bluuebunny/crossref_metadata_2025 huggingface dataset:
Developing South Asia’s first structured head and neck surgery multicenter fellowship initiative.
Authors: Chopra Shamit , Mandlik Dushyant , Balasubramanian Deepak , Kekatpure Vikram , Iyer Subramania , Dabholkar Jyoti , Patel Kaustubh
Published: May 2020

11037

Background: Despite high head neck cancer incidence in South Asia, there exist few fellowship programs, which are limited by lack of structure, review processes and standard curricula. Our aim was a regionwide multicenter head and neck fellowship initiative to address the above limitations. Methods: A 10-member task force was constituted in January 2018 under the aegis of the Foundation for Head and Neck Oncology. First phase: Initial curriculum drafted by incorporating region-specific perspectives, aided by multiple source documents. Candidate eligibility criteria outlined, accommodating multiple pertinent disciplines and an international applicant base. Format for a structured entrance examination, and a mandatory/desirable rotation schedule were developed. Second Subcommittee(SC) phase: Creation of a web portal ( www.fhnofellowship.org ) by Outreach SC, approval of applicant centers by Accreditation SC, layout of exam structure by the Examination SC, and defining a rank order list-driven match process by the Match SC. Third phase: Development of standard documentation including suggested bibliography, log book format, recommended grand rounds topics, common minimum criteria for fellowship graduation. A common entrance exam was conducted in Feb 2019, which incorporated written screening, center-candidate interactions, objective interview, and the merit-based institution-fellow match. Results: Total number of applicants: 92, the majority Oral Maxillofacial Surgeons(83.7%). Seventeen fellows matched in the first cycle, the initial and 6-month program compliance 94.1% and 88.2% respectively. More eligible institutions accredited(36.8% increase) prior to the second cycle in Nov 2019, during which 19 fellows(11.8% increase) were matched. An interim review was done in Oct 2019, and periodic reviewing set at 6-month intervals. Planned fourth phase: Objective center/candidate feedback, surgical video repository, online training schedule, develop the fellowship exit examination, and expand outreach to other countries. Conclusions: Owing to high head neck cancer incidence in the subcontinent, anatomic complexity, need to balance outcomes/toxicities and requirement of expert multidisciplinary care; structured head neck fellowship training is imperative. Despite inherent challenges of concept and implementation in a diverse multicultural resource-limited setting, we foresee the application of region-relevant perspectives helping us achieve the objective of furthering subspecialty head neck training in South Asia.
Quality and reliability of online video information of breast cancer in Spanish.
Authors: Diaz Fernando Cristobal , Polo Perez Ismael Pavel , Corria Cedeno Dailis Barbara , LaPelusa Michael , Patel Dave , Rodrigo Hansapani Sarasepa
Published: May 2020

11039

Background: Online health information is a central part of how patients learn about a cancer diagnosis. Involving patients in shared decision making is associated with better outcomes. Previous studies have identified a lack of high-quality, reliable online material related to cancer in English using validated tools. As the number of Spanish speaking people in the US, and globally, continues to grow, it is important that high-quality, reliable information is available in Spanish. No studies have evaluated online breast cancer informational videos in Spanish. Methods: A search using the phrase “cancer de mama” (translation: “breast cancer”) was conducted on YouTube. The first 200 video URLs were included for study with duplicates, non-Spanish, and non-informational videos excluded. The videos were characterized by several variables, including year of upload, country of origin, content discussed, views, likes, dislikes, and typology group (“Personal”, “Professional”, “Health Portal”, etc.). The quality and reliability of these videos were examined by measuring Global Quality Scale (GQS), a 5-point DISCERN score, and JAMA scores. Results: 173 videos met inclusion criteria in the study. The majority of the videos which discussed signs and symptoms were uploaded by a ‘commercial’ typology, risk factors mainly uploaded by ‘health portals’ (21%), and treatment options by ‘professionals’ (50%). Relatively few videos have discussed reconstruction, survivorship, and breast cancer in men. 57% of these videos were uploaded prior to 2017, 36% by different personnel followed by government/news agency (25%), and professionals (23%). There was no significant difference between number of views (p-value: 0.526) and likes (p-value: 0.122) among the five typology groups. Professional videos had the highest average GQS (2.55), DISCERN score (1.90), and JAMA score (2.05). Personal videos had the lowest average GQS (1.98) and DISCERN score (1.06). GQS, DISCERN, and JAMA scores were all statistically significantly different between each typology. Conclusions: The majority of online breast cancer videos in Spanish are older than 3 years and produced outside the US. They are generally of poor quality and reliability, although higher in professional videos. Given the lack of current, high-quality, and reliable informational videos available, needs assessments should be conducted to identify the most useful learning resources for Spanish-speaking patients. Specialists should consider uploading educational videos to improve the paucity of high-quality, reliable information online.
Long-term follow-up for duration of response (DoR) after weekly nab-sirolimus in patients with advanced malignant perivascular epithelioid cell tumors (PEComa): Results from a registrational open-label phase II trial, AMPECT.
Authors: Wagner Andrew J. , Ravi Vinod , Riedel Richard F. , Ganjoo Kristen N. , Van Tine Brian Andrew , Chugh Rashmi , Cranmer Lee D. , Gordon Erlinda Maria , Hornick Jason L. , Kwiatkowski David J. , Du Heng , Grigorian Berta , Schmid Anita N. , Hou Shihe , Harris Katherine , Desai Neil , Dickson Mark Andrew
Published: May 2020

