tbuckley/cabot-search huggingface dataset:
Full enrollment results from an extended phase I, multicenter, open label study of marizomib (MRZ) with temozolomide (TMZ) and radiotherapy (RT) in newly diagnosed glioblastoma (GBM).
Authors: Warren P. Mason, Santosh Kesari, Roger Stupp, Dawit Gebremichael Aregawi, David Eric Piccioni, Patrick Roth, Annick Desjardins, Steven D. Reich, Marie-Laure Casadebaig, Ileana Elias, Benjamin Winograd, Nancy Levin, Daniela Annenelie Bota
Journal: Journal of Clinical Oncology (2019)

2021 Background: Proteasome inhibition sensitizes glioma cells to TMZ and RT, providing a novel therapeutic strategy for GBM. MRZ, an irreversible, brain-penetrant, pan-proteasome inhibitor with anti-glioma activity was combined with standard TMZ/RT → TMZ in newly diagnosed GBM (NCT02903069), to determine the recommended dose (RD). The primary endpoint of this expanded phase 1 trial was toxicity, with secondary endpoint of OS. Methods: Patients were enrolled in separate cohorts (TMZ/RT+MRZ→TMZ+MRZ, N=15; TMZ/RT→TMZ+MRZ, N=18) in dose-escalation (3+3 design), followed by dose-expansion (N=20) with TMZ/RT+MRZ at RD → TMZ+MRZ at RD. A separate cohort received TMZ/RT→TMZ+MRZ at RD with Tumor Treating Fields (Optune, N=13). MRZ was infused IV (10 min at 0.55, 0.7, 0.8, and 1.0 mg/m 2 ) on Days 1, 8, 15, 29, 36 (42-day TMZ/RT+MRZ cycle) and Days 1, 8, 15 (28-day TMZ+MRZ cycle). Results: 66 patients treated; median age 58 years, 68% male, 50% receiving corticosteroid at baseline, 52% unmethylated MGMT. Dose-limiting toxicities (DLTs) in dose-escalation cohorts: 1 (fatigue) at 0.7 mg/m 2 MRZ, 5 (ataxia/diarrhea; ataxia/confusion; myocardial infarction, delirium/ataxia; ataxia/fatigue) in 1.0 mg/m 2 cohorts. MRZ demonstrated a steep dose-response with treatment-emergent adverse events (TEAEs)/DLTs predominately CNS AEs (Grade ≥3 TEAEs in 12 of 12 patients at 1.0 mg/m 2 vs 22 of 41 patients at ≤0.8 mg/m 2 ); the RD for MRZ was determined to be 0.8 mg/m 2 . Most common TEAEs (all grades): fatigue, nausea (both 70%), hallucination (54%), vomiting (53%), headache (47%), confusional state (33%), ataxia, constipation, muscular weakness (all 29%). Conclusions: CNS TEAEs were short-lasting, reversible and ameliorated by early dose reductions (29% patients dose-reduced), allowing patients to remain on treatment. For patients receiving MRZ with TMZ/RT→TMZ (N=35), the median OS was 14.8 months (17 deaths, median follow-up 14.3 months), and 7 patients remain active (Cycles 11-23). The MRZ RD + TMZ/Optune combination was tolerated, with 4 of 13 patients treated on this arm remaining active. An international Phase 3 trial (EORTC 1709-BTG/CCTG CE.8, NCT03345095) is ongoing. Clinical trial information: NCT02903069.
Fulvestrant in hormone receptor-positive advanced breast cancer: A UK retrospective multicenter study.
