bluuebunny/crossref_metadata_2025 huggingface dataset:
Umbrella study of anticancer agents in Chinese patients with NSCLC.
Authors: Zhao Xin , Xiao Liyun , Yang Yunpeng , Xie Guoyun , Fang Wenfeng , Ma Yuxiang , Zhao Hongyun , Wu Kui , Zhang Li
Published: March 2020

e20044

Background: As the rapidly increasing of potential anti-cancer agents, it has significantly improved clinical outcomes of non-small cell lung cancer (NSCLC). However, it has been challenged by the accurately characterize the genome changes which link to the response to specific targeted therapeutics. This umbrella study aimed to provide real-world data on the efficacy of targeted therapies by multiple gene sequencing in NSCLC of Chinese population and explore for the implementation of personalized lung cancer therapy in clinical practice. Methods: This study consists of five biomarker matched arms and one non-biomarker matched arm. Within biomarker matched arms, the different cohorts will test, 1) EGFR mutation for response to gefitinib, apatinib or osimertinib; 2) ALK fusion for response to crizotinib; 3) BRAF V600E mutation for response to trametinib; 4) MET amplification for response to CT053PTSA; 5) VEGFR mutation for response to apatinib or famitinib. Within the non-biomarker matched arm, cohort will test docetaxel or carboplatin. We will perform multiple gene testing on tumor tissue, pleural fluid, plasma and peripheral blood leucocyte of all patients. Results: A total of 336 patients were enrolled in this study, including 307 lung adenocarcinomas, 27 squamous cell carcinomas, and two adenosquamous carcinomas. Approximately 40% of patients carried at least one actionable mutation. The most frequently mutated genes were TP53 and EGFR, and the percentage of EGFR mutation subtypes 19Del, L858R and T790M were 25%, 19% and 16% respectively. In addition, the mutually exclusive mutations were significantly observed between EGFR and STK11 in TP53-mut patients. All patients will be allocated a corresponding arm according to their mutated genome profile and the clinical follow-up was still in progress. Conclusions: Multiple gene sequencing could be a useful selector for personalized lung cancer targeted therapy. Furthermore, mutation coexistence and mutual exclusion might be further predictors for the risk of drug resistant, recurrence at multivariate analyzes.
The impact of heart radiation dose in lung SABR.
Authors: Gan Hao Wen, Gerald , Stobo Jon , Mohammed Nazia
Published: March 2020

e20054

Background: Lung cancer has poor outcomes, but those patients diagnosed with stage 1 NSCLC have 5-year survival of 60-70%. Stereotactic ablative body radiotherapy (SABR) is routinely considered for patients unfit for surgery. SABR is very well tolerated hence a treatment option for patients unfit for surgery, with > G2 lung toxicity of 1.8-9.1%, but propensity-matched analyses of stage 1 NSCLC treated with surgery or SABR have shown superiority of surgery in terms of overall survival, but not lung cancer-specific survival. Excess risk of CVD is a complication of breast cancer RT, but there is limited evidence in lung cancer. The aims of this study is to investigate the impact of radiation dose to the heart in lung SABR. Methods: In a single centre from November 2011-2012, patients who treated with lung SABR outwith the “no fly zone”, using ROSEL guidelines for OARS and with the lowest or highest heart maximum point dose were selected. 9 patients in each group were analysed for dose and clinical factors retrospectively from electronic patient notes. Results: The median (range) heart dose of the high dose (HD) group was 25.3Gy (17.6–34.1) and that of the low dose (LD) group was 0.88Gy (0.18–4.8). At the end of a median follow-up of 6.7 years, OS was poorer in the HD group at 11% than the LD group at 56% (p = 0.127). While 5-year cancer-specific mortality was similar in both groups at 22%, non-cancer-associated mortality was higher in HD (44% vs 11%, p = 0.127). In addition, HD were associated with a greater risk of CV hospital admission (56% vs 11%, p = 0.131) and new cardiac abnormalities (56% vs 0%, p = 0.029). Conclusions: In this group of medically unfit NSCLC patients treated with lung SABR, there were differences in outcome possibly associated with heart dose. The HD group showed higher mortality, specifically non-cancer-related mortality and cardiac events. Investigation of a larger cohort is warranted. [Table: see text]
Potential interaction of radiation therapy, antibiotic, and steroid use in non-small cell lung cancer patients treated with checkpoint inhibitors: A retrospective analysis.
Authors: Wang Fen , D'Rummo Kevin , Al-Jumayli Mohammed , Pei Lei , Huang Chao Hui
Published: March 2020

