bluuebunny/crossref_metadata_2025_split huggingface dataset:
Safety profile of ripretinib, including impact of alopecia, and Palmar-Plantar Erythrodysesthesia Syndrome (PPES) on patient-reported outcomes (PROs), in ≥ fourth-line advanced gastrointestinal stromal tumors (GIST): Analyses from INVICTUS.
Authors: George Suzanne , Heinrich Michael C. , Zalcberg John Raymond , Bauer Sebastian , Gelderblom Hans , Schoffski Patrick , Serrano Cesar , Jones Robin L. , Attia Steven , D'Amato Gina Z. , Chi Ping , Reichardt Peter , Lacouture Mario E. , Cha Elva , Meade Julie Nicole , Ruiz-Soto Rodrigo , Blay Jean-Yves , von Mehren Margaret 
Published: May 2020

11539 Background: Ripretinib is a novel switch-control TKI that broadly inhibits KIT and PDGFRA kinase signaling. In INVICTUS (NCT03353753), a randomized, double-blind, placebo (PBO)-controlled trial of ripretinib in ≥4th-line advanced GIST, ripretinib reduced the risk of disease progression or death by 85% vs PBO with a favorable overall safety profile. Common ( > 20%) adverse events (AEs) included, but were not limited to, alopecia and PPES. Exploratory analyses evaluated the impact of alopecia and PPES on quality of life (QoL). Methods: Patients (pts) with advanced GIST previously treated with at least imatinib, sunitinib, and regorafenib were randomized (2:1) to ripretinib 150 mg QD or PBO. AEs were graded using CTCAE v4 and PROs collected using EQ-5D-5L (EQ5D) and EORTC QLQ-C30 (C30). Repeated measures (RM) models assessed the impact of alopecia and PPES on 5 PROs (EQ5D visual analogue scale; and C30 physical functioning, role functioning, and the overall health and overall QoL questions) within the ripretinib arm. Fixed effects were sex, alopecia/PPES, and ECOG scores at baseline. Results: 128/129 randomized pts received treatment (85 ripretinib 150 mg QD; 43 PBO). Alopecia, regardless of causality, occurred in 44 (51.8%) on ripretinib (34 [40.0%] grade 1; 10 [11.8%] grade 2) and 2 (4.7%) on PBO (both grade 1). PPES occurred in 18 (21.2%) on ripretinib (11 [12.9%] grade 1; 7 [8.2%] grade 2); none on PBO. The median times in days to first occurrence and worst severity grade with ripretinib were 57.0 and 62.5 for alopecia; 56.5 and 57.0 for PPES. The RM models showed a slight trend towards improvement in PRO score over time for pts with alopecia; the only association reaching a P-value of < 0.05 was between alopecia and increased overall QoL. None of the associations between PPES and PRO scores reach P < 0.05. All PRO p-values are nominal, and no statistical significance is being claimed. Conclusions: Ripretinib had a favorable overall safety and tolerability profile. When stratified by alopecia and PPES, patient-reported assessments of function, overall health, and overall QoL were maintained over time. For both alopecia and PPES, onset and maximum severity occurred almost simultaneously, indicating that these events generally did not progressively worsen. These results suggest that alopecia and PPES are manageable and do not have a negative effect on function, overall health, and QoL. Clinical trial information: NCT03353753 .
Primary adult retroperitoneal sarcoma (RS): Comprehensive genomic profiling (CGP) study.
Authors: Necchi Andrea , Grivas Petros , Bratslavsky Gennady , Killian Jonathan Keith , Lin Douglas I. , Williams Erik Abraham , Ramkissoon Shakti H. , Severson Eric Allan , Alexander Brian Michael , Venstrom Jeffrey , Reddy Venkataprasanth P. , McGregor Kimberly , Elvin Julia Andrea , Schrock Alexa Betzig , Pavlick Dean , Jin Dexter X , Trabucco Sally E. , Danziger Natalie , Ross Jeffrey S. 