Authors: Karim Keshwani, anna lerner, Benjamin Sanderson, Ruth E. Board, Michael Flynn, Elizabeth Sharkey, Alicia Frances Clare Okines, Apostolos Konstantis, Rebecca Roylance, Daire Hanna, Judy King, Ravindhi Murphy, Farah Rehman, Amy Elizabeth Guppy, Charlotte Westbury, Elena Takeuchi, Emma Spurrell, Fharat Raja
Journal: Journal of Clinical Oncology (2019)

e12525 Background: Fulvestrant is a selective oestrogen receptor (ER) down regulator used to treat hormone receptor-positive advanced breast cancer in postmenopausal women. It is used at various time points in treatment. However, variations in funding across the UK limit universal patient access to fulvestrant. We sought to investigate its use and efficacy in UK clinical practice. Methods: Medical records of 458 patients with ER positive advanced breast cancer treated with fulvestrant between August 2011 and November 2018 at ten UK centres were reviewed. Demographics and treatment responses were recorded. Efficacy was analysed by progression free survival (PFS), clinical benefit rate (CBR) and overall survival (OS) with alive patients censored to December 2018. Results: Of the 445 patients with analysable data, median age was 70 (range 21-95). ECOG performance status was 0-1 in 70% (n = 285). Bone was most commonly involved (73%, n = 323), 307 (69%) had visceral involvement and 228 (51%) had nodal metastases. Both locally advanced and metastatic patients had received a median 2 (range 0 – 5 for all patients) prior endocrine therapy lines and 0 (range 0 – 6) prior chemotherapy lines. Fulvestrant was the first line treatment in 49 (11%). Median duration of fulvestrant use was 5 months (range 1-88). Overall, median PFS was 6 months. This increased to 7 months in absence of visceral disease, in whom 22% of patients achieved a prolonged PFS extending to 30 months. Fulvestrant produced a CBR of 41% in 355 patients assessed, of which 16% partially responded. First radiological assessment occurred at median 3 months (range 1-37). Progressive disease accounted for 82% of discontinuation compared to 4% owing solely to adverse events in 341 assessed patients. Median OS for the whole cohort was 23 months. Conclusions: This is one of the largest studied patient cohorts treated with fulvestrant. This heavily pre-treated population reflects real life fulvestrant use. Reassuringly the results confirm its clinical benefit in maintaining disease response. Given its potential synergistic action with other systemic agents, fair access to this highly active drug for all patients is as important now as ever before.
Integrated multi-omic analysis to reveal comprehensive tumor heterogeneity and novel immunophenotypic classification in primary liver cancer.
Authors: Qi Zhang, Yu Lou, Xueli Bai, Tingbo Liang
Journal: Journal of Clinical Oncology (2019)

e15662 Background: Hepatocellular carcinoma (HCC) is heterogeneous,especially in multifocal tumors, which decreases the efficacy of clinical treatments. Understanding tumor heterogeneity is critical when developingnovel treatment strategies. However, a comprehensive investigation of tumor heterogeneity in HCC is lacking, and the available evidence regarding tumor heterogeneity has not ledto improvements inclinical practice. Methods: We harvested 42 samples from eight HCC patients and evaluatedtumor heterogeneity using whole-exome sequencing, RNA sequencing, mass spectrometry-based proteomics and metabolomics, cytometry by time-of-flight, and single-cell analysis. Immunohistochemistry and quantitative polymerase chain reactions (qPCRs) were performed to confirm the expression levels of genes. Results: Tumor heterogeneity is considerable with regard to the genomes, transcriptomes, proteomes, and metabolomes of lesions and tumors. The immune status oftheHCC microenvironment had a relatively low level of heterogeneity. Targeting local immunity could be a suitable intervention with balanced precision and practicability. By clustering immune cells in the HCC microenvironment, we identified three distinctive HCC subtypes with immunocompetent, immunodeficient, and immunosuppressive features. We further revealed the specific metabolic features and cytokine/chemokine expression levels of the different subtypes. Determiningthe expression levels of PTPRCand FOXP3using qPCR and immunohistochemistry in two independent HCC cohorts facilitated the correct classification of HCC patients and the prediction of their prognosis. Conclusions: There is comprehensive intratumoral and intertumoral heterogeneity inall dimensions ofHCC. Based on the results, we propose a novel immunophenotypic classification of HCCs that facilitates prognostic prediction and may support decision making with regard to the choice of therapy.
Clonal hematopoiesis of indeterminate potential (CHIP) mutations in solid tumor malignancies.
