bluuebunny/crossref_metadata_2025_split huggingface dataset:
Tumor growth rate as an early indicator of the efficacy of anti-PD-1 immunotherapy in advanced melanoma.
Authors: Tang Bixia , Chi Zhihong , Sheng Xinan , Si Lu , Cui Chuanliang , Kong Yan , Yan Xieqiao , Li Siming , Mao Lili , LIAN BIN , Wang Xuan , Bai Xue , Zhou Li , Dai Jie , Guo Jun 
Published: May 2019

e21050 Background: As immunotherapeutics take longer time to show clinical efficacy compared with chemotherapy and targeted therapy, it is critical to select patients with low tumor growth rate (TGR) prior immunotherapy as to get sufficient time for immunotherapeutics to play functions. However, which threshold of TGR before immunotherapy may be associated with good outcome remains unknown. Methods: Medical records from patients with advanced refractory melanoma prospectively treated in clinical trials (NCT02836795 and NCT03013101) of anti-PD-1 antibody toripalimab were analyzed. TGR was computed during the pretreatment period (reference) and the treatment period (treatment). Associations between TGR and objective response at the first evaluation, progression free survival (PFS), overall survival (OS) were computed. Results: We analyzed a total of 142 patients enrolled in these two clinical trials. Excluded for no measurable lesions in pretreatment period or incomplete imaging data through the pretreatment/treatment periods, a total of 90 patients could be explored for the relationship of TGR and the efficacy of anti-PD-1 antibody. TGR and hyperprogression were defined as Champiat S. used to make. The distribution of TGR is as follows: median 63.7 (range: -51~720). A total of 15 (16.7%), 41 (45.6%), 34 (37.8%) and 0 patients exhibited PR, SD, PD, CR, respectively. An association between lower TGR (TGR ≤55) and objective response was observed (P≤0.001). Among evaluable patients at week 8, 83.9% (13+34/56) and 26.5% (2+7/34) showed PR/SD from baseline tumor measurements for the group of TGR≤55 and TGR > 55, respectively. Median PFS was 5.5 0.9m in the group of TGR≤55 compared 1.8 0.4m in the group of TGR > 55 (P≤0.001). Median OS was not reached in the group of TGR≤55 group and was 15.9 1.8m in the group of TGR > 55 (p = 0·02). Two patients were confirmed pseudoprogression in the follow-up. The TGR of these two patients was lower than 55. Five patients experienced hyperprogression. The TGR of each patient was 9, 12, 54, 56, 78, respectively. Conclusions: Melanoma patients with TGR≤55 prior anti-PD-1 antibody therapy are more likely to benefit from this regimen. However, it could not predict patients who may develop hyperprogression after anti-PD-1 antibody therapy. Clinical trial information: NCT02836795 and NCT03013101.
Ingenol mebutate to treat lentigo maligna of the head (face and scalp): A prospective and multicenter single-arm phase 2 trial.
Authors: Montaudié Henri , Le Duff Florence , Butori Catherine , Hofman Veronique , Fontas Eric , Roger Coralie , Bahadoran Philippe , Perrot Jena-Luc , Desmedt Eve , Legoupil Delphine , Passeron Thierry , Lacour Jean-Philippe 
Published: May 2019

e21051 Background: Ingenol mebutate gel is indicated for the treatment of actinic keratoses. In vitro, it has been shown that ingenol mebutate can induce the apoptosis of melanoma cells, but robust clinical data are missing with only few case reports reported.The objectives of the current study was to assess the efficacy and safety of ingenol mebutate for the treatment of lentigo maligna (LM). Methods: We conducted a prospective, multicentre, and single-arm phase 2 trial (NCT02723721), from June 2016 to November 2017. This trial was planned according to Simon’s optimal two-stage design for a total sample size of 23 subjects. Adults with LM of the head were included. Ingenol mebutate gel 150 µg/g was applied daily for 3 consecutive days (one cycle). For patients having no remission or only partial remission at 2 months, a second cycle was done. Patients were evaluated 2 months after the (re)treatment and then every 3 months for 36 months if a complete response (CR) was obtained. The primary endpoint was the CR, defined as the complete clearing of the LM evaluated at 2 months clinically and histologically. Results: Twelve patients with a median age of 73 years were recruited. Only 2 achieved a CR; one patient relapsed during the first year following the treatment. Forty-seven adverse events related to ingenol mebutate were declared. Most were grade 3-4 (66%), but all were resolved without any sequelae. The mean maximum local skin reaction score was 12 (min: 3 – max: 22). These results should be interpreted with caution, because this study has limitations, such as the lack of a comparative arm and the heterogeneity of LM (size and localization). Conclusions: To our knowledge, we report the first prospective study evaluating the efficacy and safety of IM in patients with LM of the head. Unfortunately ingenol mebutate is not an effective treatment of LM in this indication at the concentration of 150 µg/g. Its use with a more intense regimen (more cycles and/or highest concentration (500 µg/g)) is also limited by a poor safety profile. Clinical trial information: NCT 02723721.
Somatic mutational profile of Merkel cell carcinoma treated with immune checkpoint blockade: Preliminary results from a planned multiplatform analysis.
Authors: Rosenbaum Evan , Kelly Ciara Marie , Barker Christopher Andrew , Adamson Travis , Kiesler Hannah , Hundal Jasreet , Paul Alexander J. , McLellan Michael D. , Walker Jason , Tap William D. , Coit Daniel G. , D'Angelo Sandra P. 
Published: May 2019