11516

Background: Malignant PEComa is a rare, aggressive sarcoma, with no approved medical treatment. Cytotoxic chemotherapies have limited benefit for patients with advanced disease. The AMPECT trial measured the effects of nab-sirolimus (ABI-009) and is the first prospective study in advanced malignant PEComa. nab-Sirolimus is a nanoparticle albumin-bound mTOR inhibitor with significantly higher intratumoral drug levels, mTOR target suppression, and anti-tumor activity in animal models versus other mTOR inhibitors. This report presents long-term follow-up of DoR after the primary analysis. Methods: Patients (N=34) received nab-sirolimus (100mg/m2 IV, weekly, 2/3 weeks) until progression or unacceptable toxicity. Primary endpoint: ORR by IRR. Key secondary endpoints included DoR, PFS6, OS, and safety. Exploratory endpoints included correlation of tumor genotype and outcome. The sample size of 30 efficacy-evaluable patients was based on an estimated ORR of 30% and the lower bound of the 95%CI of ORR to exclude values less than 14.7%. The primary analysis was conducted when all patients were treated ≥6 months (May 22, 2019). This report updates the primary response analysis and DoR with an additional 8.5-month of follow-up. Results: As of Feb 06, 2020, of the 31 efficacy-evaluable patients, the confirmed ORR by IRR was 39% (12/31, 95%CI: 21.8, 57.8), with 1 complete response (CR) and 11 partial responses (PR), 52% stable disease (SD, 16/31, with 10/16 SD ≥12 weeks), and 10% progressive disease (3/31); the disease control rate (CR+PR+SD ≥12 weeks) was 71%. PFS6 was 71% (95%CI: 47.7, 85.1). The majority of responses (67%) were reached at the first post-baseline scan at week 6, with a median time to response of 1.4 months (95%CI: 1.3 to 2.8). The median DoR by IRR was not yet reached (range 5.6-38.7+ months; calculated median 22.2+ months) with 8/12 (67%) responders still on treatment for >1 year and 5/12 (42%) >2 years. Mutational analysis available for 25 patients identified that TSC2 loss-of-function mutations significantly correlated with response; 8/9 (89%) patients with TSC2 had a confirmed response. Conclusions: Responses of advanced malignant PEComa to nab-sirolimus were highly durable and occurred in 39% of patients based on independent review. The high disease control rate with manageable toxicities suggest that nab-sirolimus is effective and represents an important new treatment option for these patients. NCT02494570. Clinical trial information: NCT02494570 .
Correlation of response with progression-free (PFS) and overall (OS) survival in relapsed/refractory Ewing sarcoma (RR-ES): Results from the rEECur trial.
Authors: Wheatley Keith , Kadir Bryar , Khan Maria , Fenwick Nicola , Gaspar Nathalie , Kanerva Jukka , Kuehne Thomas , Longhi Alessandra , Mata Cristina , Phillips Marianne , Hall Kirsten , Safwat Akmal , Valverde Morales Claudia , Westwood Andrew J. , Winstanley Mark , Evans Abigail , Strauss Sandra J , Dirksen Uta , Whelan Jeremy , McCabe Martin G.
Published: May 2020