Authors: Madison Conces, Ying Ni, Peter Bazeley, Bhumika Patel, Pauline Funchain, Hetty E Carraway
Journal: Journal of Clinical Oncology (2019)

1507 Background: CHIP predisposes to a higher risk of developing hematological malignancies and cardiac events. Multiple germline mutations have been recognized as contributing to CHIP, most notably ASXL1, DNMT3A, and TET2. The frequency of CHIP mutations in solid tumor malignancies (STM) is unknown. We report the frequency and incidence of CHIP mutations in adult patients (pts) with STM. Methods: Data from 880 pts with STM who underwent next generation sequencing (NGS) at Foundation One from 2013-2017 was collected. This excluded two pts with known primary hematological malignancies who were removed. A list of CHIP mutations using NCCN guidelines as well as numerous original research articles was created, and tabulation of pathogenic or likely pathogenic mutations ( ASXL1, DNMT3A, TET2, JAK2, SF3B1, TP53, GNAS, N/KRAS) was performed. To date, only the lung, breast, and colorectal cancer pts have been annotated (N = 372) since these cancers have an overall higher incidence and prevalence in society. Results: Annotation of lung cancer pts (155/880), breast (118/880), and colorectal cancer pts (99/880) is collected and represents about 40% of all pts. At least one CHIP mutation was present in 44.5% (69/155) lung cancer pts, 32.2% (38/118) in breast cancer pts, and 7.1% (7/99) in colorectal cancer pts. Most common mutations found were TP53 and KRAS at 29.6% (110/372) and 28.0% (104/372), respectively. Mutations in genes not known to be somatic drivers for solid tumor malignancies, particularly SF3B1, DNMT3A, and JAK2, were found at very low frequencies 0.8% (3/372), 0.5% (2/372), and 0.3% (1/372), respectively. Notably, ASXL1 and TET2 mutations were not encountered in any pts. Conclusions: In tumor NGS testing, multiple CHIP mutations were noted to be present within the cohort of lung, breast, and colorectal cancers. There is a need to further understand clinical consequences of CHIP mutations incidentally found in pts with STM given known clinical implications of CHIP. We will report on clinical data (comorbidities), response/non-response to therapy, and identify specific molecular patterns of mutations to further understand the role of CHIP in pts with STM.
RESILIENT: Study of irinotecan liposome injection (nal-IRI) in patients with small cell lung cancer—Preliminary findings from part 1 dose-defining phase.
Authors: Luis G. Paz-Ares, David R. Spigel, Christoph Zielinski, Yuanbin Chen, Maria Jove, Oscar Juan Vidal, David Chu, Patricia Rich, Theresa M. Hayes, M Vanesa Gutierrez Calderon, Reyes Bernabe Caro, Alejandro Navarro, Afshin Dowlati, Bin Zhang, Yan Moore, Haofei Tiffany Wang, Natalya Nazarenko, Santiago Ponce Aix, Paul A. Bunn
Journal: Journal of Clinical Oncology (2019)

8562 Background: Nal-IRI is investigated as monotherapy in patients with SCLC who progressed on or after platinum regimen. The RESILIENT study is a Part 1 study of a Phase 2/3 trial to assess safety, tolerability, and efficacy of Irinotecan Liposome Injection in patients with SCLC. Methods: Nal-IRI is evaluated in patients ≥18 yrs with advanced SCLC with an ECOG performance status ≤1 and adequate organ function; prior exposure to immunotherapy is allowed. Safety and tolerability at dose levels of 85 mg/m 2 and 70 mg/m 2 are the primary endpoints, with assessment of exploratory efficacy signal. Results: At 24 Dec 2018 safety cutoff 12 patients in Part 1 received ≥1 dose of nal-IRI (Cohort 1 [C-1] at 85 mg/m 2 dose n=4; Cohort 2 [C-2] at 70 mg/m 2 dose n=8; median age 60.0 yrs; range 49–73 yrs). Three patients experienced ≥1 DLT (Cohort 1 n=3/4; Cohort 2 n=0/8). Most frequent treatment-emergent adverse events (TEAE) were gastrointestinal (GI) disorders (any grade): diarrhea (91.7%), nausea (58.3%), vomiting (41.7%), decreased appetite (58%), abdominal pain (33%) manageable by antidiarrheal regimen and antiemetics; as well as fatigue (50%) and asthenia (37.5%). Overall, hematologic toxicity was neutropenia (any grade) at 16.7% and anemia (any grade) at 16.7%. At 11 Dec 2018 efficacy cutoff the best objective response was partial response (PR) at 33.3% in 4/12 patients (C-1 n=1/4; C-2 n=3/8), median time to response was 6 wks. Overall disease control rate (DCR) was 58.3%; progressive disease (PD) was observed in 2 patients (16.7%), and 3 patients were non-evaluable (25%). Conclusions: Initial assessment suggests that nal-IRI at 70 mg/m 2 dose given bi-weekly is well-tolerated and has promising antitumor activity in patients with SCLC who progressed on or after platinum regimen. Part 1 dose expansion is ongoing. Clinical trial information: NCTN03088813. [Table: see text]
Phase I/II study of axitinib (axi) and nivolumab (nivo) in patients with metastatic renal cell carcinoma (mRCC).