e21064 Background: Merkel cell carcinoma (MCC) is an immunogenic neuroendocrine malignancy with promising responses to immune checkpoint blockade (ICB). Although ICB is standard of care in advanced MCC patients, approximately 50% of patients are resistant to ICB. Thus, it is crucial to identify biomarkers predictive of response. Methods: To understand the genomic landscape of MCC, we performed exome capture sequencing on 27 tumor and matched normal samples from 25 patients with MCC treated at Memorial Sloan Kettering. Herein, we report the analysis of 16 paired samples from 14 patients. Nonsynonymous, high-confidence somatic mutations were identified and tumor reads aligned to the Merkel cell polyoma virus (MCPyV) were quantified. Results: Tumor and matched normal samples were sequenced to a median target coverage depth of 53x and 79x reads, respectively. One sample was not analyzed due to inadequate coverage. The MCPyV genome was detected in 12 of 13 patients (92%). The median somatic mutation burden among analyzed samples was 19 nonsynonymous variants per exome (range: 8 - 120). No recurrent driver mutations were identified in any sample. Four samples lacked potential driver mutations and, among the remaining 11 samples, 36 putatively oncogenic mutations were detected in 33 genes (variant allele frequency: 0.08 – 1), including genes involved in the cell cycle checkpoint ( TP53, RB1), DNA damage repair ( ERCC4, FANCA, FANCD2), PI3K-AKT-mTOR ( PIK3CA, PIK3CG), and Notch ( NOTCH1, NOTCH2) pathways. One sample with undetected MCPyV DNA demonstrated loss of heterozygosity of both TP53 and RB1. Four samples contained strand coordinated clusters of mutations in more than 20 distinct gene regions, suggesting an APOBEC-high mutagenesis signature. Conclusions: The MCPyV genome was detected in most tumors analyzed and tumor mutation burden was low in such tumors, consistent with published literature. Analysis of an additional 11 sample pairs is ongoing, along with personalized neoantigen binding predictions on all samples. Immunohistochemistry (IHC) for PDL1 and CD8 expression is in progress. Associations between the aforementioned and response to ICB will be reported.
INFORM2 exploratory multinational phase I/II combination study of nivolumab and entinostat in children and adolescents with refractory high-risk malignancies: INFORM2 NivEnt.
Authors: van Tilburg Cornelis Martinus , Witt Ruth , Pajtler Kristian W. , Christoph Plass , Poschke Isabel , Platten Michael , Harting Inga , Sedlaczek Oliver , Freitag Angelika , Meyrath David , Taylor Lenka , Balasubramanian Gnana Prakash , Jäger Natalie , Pfaff Elke , Worst Barbara Christine , Milde Till , Pfister Stefan M. , Jones David T. W. , Kopp-Schneider Annette , Witt Olaf 
Published: May 2019