11524

Background: Survival for RR-ES at 5 years remains < 15%, so novel treatments are needed. Almost all Phase II trials for RR-ES use response as the primary outcome measure. It is unclear whether response is a valid surrogate for survival outcomes. Methods: Patients (pts) were eligible if they had RR-ES and were evaluable for imaging response (primary outcome) if they had measurable disease by RECIST 1.1. The randomization was initially between four chemotherapy regimens: topotecan-cyclophosphamide, irinotecan-temozolomide, gemcitabine-docetaxel (GD), high-dose ifosfamide. Response was assessed after 2, 4 (primary) and 6 cycles of therapy and was classified as complete response (CR), partial response (PR), stable disease (SD), progressive disease (PD). PFS and OS were secondary outcomes. Survival from each assessment point by response status was analyzed, by Cox models, with hazard ratios (HR) given for PR v. SD and CR+PR v. SD. Results: From 2015-19, 241 pts with response data were entered. The relationship between response status and PFS and OS is shown in the table (HR < 1.0 indicates better outcome for PR or CR+PR than SD). Both PFS and OS were similar for pts with PR or CR+PR compared to those with SD. OS was inferior for patients with PD (all p < 0.01) (PFS is by definition zero for patients with PD at that timepoint). Small numbers mean CR results are not reliable. Results were consistent across all treatments and between refractory and relapsed disease. At the first interim assessment the GD arm was dropped, with risk ratios for response compared to the other three arms (blinded as still open) of 0.3, 0.5 and 0.5. If a new outcome – disease control (CR+PR+SD) – is defined, the risk ratios are 0.7, 0.8 and 0.7; i.e. still inferior for GD, but less so. Conclusions: Response does not correlate with survival outcomes in RR-ES, so considering PR, or even CR, a success and SD a failure when evaluating treatments may be misleading. We propose PFS as a better primary outcome for future trials and it will be introduced as such in the rEECur trial. Clinical trial information: ISRCTN36453794 . [Table: see text]
Increased pathological complete response rate with neoadjuvant denosumab in locally advanced giant cell tumor.
Authors: Taveira Gabriela Monte Tenorio , Marinho Felipe Da Silva , Souza Antonio Marcelo Gonçalves de , Carneiro Wagner cabral Gomes
Published: May 2020

11528

Background: Giant cell bone tumor corresponds to 5% of bone tumors, has an osteolytic pattern and mainly affects long bone epiphyses in young adults. Despite being considered benign, it can metastasize and is treated as a locally destructive tumor, since it causes pain, limited joint movement and impaired function, with a risk of pathological fractures. The use of denosumab for surgical downstaging and reduction of recurrence is being studied, but the standard of treatment is still surgical. Methods: 15-year experience in monitoring 40 patients at the Cancer Hospital of Pernambuco-BR, who used neoadjuvant denosumab. They received Denosumab 120mg on D1, D8 and D15 as attack phase and subsequent maintenance with 120mg monthly. Results: The 40 patients made an average of 10 doses of neoadjuvant denosumab. Mostly located in the femur (41%) and tibia (23%), but with rare disorders in talus or orbit. Metastasis occurred in 6%, with site in lung and bones. Most were women (62%) around 21-40 years old, with Capanacci III classification at 72%. In this group, 28 had locally advanced disease and 12 had unresectable or metastatic disease. After using neoadjuvant denosumab, 75% have already had a biopsy, of which 63% (19/30) had a complete pathological response in biopsy. Of the patients with no post-denosumab neoplasia, 26% (5/19) had recurrence after medication and surgical procedure. Neoadjuvant treatment with denosumab, a monoclonal antibody that binds to RANKL, has been shown to benefit from histological response and surgical downstaging. We found 63% of complete pathological response in the 30 patients who underwent biopsy after medication, with bone sclerosis and hypocellular fibrous tissue as the main finding. Of these, 26% had disease recurrence after surgery. These data follow the international standard of disease recurrence rate, which is around 30%. Conclusions: We hope that the use of neoadjuvant desonumab will be more widespread and that it will be able to perform surgical downstaging, allowing less invasive and morbid procedures. Thus achieving greater joint preservation at the expense of a disease recurrence rate similar or less than standard surgical treatment.
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 .
Prognostic role of % changes in longest tumor diameter (LTD) in localized high-risk soft tissue sarcoma (STS) treated with neoadjuvant chemotherapy in a randomized clinical trial.
Authors: Stacchiotti Silvia , Morosi Carlo , Braglia Luca , Palmerini Emanuela , Quagliuolo Vittorio , Martin Broto Javier , Lopez-Pousa Antonio , Grignani Giovanni , Brunello Antonella , Blay Jean-Yves , Tendero Oscar , Diaz Beveridge Robert , Lugowska Iwona , Fontana Valeria , Marchesi Emanuela , Palassini Elena , Bruzzi Paolo , Merlo Franco Domenico , Casali Paolo Giovanni , Gronchi Alessandro
Published: May 2020