e20724

Background: The activity of Checkpoint inhibitors (CPI) can be predicted by PD-L1 expression. Recent studies showed that other factors can also have an impact including radiation which is beneficial but the use of antibiotics and steroids can have a deleterious effect. We performed a retrospective analysis of stage IV lung cancer patients treated with CPI at our institution and the impact of radiation treatment as well as the use of antibiotics or steroids in their outcome. Methods: We reviewed the data of 121 patients with stage IV non-small cell lung that were treated with CPI from 2015 to 2017 and analyzed the impact of PD-L1 expression, radiation treatment, steroid and antibiotic use on their progression-free survival (PFS) and overall survival (OS). We determined the use of antibiotics and steroids during any time within 30 days of initiation of treatment with CPI. Results: The median age was 66; there were 57 females and 64 males;23 current smokers, 11 non-smokers and 87 previous smokers; 87 adenocarcinomas, 24 squamous cell histology, and 10 others; 38 patients had low PD-L1 ( < 50%), 46 had high PD-L1 (≥50%) and 37 was unknown. The PFS and OS of patients treated with CPI who had radiation (RT) were not different from patients that did not have RT by Gehan-Breslow Wilcoxon test nor there was a difference based on the PD-L1 expression. The use of steroids (S) had a beneficial impact on PFS but it was numerically better but not significant on OS. Antibiotic (AB) use also had a beneficial impact on PFS and OS. Patients that had CPI as first-line therapy had shorter PFS than patients that had CPI as second-line therapy. There was no difference whether RT was used or not in patients that had antibiotics or steroids. Conclusions: Our analysis showed that several factors can potentially impact the PFS and OS of patients treated with CPI. Contrary to the previous report, the use of Ab or S did not affect adversely the PFS and OS. We did not observe a beneficial effect of RT. The sequence of use of CPI could potentially affect the PFS. This data should be taken with caution as it is a retrospective analysis with a small sample number but it reflects the real-life practice of patients treated outside of a clinical trial setting. [Table: see text]
Characteristics of T-cell receptor repertoire between lung cancer patients and healthy people.
Authors: Liang Naixin , Chen Si , Yi Yuting , Guan Yan-Fang , Xia Xuefeng , Yi Xin
Published: March 2020

e20728

Background: Deep sequencing studies on T cell receptor (TCR) repertoire have provided a wealth of information, such as immune status, virus infection history and so on. As we all known, the thymus begins to involute at the time of birth, so does the immune system. We can use TCR sequence to describe changes in human’s immune system with age, the difference between males and females and immune stat of cancers. Methods: We analyzed TCRβrepertoire in 334 healthy individuals without cancer, aged 2–83 years, and 207 lung cancers. In detail, genomic DNA was extracted from peripheral blood and used to amplified and sequenced the CDR3 region of rearranged TCRβ genes. Finally, we got the relative frequencies of individual T cell clones. Shannon’s entropy was calculated on the clonal abundance of all productive TCR sequences. The normalized Shannon’s entropy (Shannon index) was determined by dividing Shannon’s entropy by the natural logarithm of the number of unique productive TCR sequences. HEC was defined by a CDR3 aa clonotype clonal frequency exceeding 0.1%. Results: Analysis had been made to test the age relationship among a cluster of commonly used immune parameters, such as Shannon’s entropy, clonality and so on. Two outcomes, Shannon index and HEC, had showed a more closed correlation with age. Shannon indexs were significantly decreasing with age (p = 6.2×10-11), while HECs increased with age (p = 5.3×10-10) . Comparison of the peripheral blood T cell repertoire diversity between male and female, we found TCRβdiversity decreases more rapidly in 20 to 40 years for males than for females. No gender difference was observed in the youngest cohort and the oldest age cohort. Lung cancer patients has a lower T cell diversity compared with health people aged 40 years or more (6.43±1.30 vs 6.71±1.70, p = 6.3×10-5). Conclusions: Our data suggest that the human peripheral blood TCR repertoire diversity decrease from young ( < 20 years) to middle-aged ( 20 to 65 years ) to elderly adults ( > 65 years). Moreover, TCR repertoire displays significant gender difference in the 20-40 years age group. Lung cancer patients suffer a poorer immune state than healthy people.
Carcinomas in the children and young adults: A report form Children’s Oncology Group APEC14B1 study.
Authors: Venkatramani Rajkumar , Piao Jin , Krailo Mark D. , Rodriguez-Galindo Carlos , Pashankar Farzana D.
Published: March 2020