TPS10065 Background: Immune checkpoint inhibition in children has shown limited success rates until now. This is most likely due to the fact that the vast majority of pediatric cancers are so-called immunologic cold tumors, and that patients have been enrolled in an unselected manner in single agent trials. Recently, it has been shown that the class I selective HDAC inhibitor entinostat has significant immune enhancing activity in vitro and in vivo. This is mediated through multiple mechanisms including depletion of myeloid-derived suppressor cells, activation of neoantigen transcription and increase of MHC expression. Methods: INFORM2 NivEnt is an exploratory nonrandomized, open-label, multinational and multicenter seamless phase I/II basket trial of nivolumab and entinostat in children and adolescents with relapsed, refractory or progressive high-risk solid and CNS tumors. Patients aged 6-21 will be allocated to the following biomarker-defined groups: high mutational load ( > 100 somatic SNVs/exome; group A), high PD-L1 mRNA expression (RPKM > 3; group B), focal MYC(N) amplification (group C), low mutational load and low PD-L1 mRNA expression and no MYC(N) amplification (Biomarker low group D). Phase I determines the recommended phase 2 dose for the combination for the age groups 6-11 and 12-21 years. Patients will receive nivolumab 3mg/kg every 2 weeks. Entinostat has 2 dose levels: 2mg/m2 and 4mg/m2 once per week. Patients can seamlessly enter the phase II which investigates activity (defined as best response during the first 6 cycles) in the 4 biomarker groups A-D. The duration of treatment is 12 cycles, preceded by 1 entinostat priming week. Interim analyses for futility will be performed after every 10 patients in each group. The study will enroll a maximum of 128 patients in Germany, The Netherlands, Sweden, France, Australia and additional countries under discussion. A comprehensive accompanying biomarker program will investigate a series of immune and epigenetic pharmacodynamic biomarkers. Clinical trial information: NCT03838042.
EMERALD: A randomized, open label, phase III trial to evaluate the efficacy and safety of elacestrant (RAD1901) versus investigator’s choice (IC) of endocrine therapy (ET) for ER+/HER2- advanced breast cancer (BC) following CDK4/6 inhibitor (CDK4/6i) therapy.
Authors: Bardia Aditya , Aftimos Philippe Georges , Jiang Hai , Bihani Teeru , Anderson-Villaluz Alfred T , Conlan Maureen G. , Kaklamani Virginia G. 
Published: May 2019

TPS1104 Background: Estrogen receptor-positive (ER+) BC comprises ~70% of all BC and advanced/metastatic ER+ disease (mBC) remains a major clinical challenge. The addition of CDK4/6i to ET has improved progression-free survival (PFS); however, novel treatments are needed after progression. Putative mechanisms of endocrine resistance, such as ESR1 mutations (mESR1), also indicate the need for additional therapies. Elacestrant, an oral selective estrogen receptor degrader (SERD), demonstrated anti-tumor activity in preclinical models of ER+ BC, including models resistant to CDK4/6i and models with mESR1. An interim evaluation of a phase 1 trial ( NCT02338349 ) of elacestrant in heavily pretreated patients (pts) with mBC, demonstrated an overall response rate (ORR) of 27% with a PFS of 5.4 mo (Bardia, SABCS, 2017). Responses were seen in pts with prior CDK4/6i and with wild-type (WT) or mESR1. Methods: This is a multicenter, international, randomized, open-label, active-controlled phase 3 trial for post-menopausal women or men with mBC. Pts must have received 1-2 prior lines of ET, ≤1 line of chemotherapy for mBC, and have documented progression on a CDK4/6i. Pts with measurable disease (RECIST v1.1) or bone-only disease are eligible. Pts are randomized 1:1 to elacestrant (400 mg orally daily) or IC of fulvestrant or an aromatase inhibitor. Stratification factors include ESR1 mutation status (detected by ctDNA), prior fulvestrant treatment and presence of visceral disease. The primary endpoints are PFS by blinded independent review committee (IRC) in pts with mESR1 and in all pts (WT or mESR1). Secondary endpoints include: overall survival; PFS by IRC in WT, PFS by investigator review; ORR, duration of response, and clinical benefit rate; safety; pharmacokinetics; and quality of life. Approximately 466 pts will be enrolled to detect 340 PFS events in all pts (power ≥90%, hazard ratio (HR) = 0.667) and 160 PFS events in the mESR1 subset (power ≥80%, HR = 0.610), overall α level at 2-sided 5% using the Hochberg procedure. The EMERALD study is open for enrollment. Clinical trial information: NCT03778931.
A multicentered randomized phase II comparison of single-agent carboplatin versus the combination of carboplatin and everolimus for the treatment of advanced triple-negative breast cancer.
Authors: Fukui Jami Aya , Shapiro Charles L. , Ru Meng , Klein Paula , Fasano Julie , Bhardwaj Aarti , Irie Hanna , Mandeli John P. , Goel Anupama , Kumarley Neha , Gomes Joni , Shuman Nicholas , Francois Damien , Tiersten Amy 
Published: May 2019