Published: May 2020

11541 Background: We performed CGP on 315 cases of RS to discover targetable genomic alterations (GA) and their potential impact on potential targeted and immunotherapy (IO) selection. Methods: FFPE tissues from 315 clinically advanced RS tissues underwent hybrid-capture based CGP (DNA and RNA). Tumor mutational burden (TMB) was determined on up to 1.2 Mbp of sequenced DNA, and tumor cell PD-L1 expression was determined by IHC (Dako 22C3) (low = 1-49%; High = >50% tumor cell staining). Results: 155 liposarcomas (LPS), 74 leiomyosarcomas (LMS), 46 pleomorphic sarcomas (PLS), 7 solitary fibrous tumors (SFT), 6 malignant peripheral nerve sheath tumors (MPNST), 5 synovial sarcomas (SS) and 5 dendritic follicular cell sarcomas (DFCS) were studied; 17 cases were excluded. Median age was 59. There were 5.1 GA/tumor, none were MSI-high, median TMB was low at 2.4; PD-L1 IHC staining was low-positive in 21% and high-positive in 5%. MPNST patients were younger (median 28 years vs. 59 years). LPS was more frequent in men and LMS in women. LPS had more GA/tumor than LMS, with DFCS having the highest and SS the lowest. TP53 and RB1 GA were the highest in LMS and CDK4/6 and MDM2 GA the highest in LPS. Molecular targets in mTOR pathway were most frequently altered. Targetable gene fusions in ALK, ROS1 and NTRK1-3 were rare. Non-targetable fusions in HMGA2 (LPS and some PLS), STAT6 (SFT) and SS18 (SS) were also identified. Conclusions: RS in our cohort are predominantly composed of LPS, LMS and PLS and we identified a small proportion with “actionable” genomic targets on CGP, albeit in association with uncertain mTOR pathway inhibitor benefit and uncommon targetable kinase fusions. Our analysis suggests that a small subset of RS may respond to immunotherapy based on putative biomarker expression. [Table: see text]
Phase I study results of APG-115, a MDM2-p53 antagonist in Chinese patients with advanced liposarcoma and other solid tumors.
Authors: Zhang Xing , Wen Xizhi , Chen Guojuan , Zeng Shan , Men Lichuang , Wang Hengbang , He Shulan , Ma Yuxiang , Pan QiuZhong , Zhang Yang , Peng Ruiqing , Weng Desheng , Liu Wenqin , Zhang Li , LIANG ZHIYAN , Yang Dajun , Zhai Yifan 
Published: May 2020

11542 Background: APG-115 is a potent, small-molecule MDM2 inhibitor and immune modulator with promising antitumor activities in various tumors, especially those wild-type TP53 with MDM2 amplification ( TP53wt+MDM2 amp). To better delineate safety, optimal dosage, and potential target population, we report updated results. Methods: Patients with advanced liposarcoma and other solid tumors received APG-115 (100-200 mg) orally every other day for 21 days of a 28-day cycle. The primary endpoints were safety and tolerability. Efficacy (assessed by RECIST v1.1), pharmacokinetics (PK) and pharmacodynamics (PD) have also been analyzed. Results: Enrollment of this Phase I study (CTR20170975) was completed. As of January 7, 2020, 21 patients (14 liposarcomas, 2 synovial sarcomas, 2 adenoid cystic carcinomas, 1 chondrosarcoma, 1 osteosarcoma, 1 rhabdomyosarcoma) were treated in 3 dose levels of APG-115: 100 mg (n = 11), 150 mg (n = 8) and 200 mg (n = 2). The median number of cycles of APG-115 was 2 (0; 6). Two DLTs were observed at 200 mg, thrombocytopenia and febrile neutropenia. The most common treatment-emergent adverse events (TEAEs) (≥20%) included leukopenia, thrombocytopenia, neutropenia, anemia, increased blood creatinine, hypercholesterolemia, hypertriglyceridemia, hypoalbuminemia, vomiting, and nausea. The incidence of TEAEs was much lower at 100 mg. Serious AEs occurred in 5 patients (23.8%) which were assessed as possibly drug related by investigators. In 20 efficacy-evaluable patients, there was 1 patient with a partial response, 12 patients with stable disease, and 7 patients with progressive disease, yielding a disease control rate (CR, PR, SD) of 61.9%. Among the 13 patients (9 liposarcomas) who benefited, 11 had TP53wt and 7 had TP53wt+MDM2 amp, including one liposarcoma patient (150 mg) who had a PR, she was kept-up over 10 months, even though the treatment was discontinued for over 5 months, indicating the host immune modulatory effects of APG-115. Another patient with liposarcoma (100 mg, TP53wt+MDM2 amp) had 28.5% tumor shrinkage at cycle 4 and remained on treatment. PK results showed an approximately dose-proportional increase in exposure on Day 1. PK-PD analyses showed the serum macrophage inhibitory cytokine-1 (MIC-1) increased with increased APG-115 exposure. Conclusions: The phase I data have demonstrated that APG-115 monotherapy was well tolerated, with minimal toxicity at 100mg (RP2D), and conferred encouraging anti-tumor activities in patients with liposarcomas. Clinical trial information: CTR20170975 .