e21505

Background: Carcinomas are rare in the children and young adults. Systematic study of epidemiology and biology of carcinomas in this age group is lacking. Project:EveryChild, A Registry, Eligibility Screening, Biology and Outcome Study (APEC14B1) aims to collect demographic and epidemiologic information of every child and young adult diagnosed with cancer in Children’s Oncology Group institutions. It also serves as a biobank for tumor and biological tissue collected from cancer patients and their parents. Methods: We analyzed the clinical and demographic characteristics of patients with the following diagnosis enrolled in the APEC14B1 study: Thyroid cancer, adrenocortical cancer, colorectal cancer, nasopharyngeal carcinoma, and any other carcinoma. Patients with renal cell carcinoma were not included. Results: Between December 2015 and October 2018, 120 patients with carcinomas were enrolled; thyroid (n = 42, 35.0%), nasopharyngeal (n = 22, 18.3%), colorectal (n = 7, 5.8%), adrenocortical (n = 3, 2.5 %), and others (n = 46, 38.3%). Majority were female (n = 74, 61.7%), mainly due to female predominance (31/42, 73.8%) in thyroid cancer. Majority were white race (n = 81, 67.5 %) and not Hispanic (n = 89, 74.2%). Two patients were enrolled in 2015, 24 in 2016, 47 in 2017, and 47 in 2018. The median age at diagnosis was 15.6 years (range 0.5- 24.6 years). Lymph node involvement was reported in 92 patients and was positive in 58 (63.0%). Metastasis status was reported in 108 and 29 (26.8%) patients had distant metastases. Seventy eight percent (n = 94) of patients agreed to banking of biological material for future research and 90% agreed to be contacted in future for other research studies. Biological samples were banked from 46 patients (48.9%) including tissue submissions from 39 patients, blood submissions from 21 patients and serum submissions from 5 patients. Conclusions: APEC14B1 study was successful in enrolling a large number of children and young adults with carcinomas in a short period of time. Lymph node and distant metastases were common in children and young adults with carcinomas. The enrollment of patients with carcinomas will likely accelerate in the coming years as more institutions open the study. This study will serve as an important resource for investigators interested in clinical and biological research of carcinomas which occur in children and young adults.
Effect of miR-506 on pirarubicin sensitivity and on mesenchymal to epithelial transition and DNA damage homologous recombination repair process in leiomyosarcoma.
Authors: Yang Jilong , Li Ting , Li Feng
Published: March 2020

e22503

Background: MicroRNAs has been shown to be involved in many processes of tumorigenesis. Furthermore, miR-506 has been confirmed to be related to the occurrence of epithelial to mesenchymal transition (EMT) and tumor chemoresistance. However, the role of miR-506 in leiomyosarcoma has not yet been reported. Methods: A retrospective review of the 61 Chinese patients diagnosed with soft tissue leiomyosarcoma from January 2000 to December 2012 was investigated. Patient survival trends were examined by Kaplan-Meier analysis and log-rank tests. In vitro experiments were used to determine the biological function and physiological mechanism of drug sensitivity of miR-506. Results: In Chinese leiomyosarcoma patient cohort, we detected a decreased expression of miR-506 in the tumor tissues than that in marginal normal tissues. Tissue microarray analysis detected and confirmed a novel mesenchymal to epithelial transition (MET) in soft tissue leiomyosarcoma, also this MET phenomena was correlated with survival. In vitro, miR-506 inhibited the proliferation, migration, and invasion of leiomyosarcoma cells by promoting the occurrence of MET. Furthermore, RAD51, RAD52, ATM and ATR, which are defined as DNA damage homologous recombination repair related proteins, were highly expressed and associated with worse overall survival of leiomyosarcoma patients. Through targeting MET and DNA damage homologous recombination repair related proteins, miR-506 promoted the sensitivity of leiomyosarcoma cells to Pirarubicin. Conclusions: The current study reveals a novel mechanism that miR-506 increases the drug sensitivity of tumor cells, which are probably in association with the MET and DNA damage homologous recombination repair process.
Chemotherapy combined with antiangiogenesis drugs in stage IV sarcoma patients: Efficacy data from the largest cohort study from China.
Authors: Ren Zhiwu , Liao Zhichao , Yang Jilong
Published: March 2020