TPS1109 Background: Triple negative breast cancer (TNBC) is an aggressive disease with unmet clinical needs. Women with TNBC tend to be younger and demonstrate early recurrence, higher histological grade, higher rate of visceral metastasis and increased mortality rates when compared to hormone positive breast cancer. Prognosis for metastatic TNBC is especially poor. Due to lack of targeted therapies, there is no standard treatment of choice for triple negative breast cancer and chemotherapy remains the accepted standard. Many chemotherapeutic agents have been reported to have clinical activity either as single agent or in combination. Seventy percent of breast cancers with BRCA-1 germline mutations are triple negative, which suggests a shared carcinogenic pathway between them. In preoperative and metastatic settings, both TNBC and BRCA-1 associated breast cancers are particularly sensitive to DNA cross-linking agents such as platinum compounds due to defective DNA repair by homologous recombination. The recent TNT trial showed in patients with triple negative metastatic or recurrent locally advanced breast cancer with BRCA1/2 mutations, carboplatin resulted in a significantly higher overall response rate versus docetaxel (68% versus 33.3%; p=0.03). Triple negative breast cancers are associated with a high frequency of PTEN loss, which leads to mTOR activation. Moreover, it has been reported that mTOR activation may confer resistance to platinum agents such as cisplatin, a phenomenon that may be reversible by the addition of an mTOR inhibitor such as everolimus. There are reports of synergy between mTOR inhibitors and platinum compounds in pre-clinical and clinical data. Methods: We have opened a multi-centered randomized phase II trial comparing carboplatin AUC 4 q 3 weeks vs carboplatin AUC 4 q 3 weeks combined with daily 5 mg everolimus. 41 of planned 72 patients from the Mount Sinai Health System have been enrolled and are randomized in a 2:1 allocation. The primary objective is to compare progression-free survival in patients treated with carboplatin+everolimus to patients treated with carboplatin alone. Patients may have had up to 3 prior regimens for metastatic disease. Exploratory biomarker assessment is being done to identify markers of response. Clinical trial information: NCT02531932.
KX-ORAX-001: An open label, randomized, multicenter, phase III registrational study to determine the safety, tolerability, and tumor response of oraxol (HM30181A + oral paclitaxel) and its comparability to IV paclitaxel in patients with metastatic breast cancer (MBC).
Authors: Umanzor Funez Gerardo Antonio , Vassallo Rosa Haydee , Chivalan Castro Marco Antonio , Bejarano Suyapa A. , Ramirez Velasquez Julio Roberto , Kowalyszyn Ruben , Fein Luis Enrique , Cutler David , Goldfinch John , Moore Taryn , Kramer Douglas , Kwan Rudolf , Barrios Francisco 
Published: May 2019

TPS1116 Background: Paclitaxel is used in multiple cancer types including the treatment of breast cancer after failure of combination chemotherapy for metastatic disease or relapse within six months of adjuvant chemotherapy. Due to poor oral absorption, paclitaxel is administered IV and is associated with extra administration costs, inconvenience, burden for the patient, and hypersensitivity reactions to the solubilizing agent Cremophor EL. HM30181A is an intestinal P-gp pump blocker that, when administered orally with paclitaxel capsules (Oraxol), enhances paclitaxel absorption. Interim data from a phase I crossover study showed Oraxol (15-mg HM30181A + 205 mg/m2) 3 days/week had similar AUC0-∞ to IV paclitaxel 80 mg/m2 over 1 hour (Oraxol 5078 ng*hr/mL vs. IV paclitaxel 5652 ng*hr/mL), however the Cmax was substantially lower with Oraxol which may result in lower incidence of neuropathy. In a phase II single arm study of Oraxol in MBC 45.8% and 41.7% of subjects had PR or SD according to RECIST 1.1. Methods: KX-ORAX-001 is a, multi-national open-label, randomized (2:1 Oraxol to IV paclitaxel) phase III registration study comparing Oraxol (15-mg HM30181A + paclitaxel 205 mg/m2 daily x 3 days QW) to IV paclitaxel 175 mg/m2 over 3 hours every third week, in female patients with histologically- or cytologically-confirmed MBC for whom treatment with IV paclitaxel monotherapy has been recommended. The study is powered to demonstrate the superiority of Oraxol on confirmed tumor response rate vs IV Paclitaxel 175mg/m2 q3weeks. The primary efficacy endpoint is confirmed tumor response according to a blinded central radiologist using RECIST 1.1 criteria. The study is designed to enroll approximately 360 evaluable subjects. Two interim DSMB reviews were conducted at approximately 90 and 180 evaluable subjects for safety, futility, and efficacy. Enrollment was initiated Dec 2015 at 45 sites in Central and South America and enrollment has been completed. At final analysis, if there is an approximate difference of ≥10% favoring Oraxol, a p-value of 0.045 [2-tailed] will be achieved. Secondary endpoints are PFS and OS. Clinical trial information: NCT02594371.
A phase Ib trial of CB-839 (telaglenastat) in combination with radiation therapy and temozolomide in patients with IDH-mutated diffuse astrocytoma and anaplastic astrocytoma (NCT03528642).
Authors: Kizilbash Sani Haider , McBrayer Samuel , Port John , Reid Joel M. , Lanza Ian , Allred Jacob B , Chakravarti Arnab , Kunos Charles , Adjei Alex A. 
Published: May 2019