Authors: Matthew R. Zibelman, Daniel M. Geynisman, Ana M. Molina, Lois Malizzia, Karthik Devarajan, Diana Luong, Elizabeth Sullivan, Michael Anthony Carducci, Elizabeth R. Plimack
Journal: Journal of Clinical Oncology (2019)

4567 Background: Drug combinations targeting vascular endothelial growth factor (VEGF) and the programmed death one (PD-1) pathway have demonstrated encouraging efficacy in patients (pts) with mRCC. We are conducting a phase I/II trial combining the VEGF-targeting tyrosine kinase inhibitor (TKI) axi and the PD-1 inhibitor nivo in mRCC pts. Methods: The phase I portion of this investigator-initiated, multi-center trial enrolled pts with TKI-refractory mRCC (any line) and no prior anti-PD-1. It used a 3+3 design, with axi dosing starting at 3 mg orally BID, escalating to a target dose of5 mg BID. Nivo dosing was fixed at 240 mg IV Q2 weeks or 480 mg Q4 weeks. Eligible pts received axi alone for a one week induction, followed by combination dosing. There was a 4 week period to assess for dose limiting toxicities (DLTs). The primary endpoint for phase I was safety and establishment of a recommended phase II dose (RP2D) for axi. Safety and early efficacy data for the phase I cohort are presented. Results: Twelve pts received treatment during the phase I portion, with all evaluable for toxicity. Ten were 2 nd line and 2 were 3 rd line or beyond. One DLT was noted in the first cohort of three pts (grade 3 autoimmune disorder), thus that cohort was expanded. No further DLTs were reported at axi 3 mg BID, or at further expansion to 5 mg BID. Grade 3 adverse events (AEs) at least possibly related to one of the drugs included expected side effects HTN, hyperglycemia, and transaminitis. One patient received steroids for an immune related AE (grade 3 transaminitis) that resolved to grade 1 with steroids. No grade 4-5 AEs occurred. Axi at 5 mg BID was chosen as the RP2D. With 10 pts evaluable for efficacy, 4 pts had partial responses, 4 pts had stable disease, and 2 had progressive disease. Updated efficacy data will be presented. Conclusions: The phase I portion of this phase I/II trial has demonstrated expected safety and established 5 mg BID as the RP2D axi dose. This ongoing VEGF TKI/PD1 trial incorporating two drugs already approved for mRCC pts has shown encouraging signs of efficacy and has now expanded to include treatment naïve pts in addition to TKI-refractory pts as part of phase II. Clinical trial information: NCT03172754.
Insulin resistance measured by the triglyceride-glucose index and risk of obesity-related cancers: An epidemiological investigation in more than 500,000 individuals.