Genomic landscape of angiosarcoma: A targeted and immunotherapy biomarker analysis of 143 patients.
Authors: Espejo Freire Andrea P. , Elliott Andrew , Akgun Yamac , Costa Philippos , Alasfour Maryam , Rosenberg Andrew , Diaz-Perez Julio , Subhawong Ty , Arshad Junaid , Korn Wolfgang Michael , Dizon Don S. , von Mehren Margaret , Khushman Moh'd M. , Hussein Atif Mahmoud , Leu Kirsten , Trent Jonathan C. 
Published: May 2020

11545 Background: Targeted therapies for angiosarcoma (AS) patients have limited efficacy. Although significant responses to immunotherapy (IO-therapy) have been observed in cutaneous AS, its efficacy across all types of AS is not known. Herein, we describe genetic and molecular biomarkers of AS in order to propose potential therapeutic options. Methods: We retrospectively reviewed 143 AS tumors profiled by Next-Generation Sequencing (NGS) 592-gene panel (Caris Life Sciences,Irving, TX, USA). Whole transcriptome sequencing (WTS) was performed on 53 tumors. Mutations and copy number amplifications (CNAs) were analyzed and grouped by pathway. Biomarkers potentially associated with response to IO-therapy (TMB-High [≥10/Mb], MSI-High, and PD-L1 [IHC ≥ 2+ and 5%]) were also analyzed. AS subtypes based on primary tumor site were compared. P-values were corrected using a Benjamini & Hochberg method. Results: Sample median age was 67 (range 22-89), 61% were female, and 29% were classified as metastatic/recurrent. The most commonly mutated genes were TP53 (29%), ARID1A (17%), POT1 (16%), and ATRX (13%); MYC CNA was found in 23% of cases. IO-therapy markers were present in 36.4% of cases (TMB-High in 26%, PD-L1+ 21.8%, MSI-High 0.7%). Pathway alterations were detected in 86% of AS cases. By pathway, TP53 was altered in 31%, cell cycle 30%, DNA damage repair (DDR) 21%, RAS 18%, PI3K 15% and chromatin remodeling 14%. By site, head/neck (HN) AS had the highest rate of IO-therapy markers (65%, p < 0.05) [TMB-High (63%, p < 0.0001)], TP53 mutation (51%, p = 0.07), and POT1A mutation (41%, p < 0.01). MYC CNA was highest in breast (63%) and extremity (40%) AS (p < 0.0001). DDR alterations were present in 56% (p = 0.09) of cutaneous AS and ranged from 12-27% in other subtypes (not significant, NS). RAS and PI3K alterations ranged from 6-27% across all subtypes (NS). Conclusions: Our findings suggest differential angiosarcoma biology across primary sites. HN AS had more frequent markers of potential IO-therapy response, as well as DDR alterations. Next in frequency, we found ARID1A which is possibly associated with overactive EZH2, a target of tazemetostat. MYC amplification suggests a role targeting cell cycle via cyclin-dependent kinase or bromodomain inhibitors in breast and extremity ASs. Finally, RAS and PI3K are mutated in a low percentage of cases, explaining the limited benefit of tyrosine kinase inhibitors in AS. Future AS clinical trials should be designed with consideration of primary site, IO-therapy response biomarkers, and activated pathway.
Cardiac safety of trabectedin monotherapy and in combination with pegylated liposomal doxorubicin in patients with sarcomas and ovarian cancer.