e22505

Background: Chemotherapy agents such as doxorubicin are not curative and new therapies for metastatic sarcomas are urgently needed. Several anti-angiogenesis therapeutic drugs such as Apatinib and Endostar have been widely used as monotherapy or combined treatments. We performed a retrospective study with the largest Chinese sarcoma cohort to investigate the efficacy of different anti-angiogenesis strategies. Methods: Data of NCT03121833 and NCT03121846 were collected. The information of 119 sarcoma patients in stage IV treated in Tianjin Medical University Cancer Hospital from Oct. 2009 to Aug. 2018 was collected. These sarcoma patients received chemotherapy, anti-angiogenesis therapies, or combined treatments. Chemotherapy was administered with single-agent Adriamycin or combination regimens according to NCCN guideline. Endostar was given at a dose of 15mg once daily by intravenous infusion for 14 days combined with chemotherapy regimens. Apatinib were given at a starting dose of 500 mg daily. Efficacy was evaluated according to RECIST1.1. Treatment-related adverse effects (AEs) were also evaluated. Results: 119 patients (46 bone sarcomas and 73 soft tissue sarcomas) were enrolled into four groups according to different treatment strategies (Table). The ORR had no significantly difference but DCR was significantly different, with the highest rate in chemotherapy plus apatinib group. The mPFS and mOS had no significantly difference. All the AEs were manageable. Conclusions: Chemotherapy combined with anti-angiogenesis drugs such as Apatinib and Endostar significantly increase the response rate. Apatinib is effective and well tolerated for advanced sarcoma patients. As for Apatinib treatment, the patients who suffered hypertension, hand-foot-skin reaction or proteinuria have significant longer OS than those without these AEs, which is first report in sarcoma patients. Clinical trial information: NCT03121833; NCT03121846. [Table: see text]
The long term surgical outcome of spinal giant cell tumor.
Authors: Yoon Joonho , Chung Chun Kee , Lee Sunho , Kim Chiheon
Published: March 2020

e22510

Background: GCT is a benign and locally aggressive tumor that occur infrequently in the mobile spine. The radical excision is generally agreed for treatment of GCTs. Methods: We performed retrospective analysis of 20 GCTs in the mobile spine from 2005 to 2013. Verteberal involvement was classified with Weinstein-Boriani-Biagini grading system. Surgery types were classified into 3 groups; partial excision, gross total removal (GTR), and en-bloc resection. We analysis by GTR versus non-GTR group, and enbloc versus non-enbloc group in GTR group. The log rank test was used for comparison of factors, and a P value of less than 0.05 was deemed significant. Results: After first surgery of the 20 patients, 17 additional surgery performed for 10 (50%) patients. There were 7 (35%) local recurrences and 3 (15%) distant metastasis. The time to recurrence or progression of tumor ranged from 5 months to 39 months. Two (10%) patients had additional surgery for instrument failure. One (5%) patient died from the complication of the surgery. The follow up duration ranged from 24 months to 141 months. The local recurrence was associated with partial resection (P < 0.01) and history of recurrence (P = 0.39). There was no significant difference between non-en bloc GTR and en bloc GTR in local recurrence (p = 0.101). Conclusions: Gross total resection should be considered for GCTs of the mobile spine. The choice of en bloc resection must be balanced with risks of the procedure. En bloc resection or radical excision could be challenging in many cases. In that cases, the gross total removal by intralesional resection is considerable for local control.
Advanced epithelioid haemangioendotelioma: Fever, pain, and pleural effusion predict a worse outcome.
Authors: Vincenzi Bruno , Frezza Anna Maria , Brunello Antonella , D'Ambrosio Lorenzo , Baldi Giacomo G. , Badalamenti Giuseppe , Grignani Giovanni , Napolitano Andrea , Valeri Sergio , Improta Luca , Spalato Ceruso Mariella , Silletta Marianna , Dei Tos Angelo Paolo , Gronchi Alessandro , Stacchiotti Silvia
Published: March 2020