Authors: Josef Fritz, Tone Bjorge, Gabriele Nagel, Hans Concin, Jonas Manjer, Christel Häggström, Pär Stattin, Tanja Stocks, Hanno Ulmer
Journal: Journal of Clinical Oncology (2019)

1552 Background: The role of insulin resistance as a mediator in the association of body mass index (BMI) with site-specific cancer risk has, to our knowledge, never been systematically quantified. We aimed to determine to what extent insulin resistance measured as the logarithmized triglyceride glucose product (TyG index) mediates the effect of BMI on risk of obesity-related cancers. Methods: A total of 510,471 individuals from six European cohorts with a mean age of 43.1 years were included in the study. We fitted Cox models, adjusted for relevant confounders, to investigate associations of TyG index with ten common obesity-related cancer sites, and quantified the proportion of the effect of BMI mediated through TyG index. Results: During a median follow-up of 17.2 years, 16 052 individuals developed obesity-related cancers. TyG index was associated with the risk of cancers of the kidney (hazard ratio (HR) per one standard deviation increase 1.13, 95% confidence interval: 1.07-1.20), liver (1.13, 1.04-1.23), pancreas (1.12, 1.06-1.19), colon (1.07, 1.03-1.10), and rectum (1.09, 1.04-1.14). Substantial proportions of the effect of BMI were mediated by TyG index for cancers of the pancreas (42%), rectum (34%), and colon (20%); smaller proportions for kidney (15%) and liver (11%); none for endometrium, ovary and breast (postmenopausal). Conclusions: In this pooled cohort study including more than 500,000 individuals, insulin resistance measured as the logarithmized triglyceride glucose product significantly mediated the effect of overweight and obesity on risk of cancers of the kidney, liver, pancreas, colon, and rectum. In contrast, insulin resistance did not mediate the risk for cancers of the endometrium, ovary and breast. Our results confirm a promoting role of insulin resistance in the pathogenesis of gastrointestinal cancers. Although often claimed, insulin resistance does not appear to connect excess body weight with cancers of the female reproductive organs.
Safety and efficacy of PD-1 blockade-activated multiple antigen specific cellular therapy alone or in combination with apatinib in patients with advanced solid tumors: A pooled analysis of two prospective trials.
Authors: Lijun Liang, Yixuan Wen, Kaiyuan Hui, Xiaodong Jiang
Journal: Journal of Clinical Oncology (2019)

e14014 Background: The cancer-cell-killing property of Multiple Antigen Specific Cellular Therapy (MASCT) may be enhanced by blocking PD-1 in vitro and reversing vascular endothelial growth factor (VEGF)/VEGF receptor 2-mediated immunosuppression with apatinib. We analyzed pooled data from our phase Ⅰ/Ⅱ trials to assess the toxicity and efficacy of PD-1 blockade (SHR-1210)-activated MASCT (aMASCT) alone or in combination with apatinib in patients with advanced solid tumors. Methods: Patients with selected types of advanced solid tumors received aMASCT alone (n = 32) or aMASCT plus apatinib (500 mg q.d., n = 38) after standard treatment. The primary endpoint was the safety profile; antitumor response, progression-free survival (PFS), and overall survival (OS) were the secondary endpoints. Circulating regulatory T cells (Tregs) were quantified before and after aMASCT infusion. Results: Treatment-related adverse events (AEs) occurred in 18/32 (56.3%) and 25/38 (65.8%) patients in the aMASCT and aMASCT plus apatinib groups, respectively; fever and chills were the most frequently observed AEs. No serious AEs were reported, and apatinib did not increase immunotherapy-related toxicity. The objective response rate was improved with aMASCT plus apatinib group compared with aMASCT group (34.2% and 18.8%, respectively); PFS was longer (median, 6.0 and 4.5 months, respectively, P &lt; 0.05), but OS was not improved (median, 10.0 and 8.2 months, respectively, P = 0.098). Multivariate analyses indicated that two or more cycles of aMASCT treatment was an independent favorable prognostic factor of PFS and OS. Circulating Tregs decreased in both groups after one cycle of aMASCT treatment (P &lt; 0.05). Conclusions: Treatment with aMASCT plus apatinib was safe and effective in advanced solid tumors. Apatinib plus aMASCT may be beneficial for patients with advanced solid tumors. Clinical trial information: NCT02844881; NCT02858232.
A single center experience of the impact of treatment-related toxicity in the clinical outcomes of elderly patients with metastatic germ cell tumors.