Authors: Jones Robin Lewis , Herzog Thomas J. , Patel Shreyaskumar , von Mehren Margaret , Schuetze Scott , Van Tine Brian Andrew , Coleman Robert L. , Triantos Spyridon , Hu Peter , Shalaby Waleed , McGowan Tracy , Monk Bradley J. , Demetri George D. 
Published: May 2020

11547 Background: Trabectedin (T) is an established option as monotherapy for advanced soft tissue sarcomas (STS; Leiomyosarcomas and Liposarcomas in the USA) and in combination with pegylated liposomal doxorubicin (PLD) for recurrent ovarian cancer (ROC). This retrospective analysis evaluated the cardiac safety profile in over 1500 patients (pts) from clinical trials administering T monotherapy for STS or in combination with PLD (T+PLD) for ROC. Methods: Integrated cardiac safety data was analyzed from ten Phase 2 trials and one Phase 3 trial in STS (T) and two Phase 3 ROC trials (T+PLD). Cardiac-related treatment-emergent adverse events (TEAEs) were summarized using MedDRA terminology and by Kaplan-Meier analysis for time-to-event variables. Subgroup analyses were performed for cardiac-related TEAEs, including any significant decrease in LVEF. Results: Integrated data on T monotherapy included 982 pts (Table). Of these, 110 (11.2%) pts who received ≥1 dose of T experienced a cardiac-related TEAE, including tachycardia (3.1%), palpitations (1.5%), LVEF decrease (1.3%), sinus tachycardia (1.0%), and/or congestive cardiac failure (1.0%). A multivariate analysis revealed factors associated with increased risk to be cardiovascular medical history (risk ratio [RR]: 1.90; 95% CI: 1.24-2.91; p = 0.003) and age > 65 years (RR: 1.78; 95% CI: 1.12,2.83; p = 0.014). Cardiac-related TEAEs were reported in 78 (12.6%) of 619 pts receiving T+PLD (Table). Incidence of cardiac-related TEAEs was greater with T+PLD compared with PLD monotherapy (12.6% vs 5.6%). A multivariate analysis showed that pts were at increased risk for experiencing cardiac-related TEAEs when treated with T+PLD compared to PLD monotherapy (RR: 2.70; 95% CI: 1.75,4.17; p < 0.0001) and when there was a history of prior cardiac medication (RR: 1.88; 95% CI: 1.16,3.05; p = 0.010). Conclusions: Although infrequent, patients receiving T after prior anthracyclines or in combination with PLD are at risk for cardiac dysfunction, and appropriate clinical awareness and monitoring is encouraged to optimize patient outcomes. [Table: see text]
A phase Ib study of ribociclib in combination with doxorubicin in advanced soft tissue sarcomas (aSTS).
Authors: Davis Lara E. , Latour Emile , Burch Reid , Park Byung , Davis Jessica L. , Ryan Christopher W. 
Published: May 2020

11548 Background: aSTS are typically treated with single agent doxorubicin (dox). CDK4 inhibitors such as ribociclib (ribo) may have a role in treating STS, which frequently rely on hyperphosphorylation of Rb to evade the Rb checkpoint. We hypothesized that dox efficacy could be increased by inhibiting Rb phosphorylation with a short course of ribo, then removing ribo to permit cell cycle progression prior to dox, thus potentiating the DNA-damaging effects of dox. Methods: Open label, dose-finding study of ribo and dox in dox-naïve patients (pts) with Rb+ aSTS. Rb status determined by IHC. Primary objective to determine the recommended phase 2 dose (RP2D). Secondary objective of anti-tumor activity. Pts received ribo 400-600 mg PO QD x7d followed by 72h rest before dox 60-75 mg/m2 IV, q21d. Pts free from progression of disease after 6 cycles continued on ribo maintenance at 600 mg QD q3/4wk. Dose-limiting toxicity (DLT) period was cycle 1, with target toxicity rate of 30% using a modified toxicity probability interval (mTPI) design. Growth factor support was not allowed during DLT period. Results: 9 screened pts were ineligible by Rb status. 16 pts enrolled with 15 evaluable for dose determination (7 dedifferentiated LPS, 8 other subtypes). 4 of 7 pts treated at starting dose level (400 mg ribo, 75 mg/m2 dox) had a DLT; all febrile neutropenia. 1 of 8 pts treated at dose level -1 (400 mg ribo, 60 mg/m2 dox) had a DLT of gr4 anemia. Febrile neutropenia events occurred during cycle 1, when growth factors were prohibited. Toxicity was similar to historical dox AEs (Table). Two partial responses for overall response rate (ORR) of 13%. Five (33%) were progression-free at 18 wks. Correlative studies ongoing. Conclusions: This study determined a RP2D of ribo 400 mg with dox 60 mg/m2 when used in combination for the treatment of aSTS. Clinical trial information: NCT03009201 . [Table: see text]
Apatinib for patients (pts) with advanced soft tissue sarcoma (STS) after chemotherapy: A prospective, open-label, single-arm, multicentered study.