11558

Background: We investigated the prognostic relevance of % change in LTD in patients (pts) with localized high-risk STS treated with neoadjuvant chemotherapy in a phase 3 randomized trial (NCT01710176), aimed at comparing 3 cycles of a neoadjuvant histology-tailored (HT) over 3 cycles of standard anthracycline + ifosfamide chemotherapy (S). Methods: Pts with localized high-risk STS of extremities or trunk wall, and a diagnosis of myxoid liposarcoma, leiomyosarcoma, synovial sarcoma, malignant peripheral nerve sheath tumors, undifferentiated pleomorphic sarcoma were randomly assigned to receive 3 cycles of S or HT. Pts affected by myxofibrosarcoma, pleomorphic liposarcoma, pleomorphic rhabomyosarcoma unclassified spindle cell sarcoma were prospectively registered and treated by S. Change of LTD was assessed comparing baseline dimension with that measured after 3 cycles of S or HT, before surgery. Only pts treated with neodjuvant chemotherapy alone were selected for the analysis. We first investigated Overall Survival (OS) from surgery of the groups identified by “any % reduction”, “no-change” or “increase” in LTD by Kaplan-Meier estimates and log-rank tests. Then we searched for cutoffs able to separate prognosis among pts with a LTD reduction applying the change-point method proposed by Contal - O’Quigley. Results: Of 325 pts who entered the study and evaluable for response, 181 received neoadjuvant chemotherapy alone (92 S and 89 HT group respectively) and were analyzed, while 144 received concurrent chemo-radiotherapy and were excluded. In the whole population, % changes in LTD were significantly associated (log rank p = 0.032) to OS. “Any % reduction in LTD (101/181pts) displayed a better prognosis compared to “no-change” (28/181 pts) or “any % increase” (52/181). The change-point analysis was applied to all, S and HT groups separately; a cutoff of = / > 18.75% decrease in LTD was the optimal predictor of outcome for the S group (p = 0.031), while no size cut-off could be identified for the HT group. Conclusions: In our study, % change in LTD of pts treated with neoadjuvant chemotherapy for localized high-risk STS correlated with OS. However, a % decrease in LTD cut-off able to predict the best outcome could be identified only for pts treated in the S group, while no differences in outcome were found by any % LTD change in the HT group. Interestingly, the LTD cut-off identified in the S group was lower than the one selected to define a response by RECIST ( = / > 18.75% decrease in LTD vs = / > 30%). Clinical trial information: NCT01710176 .
Nationwide incidence of sarcomas and tumors of intermediate malignancy in the NETSARC network with central pathology review: Correlation with published clinical research.
Authors: De Pinieux Gonzague , Karanian Marie , Le Loarer Francois , Le Guellec Sophie , Terrier Philippe , Bouvier Corinne , Battistella Maxime , Robin Yves Marie , Emile Jean-François , Moreau Anne , Larousserie Frederique , Leroux Agnès , Stock Nathalie , Laé Marick , Collin Françoise , Italiano Antoine , Le Cesne Axel , Penel Nicolas , Coindre Jean Michel , Blay Jean-Yves ,   on behalf of the RREPS/RESOS/NETSATC ( NETSARC+) and French Sarcoma Group-Groupe d’Etude des Tumeurs Osseuses (GSF-GETO) Networks
Published: May 2020