Authors: Anand Sharma, David Palmer, Hannah Brown, Sophie Merrick, Andrew Gogbashian, Nikhil Vasdev, Ben Pullar, Marcia Hall
Journal: Journal of Clinical Oncology (2019)

e16048 Background: Germ cell tumours (GCT) are predominantly a disease of the young, with &lt; 10% of cases being diagnosed at ≥45 years. Platinum based chemotherapy is the gold standard in treating these patients. Data regarding outcomes and treatment toxicities in elderly patients is lacking. We studied the efficacy, toxicities and survival rates in a cohort of men diagnosed with GCT aged ≥45 years receiving chemotherapy in a metastatic setting. Methods: Data was collected retrospectively from 48 patient’s ≥45 years with GCT’s identified at Mount Vernon Cancer Centre, London. The histology, stage and international germ cell consensus (IGCC) risk classification was identified in all patients. Data was collected regarding chemotherapy regimens, number of cycles completed, toxicities and complications that led to treatment modifications or early cessation. Treatment toxicities were evaluated using the common terminology criteria for adverse events (ctCAE) grading. We then assessed progression free survival, relapse rates and overall survival (OS). Results: We identified 48 patients diagnosed with GCTs aged ≥45 years. The median age at diagnosis was 52 (range 45-70) and 75% of patients were aged ≥50. Classic seminoma and nonseminomatous GCTs were seen in 65% and 35% of patients, respectively. 75% of patients were ≥stage II at diagnosis. In total 29 patients received BEP, 4 EP, 7 Carboplatin AUC10, 2 Carboplatin AUC7 and 5 received POMBACE. 73 % (35/48) of patients experienced one or more complication/s from chemotherapy (15/48 ctCAE grade ≥3), of which the most common were neuropathies (27%), thromboembolism (10%) and tinnitus (10%). In 8 cases omissions or dose reductions had to be made and treatment delays occurred in 3 cases. Only 2 patients did not complete all intended cycles. Over 70% (35/48) of patients had an OS of &gt; 5 years. One patient died during chemotherapy due to gastro-intestinal bleed. Conclusions: Survival rates in patients with GCTs aged ≥45 treated with chemotherapy are good with the majority achieving a &gt; 5 year OS. Although age is not a prognostic factor, these patients are more prone to toxicities and have underlying comorbidities. This data will be of value to oncologists weighing up the risks versus benefits of treatment in this older cohort of patients in combination with similar studies.
Genome-wide study of salivary microRNAs as potential noninvasive biomarkers for detection of nasopharyngeal carcinoma.
Authors: Lirong Wu, Xia He
Journal: Journal of Clinical Oncology (2019)

e17535 Background: Since recent studies reported that blood-based microRNAs (miRNAs) could detect cancers and predict prognosis, a new field has been opened for circulating miRNAs as potential biomarkers in cancers. In this pilot study, we evaluated to our knowledge for the first time whether salivary miRNAs might be applicable as innovative biomarkers for Nasopharyngeal carcinoma (NPC) detection. Methods: By high throughput label-free microarray contained 2025 human miRNA probes, 12 down-regulated miRNAs from saliva samples from 22 newly diagnosed NPC patients and 25 healthy controls were selected. Then, their target genes enriched by gene ontology and pathway were used to construct a regulatory and interaction networks. The receiver operating characteristic analyses (ROC) and logistic regression were calculated to assess discriminatory accuracy. Results: Advanced bioinformatics analysis was conducted to understand the most significant hub gene is TP53 that probably regulated by the 12 dysregulated miRNAs. The ROC including the 12 miRNAs as well as the 6 significant deregulated miRNAs separated NPC patients from healthy controls with a very high (areas under the receiver operating characteristic curve [AUC] = 0.999, sensitivity = 100.00%, specificity = 96.00%) and high accuracy (AUC = 0.941, sensitivity = 95.45%, specificity = 80.00%), respectively. Conclusions: Differentially expressed miRNAs might play critical roles in NPC by regulating their target genes, and may have the potential to become diagnostic biomarkers.