Authors: Hu Haiyan , Yao Yang , Fan Zhengfu , Zhang Hongmei , Chen Jing , Zhang Xing , Chen Yong , Qu Guofan , Huang Gang , Zhou Yuhong , Yu Wenxi , Wang Xiaowen , Zhuang Rongyuan 
Published: May 2020

11553 Background: The development of STS therapeutics has been challenging, especially patients who failed chemotherapy. Anti-angiogenesis inhibitors had shown activity in STS, Apatinib is a TKI targeting on VEGFR-2 which has shown activity in many solid tumors. Methods: A Phase II, open-label, Single-arm, multicentered study was conducted in previously treated pts with advanced STS in China. The patients received apatinib 500mg orally qd in a 28-day-cycle, until disease progression or unacceptable adverse events. Antitumor response assessment was performed every 8 weeks per RECIST V1.1. The primary endpoint was PFS rate in 6 months and secondary endpoint was ORR and OS. Results: As cut-off on Jan 20th 2019, a total of 53 patients were enrolled in 9 centers, 51 patients received at least 2 cycles of Apatinib, 1 patient is still in treatment. The main histological subtypes were alveolar soft part sarcoma(n = 11), synovial sarcoma(n = 6), leiomyosarcoma (n = 6), clear cell sarcoma(n = 6) and undifferentiated pleomorphic sarcoma(n = 5). Overall, 27 of 51 patients were progression free at six months and the 6-m PFS rate was 53.32% (95%CI 37.76%, 66.63%). Until final follow-up, the ORR was 18.75% (9/48) and DCR was 87.5% (42/48). Additionally, median PFS was 7.13 (95%CI 3.84, 9.23) months and median OS has reached up to 24.67 (9.30-NE) months. Adverse events (AEs) were detected among all pts, hypertension and proteinuria are the most common AEs, occurred in 84.91% and 73.57% pts respectively. Grade 3/4 related adverse events were detected in 86.79% of pts, Grade 3/4 hypertension was the most common grade3/4 AE (56.60%). Conclusions: Overall, the present study demonstrates that apatinib has a clinically meaningful anti-tumor activity in pretreated STS pts, showing durable responses and prolonged overall survival. Some of the pts had a long-time benefit from the treatment. Apatinib was safe and generally well tolerated. Further studies on specific STS subtypes would be meaningful. Clinical trial information: NCT03064243 .
Activity of cabazitaxel in patients with metastatic or inoperable locally advanced dedifferentiated liposarcoma: European Organization for Research and Treatment of Cancer (EORTC) Phase II trial 1202.