e22540

Background: Epithelioid hemangioendothelioma (EHE) is an exceedingly rare soft tissue sarcoma subtype. EHE often presents as a multifocal/ multivisceral disease and its clinical behavior is highly unpredictable from indolent to very aggressive forms. A common choice in advanced patients is a close, active surveillance (AS), considering a treatment only in case of disease progression. Our retrospective study aimed to identify clinical features associated with a more aggressive behavior. Methods: Patients affected by advanced EHE treated in 6 centers of the Italian Rare Cancer Network were retrospectively reviewed. Diagnosis was confirmed by a sarcoma expert pathologist and molecular analysis was performed. Baseline clinical features were evaluated, including the presence of systemic symptoms (fever, weight loss, anorexia) and/or tumor related pain. Number of organs involved (1 vs > 1 and 1-2 vs > 2, mitotic index (< 2 vs ≥= 2 mitosis/10 high power fields - HPF). Results: 74 patients were identified (M:F = 42:32; mean age = 44 yrs - range = 16-81, median number of mitosis/10 HPF = 2 - range 0/8, systemic simptoms Y:N = 30:44; fever Y:N = 21:53; tumor related pain Y:N = 23:51; pleural effusion Y:N = 11:63). All patients had metastatic disease; 29 showed the involvement of one organ while 45 had multivisceral disease (18 of them > 2 viscera). At the time of diagnosis, all patients were naive from any systemic therapy and underwent exclusive AS. At a median FU of 32 months (range: 3-212), 48 (65%) patients progressed while 26 (35%) remained stable. No spontaneous regressions were observed. Median PFS was 30 months (range 2-115). Median OS was 54 months (range 3-151). Age, gender, mitotic index, number of involved organs, anorexia and weight loss did not correlate with median PFS (m-PFS). Fever correlated with shorter m-PFS (8 vs 45 months, P= 0.004), as well as pain (10 vs 42 months, P= 0.02) and the presence of pleural effusion (5 vs 46 months, P= 0.0001). In addition, fever and pleural effusion correlated with a shorter m-OS, respectively 29 vs 60 months (P = 0.03) and 11 vs 77 months (P < 0.001). The presence of pain corresponded to a not significant worse m-OS (39 vs 54 months, P= 0.16). Conclusions: Despite the small number of cases, this retrospective study suggests that in advanced EHE patients the presence of fever and/or tumor related pain and/or of pleural effusion can be associated with a more aggressive clinical behavior. Pleural effusion seems to be associated with the worse outcome, with a m-OS of 12 months. These data are worth confirming on a larger patient population.
Olaratumab plus anthracyline in advanced/metastatic soft tissue sarcoma: Data of real-world utilization in Austria.
Authors: Kocher Florian , Seeber Andreas , Weiss Lukas , Romeder Franz , Szkandera Joanna , Kuhr Thomas , Kostner Susanne , Pichler Petra , Jäger Thomas , Greil Richard , Brodowicz Thomas
Published: March 2020

e22550

Background: Olaratumab is a humanized monoclonal anti platelet-derived growth factor receptor α antibody that has been approved in combination with doxorubicin for the treatment of patients with metastatic soft tissue sarcoma (STS). The purpose of this retrospective study was to assess the clinical efficacy in STS patients treated with olaratumab in a real-world setting in Austria. Methods: Retrospectively collected, longitudinal data from patients treated between November 2016 and September 2018 at 9 Austrian centers were obtained from respective medical charts. Eligible patients were all patients who received at least one dose of olaratumab. Parameters of most interest collected were response rates, progression-free survival (PFS) and overall survival (OS). Results: Altogether 55 patients were included into analysis. Median age was 58 years. In total, 65.5% (n = 36), 21.8% (n = 12) and 12.7% (n = 7) received olaratumab as first-, second- or ≥ third-line treatment, respectively. Olaratumab was administered either in combination with doxorubicin (81.8%, n = 45) or liposomal doxorubicin (16.4%, n = 9); 1 patient received olaratumab as upfront monotherapy. Median PFS and OS were 2.6 and 11.4 months. The objective response rate was 11.4 % and the disease control rate was 40.9 %. Conclusions: In this real-world analysis outcome was less pronounced compared to the results of the Phase Ib/II approval trial ( Tap WD et al. Lancet 2016). Thus, the results of the ongoing phase III trial (NCT02451943) are urgently needed to confirm the efficacy of the combination of olaratumab and doxorubicin in STS patients.
Treatment of soft tissue sarcoma with a novel cold plasma jet.
Authors: Cheng Xiaoqian , Blank Alan , Ly Lawan , Murthy Saravana R , Wakefield Connor , Colman Matthew W. , Batus Marta , Gitelis Steven , Keidar Michael , Canady Jerome
Published: March 2020