11560

Background: Since 2010, presentation to a designated sarcoma tumor board and pathological review by an expert network are mandatory for sarcoma patients in France. NETSARC+ (merging the 3 initial RREPS, RESOS & NETSARC) collected prospectively all cases of reviewed sarcomas and tumors of intermediate malignancy (TIM) nationwide. We report on the incidence of subtypes according to WHO classification from 2013 to 2016. Methods: Sarcoma expert pathologists reviewed samples were all prospectively integrated in the database; the results using the latest WHO classification are presented for the years 2013 to 2016, including yearly variations. Correlation of the incidence of each histotype with dedicated published clinical trials was conducted. Results: 139 different histological subtypes are reported among the 25172 patients with sarcomas (n = 18710, 64%) or TIM (n = 6460, 36%), respectively n = 5838, n = 6153, n = 6654, and n = 6527 yearly from 2013 to 2016. Over these 4 years, the observed yearly incidence of sarcomas, TIM, and all was therefore 79.7, 24.9 and 95.1/10e6/year, above that previously reported. GIST, liposarcoma, leiomyosarcomas, undifferentiated sarcomas represented 13%, 13%, 11% and 11% of all sarcomas. Only GIST, as a single entity exceeded a yearly incidence above 10/million per year. There were respectively 30, 63 and 66 different histological subtypes of sarcomas or TIM (single entities or lumped together, e.g. MPNST, or vascular sarcomas...) with an incidence ranging from 10 to 1/10e6/year, 1-0.1/10e6 per year, or < 0.1/10e6/year respectively. The 2 later “incidence groups” included 21% of the patients. The incidence of 8 histotypes varied significantly over this 4 years. Patients with tumors with an incidence above 1/10e6 per year have significantly higher numbers of dedicated published phase III and phase II clinical trials (p < 10e-6). Conclusions: This nationwide registry of sarcoma patients with an histology reviewed by sarcoma experts shows that the incidence of sarcoma and TIM is higher than previously reported, may vary over years for some histotypes, and that tumors with an incidence < 10e6 have a much lower access to clinical trials.
A randomized phase II study of MLN0128 (M) versus pazopanib (P) in patients (pt) with advanced sarcoma (Alliance A091304).
Authors: Ingham Matthew , Mahoney Michelle R. , Remotti Fabrizio , Shergill Ardaman , Dickson Mark Andrew , Riedel Richard F. , Attia Steven , Elias Anthony D. , Liebner David A. , Agulnik Mark , Thornton Katherine Anne , Monga Varun , Van Tine Brian Andrew , Schwartz Gary K. , Tap William D.
Published: May 2020

11562

Background: Soft tissue sarcoma (STS) is a heterogeneous malignancy of connective tissue. Although mTOR is implicated in STS pathogenesis, clinical activity from mTORC1 inhibitors is modest. M, a potent selective mTORC1/mTORC2 inhibitor, was more effective in STS preclinical models than inhibitors of mTORC1, IGF1R and mTORC1+IGF1R, owing to more complete suppression of PI3K/AKT/mTOR and abrogation of feedback AKT activation. P, an oral multikinase inhibitor, is approved for non-adipocytic STS and often used after progression (PD) on chemotherapy. In phase 1, the RP2D of M was 30 mg weekly. A091304 was to evaluate M as a novel targeted therapy for STS. Methods: In A091304, pts were randomized 1:1 to M 30 mg weekly or P 800 mg daily. Eligibility required Eastern Cooperative Oncology Group PS ≤ 1, progression on ≥ 1 prior chemotherapy and specific STS subtypes (cohort 1: UPS; 2: LMS; 3: MPNST, SS). Crossover to M was allowed after PD on P. 1° endpoint was progression-free survival (PFS). Assuming median PFS of P was 4.6 months (mo), 98 pts yielded 80% power to detect a hazard ratio of 0.66 favoring M [1-sided test, alpha = 0.15] and including 1 planned futility analysis. 2° endpoints were response rate, clinical benefit rate (CBR) at 4 mo and safety. After 4 of the first 12 pts randomized to P experienced ≥ grade (gr) 3 toxicity, the study was amended to begin at P 400 mg, allowing titration to 800 per investigator discretion. Results: After protocol amendment, 114 pt underwent randomization (M: 56, P: 58), and 111 initiated treatment. Median PFS was 2 mo for M and 2.1 mo for P (HR = 1.47; 1-sided 85% upper confidence boundary = 1.85), with 2 partial responses in each arm. CBR was 5.4% for M and 13.8% for P. Median OS was 10.7 mo for M and 13.9 mo for P (HR = 1.41; 95% CI 0.80-2.49). 26/43 pt with PD on P crossed over to M. Median PFS after crossover was 1.8 mo (95% CI 1.5-3.5). Gr 3 drug-related adverse events (AEs) occurred in 36% on M and 41% on P; gr 4 toxicity was rare. AEs were consistent with known effects of M and P. Conclusions: P at 400 mg daily (allowing escalation to 800 mg per investigator discretion) demonstrated a shorter PFS as compared prior randomized studies with P. Despite this, M failed to demonstrate superior clinical activity as compared to P at the interim analysis. Further work will examine activity within histology-specific cohorts and evaluate available tissue samples for evidence of pharmacodynamic activity. Support: U10CA180821, U10CA180882, U10CA180888, UG1CA233324 (SWOG); https://acknowledgments.alliancefound.org . Clinical trial information: NCT02601209 .