pre-operative 8 cycles of CAPOX-Bev (arm A) plus radical surgery compared with post-operative 8 cycles of CAPOX-Bev (arm B) for patients (pts) with resectable CLM. Methods: The primary endpoint in the Phase II was completion rate of protocol treatment (more than 6 cycles of CAPOX-Bev plus R0 surgical resection) and PFS in the Phase III. The secondary endpoints were OS, ORR (arm A), liver damage (arm A), safety. The Phase III part was terminated due to slow enrollment. Results: 81 pts were enrolled from 10 centers between November 2010 and November 2017. The full analysis set consisted of 76 pts who started protocol treatment (arm A 37 vs. arm B 39). 76 pts had the following characteristics: median age 66 (27-80), median number of liver metastases 2 (1-14), 69.7% male, 67.1% synchronous and 94.7% primary resected. Completion rate of protocol treatment was 89.2% in arm A and 71.8% in arm B (p = .06). ORR was 63.9%, including 2 pts who had pathologically complete response (5.6%). Only 1 pts in arm A could not undergo surgery due to progression of disease. In the chemotherapy safety population, arm B was associated with more grade 3 neutropenia and grade 3 gastrointestinal disorder than arm A. The most frequent surgical adverse event was biliary fistula, with an incidence of 0% in arm A and 10.3% in arm B (p = .02). No patient died from treatment-related adverse events. The median follow-up time was 40 months. The rate of PFS at 3 years was 32.2% in arm A versus 38.5% in arm B (p = .99). Conclusions: Pre-operative 8 cycles of CAPOX-Bev is compatible with radical surgery, but may have no impact on progression-free survival compared with post-operative chemotherapy. Clinical trial information: UMIN000003783 .
High amphiregulin mRNA expression is a strong prognostic biomarker with response to cetuximab in FIRE-1, CIOX, and FIRE-3.
Authors: Stahler Arndt , Stintzing Sebastian , Modest Dominik Paul , Ricard Ingrid , Kapaun Christine , Ivanova Boryana , Vehling-Kaiser Ursula , Fischer von Weikersthal Ludwig , Schalhorn Andreas , Stauch Martina , Kiani Alexander , Neumann Jens , Kirchner Thomas , Heinemann Volker 
Published: May 2020

4026 Background: Amphiregulin ( AREG) and epiregulin ( EREG) were discussed as biomarkers for treatment of metastatic colorectal cancer (mCRC). Data from randomized controlled trials (RCT) are limited. Methods: AREG and EREG mRNA expression by RTqPCR in relation to housekeeping genes were available from 688 patients of three RCT (FIRE-1, n = 192, FUFIRI vs. mIrOx; CIOX, n = 113, cetuximab + CAPIRI/CAPOX; FIRE-3, n = 383, FOLFIRI+cetuximab/bevacizumab) and were normalized to their respective range of each trial with median and 3rd quartile as threshold values. Kaplan-Meier estimated overall survival (OS) and progression-free survival (PFS). Cox regression analysis calculated hazard ratio (HR) and 95% confidence interval (95% CI). Overall response rate (ORR) was compared by chi square test. Results: Across all trials, high AREG mRNA expression appeared as strong prognostic biomarker for OS, PFS and ORR for all threshold values. In RAS wildtype patients, high AREG expression was associated with better OS and PFS for cetuximab but not bevacizumab treatment. (Table) No effects were seen for epiregulin when all trials were analysed together. Conclusions: High AREG mRNA expression appeared as strong prognostic biomarker in mCRC. Positive predictive information might exist for cetuximab treatment. [Table: see text]