Authors: Sanfilippo Roberta , Hayward Richard L , Musoro Jammbe , Benson Charlotte , Leahy Michael Gordon , Brunello Antonella , Blay Jean-Yves , Steeghs Neeltje , Desar Ingrid M.E. , Ali Nasim , Hervieu Alice , Thway Khin , Marreaud Sandrine , Litiere Saskia , Gelderblom Hans 
Published: May 2020

11556 Background: The optimal treatment for patients with advanced dedifferentiated (DD) liposarcoma (LPS) remains uncertain. Single agents which are most effective include doxorubicin and ifosfamide but, as with soft tissue sarcomas (STS) in general, objective response rates (ORR) and progression free survival (PFS) are very modest. Cabazitaxel exerts its effect through inhibition of microtubular disassembly and has been shown to be relatively safe, effective and well-tolerated. EORTC 1202 assessed whether cabazitaxel demonstrated sufficient antitumor activity in patients with metastatic or inoperable locally advanced DD LPS to justify further investigation in a phase III setting. Methods: This was an international multi-center, open label single arm phase II trial. Eligible patients with metastatic or inoperable locally advanced DD LPS were treated with cabazitaxel 25mg/m² IV infusion over 1 hour every 21 days. Primary endpoint was PFS rate at 12 weeks assessed by local investigator per RECIST 1.1. Based on a Simon two-stage design, at least 4 out of 17 (Stage 1) and 11 out of 37 (Stage 2) eligible and evaluable patients who are progression-free at 12 weeks were needed. Results: Forty patients were registered by 10 institutions in 4 countries between March 2015 and March 2019, with 2 patients being ineligible. Among the 38 eligible patients who started treatment, 3 (7.5 %) were still on treatment at the time of analysis. The number of cycles ranged from 1 to 30, with a median of 5; 26 patients (65%) received at least 4 cycles of cabazitaxel. Among the first 17 (Stage 1) and 37 (Stage 2), 11 and 20 patients were progression-free at 12 weeks respectively, satisfying the study decision rules. The PFS rate at 12 weeks for all 38 eligible patients was 52.6% (conditional 1-sided 95 % CI 38.3 – 100). Two patients (5.3%) achieved a confirmed partial response (PR) and 23 stable disease (SD) (60.5%). Disease control (PR+SD) was achieved in 25 patients (65.8%). Median PFS was 7.4 months (95%CI 2.8-10.3). The most common cabazitaxel -related grade >3 adverse events in all 40 registered patients were neutropenia (60%), febrile neutropenia (25%), fatigue (12.5%), and anemia (10%). There were no cabazitaxel-related deaths. Conclusions: EORTC 1202 met its primary endpoint, with 20/37 pts (54%) being progression-free at 12 weeks. Results of this trial confirm activity of cabazitaxel in patients with metastatic or inoperable locally advanced DD LPS and warrant further exploration of the drug. Clinical trial information: NCT01913652 .
A phase I study of TGF-β inhibitor, vactosertib in combination with imatinib in patients with advanced desmoid tumor (aggressive fibromatosis).
Authors: Kim Hyo Song , Ahn Jin-Hee , Kim Jeong Eun , Hong Jung Yong , Lee Jeeyun , Kim Sung Hyun , Lee Jin , Hwang Sunjin , Jeon Min Kyung , Kim Seong-Jin 
Published: May 2020

11557 Background: Desmoid tumor (aggressive fibromatosis) is fibroproliferative neoplasm arising from deep connective tissues. TCGA pan-cancer analysis revealed high expression TGF-β responsive signature in desmoid tumor. This phase I study assessed the safety, tolerability, and pharmacokinetics of the TGF-β inhibitor, vactosertib in combination with imatinib for desmoid tumor. Methods: Patients with advanced desmoid tumors not treatable by surgery or radiotherapy were eligible. The primary objective is to assess the safety and recommended phase 2 dose (RP2D) of vactosertib given 5 days on and 2 days off in combination with imatinib (400 mg QD). Two dose levels of vactosertib were tested; cohort -1 (100 mg BID) and cohort 1(200 mg BID). Secondary objectives include pharmacokinetics, anti-tumor activity by response rate (RECIST v1.1), and biomarker analysis. Results: Seven patients (cohort -1, n = 4; cohort 1, n = 3) were enrolled and finished the safety evaluation. The most frequently reported treatment related adverse events were myalgia (57.1%), fatigue (42.8%), diarrhea (42.8%), anemia (28.5%) and stomatitis (28.5%) with mostly grade 1. No dose limiting toxicity was observed. Tumor response included 2 (28.5%) partial response (PR) and 2 stable disease (SD) in the cohort -1, and 3 SD in the cohort 1. The time to response were 5.5 and 8.2 months and all 7 cases are ongoing. Updated safety, pharmacokinetics, efficacy and biomarker data will be presented at the meeting. Conclusions: The combination of vactosertib plus imatinib was well tolerated and showed promising activity in desmoid tumor. RP2D of vactosertib was defined as 200 mg BID. Further efficacy will be explored in the phase 2 part of the study. Clinical trial information: NCT03802084 .