TPS2075 Background: IDH mutant astrocytomas express high levels of 2-hydroxyglutarate (2-HG), an oncogenic metabolite which drives gliomagenesis. Excess 2-HG inhibits branched chain amino acid transaminase, which catalyzes glutamate synthesis from branched chain amino acids. This defect causes these tumors to become more reliant on glutaminase for glutamate biosynthesis from glutamine. CB-839 (telaglenastat) is a novel glutaminase inhibitor which is well tolerated in humans. McBrayer et al have recently demonstrated that CB-839 further depletes intracellular glutamate and glutathione in IDH mutant glioma cells, and enhances RT (radiation therapy) efficacy in an orthotopic glioma model. Methods: NCI #10218 is a CTEP supported phase I clinical trial investigating the safety and tolerability of CB-839 when combined with RT/TMZ (temozolomide) in patients with previously untreated IDH mutant grade II/III astrocytoma. Patients with grade II and III astrocytomas will be treated with 50.4 and 59.4 Gy of RT, respectively, with standard doses of concurrent TMZ. CB-839 will also be administered orally concurrently with RT, with doses escalated in cohorts based on a standard 3+3 design. After defining the maximum tolerated dose (MTD) of CB-839, an expansion cohort will evaluate the pre- and post-CB-839 therapy metabolome of patients with IDH mutant astrocytoma. Enrollment to this cohort will require measurable disease and patients will additionally be treated with a 7 day run-in of CB-839 at MTD prior to RT. The effect of CB-839 on the metabolome will be studied in both plasma (LC/MS/MS) and tumor (magnetic resonance spectroscopy), along with PK to confirm adequacy of systemic exposure. Preliminary data on neurocognitive endpoints will also be acquired. NCI #10218 is currently activated for enrollment to cohort 1. Clinical trial information: NCT03528642.
The "INSIGHT" Trial: Two new strata of an explorative, open-labeled phase I study evaluating the feasibility and safety of subcutaneous IMP321 injections (LAG-3Ig fusion protein, eftilagimod alpha) combined with either standard-of-care drug therapy or PD-L1 inhibition (avelumab) in advanced-stage solid tumor entities.
Authors: Mueller Daniel Wilhelm , Goetze Thorsten Oliver , Atmaca Akin , Rafiyan Mohammad-Reza , Weidmann Eckhart , Brandts Christian H. , Pabst-Giger Urs , Duex Markus , Kraus Thomas Werner , Stahn Simon , Eickhoff Regina , Al-Batran Salah-Eddin 
Published: May 2019

TPS2651 Background: The two new strata of the INSIGHT trial evaluate feasibility and safety of s.c. injections of IMP321 (eftilagimod alpha) in combination with either SOC first/second-line drug therapy (Stratum C) or in combination with an PD-L1 inhibitor (avelumab; Stratum D) in advanced stage solid tumors as well as to generate first efficacy data. This proof-of-concept data could build the basis for further clinical studies exploring the therapeutic potential of combinations of active immunotherapy using IMP321 with SOC drug therapies or immunotherapies targeting the PD-1/PD-L1 axis in various solid tumor entities. IMP321 is a MHC class II agonist that activates antigen-presenting cells (primary target cells) and then CD8 T cells (secondary target cells). Activation of the dendritic cell network and subsequent T cell recruitment at the tumor site with IMP321 may lead to enhanced anti-tumor CD8 T cell responses. Thus, especially combinations with PD-1/PD-L1 inhibitors might display interesting effects by activating immune cells and disabling immune inhibitory mechanisms at the same time. Methods: This is a prospective investigator initiated phase I trial consisting of four strata. New stratum C: Patients with solid tumors treated with SOC chemo- or targeted therapy in first or second line receive concomitant s.c. IMP321 injections. This combination is aimed to enhance the immune response against tumor cells compared to chemo-/targeted SOC therapy alone. New stratum D: Patients will receive avelumab i.v. q2w along with s.c. IMP321 injections. This combination is aimed to enhance efficacy by combining IMP321’s activating effects on immune cells with the release of immune inhibitory effects caused by interruption of the PD-1/PD-L1 axis. It is planned to enroll 20 patients in Stratum C and 12 patients in stratum D. Main efficacy endpoint is the overall response rate (RECIST 1.1). Overall recruitment has started; currently (Feb 2019) 14 patients have been enrolled. EudraCT: 2016-002309-20. Clinical trial information: NCT03252938.