e22562

Background: Soft tissue sarcoma is a malignant tumor that most often develops in adults, but can occur in children as well. Treatment with radiation, en bloc surgical resection and chemotherapy have achieved long-term survival rates up to 65% to 80% in non-metastatic disease. Local microscopic tumor cells can still exist despite complete R-0 surgical excision of the tumor. A novel technology Cold Atmospheric plasma (CAP) is an emerging technology that has shown promising anticancer effects i.e anti-mitotic and less effective on non-cancerous tissue. A new field has developed in medicine Plasma Onco-therapeutics. CAP treatment has the potential to improve the outcome of osteosarcoma patients. Methods: CAP was generated using a US Medical Innovations LLC (USMI) SS-601 MCa high-frequency electrosurgical generator (USMI, Takoma Park, MD, USA) integrated with Canady Cold Plasma Conversion Unit and connected to a Canady Helios Cold Plasma Scalpel. Three types of human sarcoma cells, synovial sarcoma (SW982), connective tissue fibro sarcoma (HT-1080), and rhabdomyosarcoma (RD) were used in this study to test the effect of the CAP generated by the Canady Cold Plasma Conversion System. Cells were treated with various CAP settings including different helium flow rates (1 and 3 LPM) and power settings (20-120p) in order to establish an optimal treatment condition for each cell line. Viability was performed on the cells using MTT assay 48 hours after CAP treatment. Student t test was performed on the data (*p < 0.05). Results: The reduction of the viability of all three sarcomas were dose-dependent and significantly reduced at various time and power combinations tested (Figure 1-3). Helium flow alone did not significantly impact cell viability. The decrease in viability of the sarcoma cells when using 1 LPM required a higher dose. About 20 to 40% of viability reduction was seen on the three cell lines. With 3LPM, viability was reduced to 20% using 80p 2 min for SW982 and HT-1080, and 100p 2min for RD. Conclusions: Our data demonstrates that CAP reduced sarcoma cell viability in a time- and power-dependent manner. With optimal dosage for each cancer type, this study provides a promising treatment for future therapeutic interventions for soft tissue sarcomas.
Oncology provider perceptions of shared-decision making.
Authors: Sathe Nila , Polacek Cate , Fenk Sunnie , Rossi Wendy , Christopher Roni
Published: March 2020

e23168

Background: Adoption of shared decision making (SDM), a key strategy for improving patients’ care experience, may be limited. We explored oncology professionals’ SDM perceptions to understand patient-provider decision-making communication. Methods: Semi-structured phone interviews or web-based surveys with purposively recruited participants from a range of perspectives to increase generalizability. Content analysis to identify overarching themes. Results: Respondents (n = 20) valued SDM but described challenges including: Evolving and variable communication needs. Evolving care trajectories constrain full SDM discussions. Differences in goals in curative or palliative situations dictate different approaches. Communication along care continuum. Providers noted that discussions of elements of care occur with multiple providers and staff, potentially in a piecemeal fashion. Communicating about costs. Costs vary considerably in terms of cost to the patient and to the system. Impact on care is more than a simple higher/lower dichotomy. Directing decisions vs. fostering discussion: Most respondents understood a “literature-based” SDM definition, but some conflated patient education and SDM. Some implied “nudging” patients toward choices vs. open discussion. Balancing clinical imperatives and patient preferences. Respondents noted balancing professional imperatives to share information with patient values. External influences on communication. Families were seen as a help and hindrance to SDM, particularly when care goals differ. Cultural meanings ascribed to cancer also vary. Decision making style. Participants suggested that patients approach decision making from overarching mindsets regarding engagement (e.g., prioritizing provider input). Conclusions: Respondents valued communication and SDM but described challenges in exigencies of care delivery, provider attitudes, and patient influences. Respondents’ discussion of challenges suggests that exploiting communication opportunities across the care trajectory and deliberate consideration of patients’ preferences for decision-making conversations could help to inform/prime communication and potentially improve SDM processes.
Unpacking clinical trial offers: A qualitative analysis of interactions with physicians and patients potentially eligible for a prostate cancer trial.
Authors: Hamel Lauren M. , Dougherty David W. , Manning Mark A. , Penner Louis , Albrecht Terrance Lynn , Heath Elisabeth I. , Carducci Michael Anthony , Lansey Dina , Kim Seongho , Eggly Susan
Published: March 2020

e23169

Background: Clinical trial accrual among cancer patients is low (2-5%). More data are needed to identify barriers to enrollment and inform interventions. One way to identify the greatest barriers is by examining clinical interactions. We investigated whether and under what circumstances patients potentially eligible for a trial at a major cancer center were offered the chance to enroll. Methods: We conducted a qualitative content analysis of 50 recorded interactions with physicians (n = 8) and patients (n = 36) with intermediate- or high-risk prostate cancer who were initially eligible for a trial at two NCI-designated comprehensive cancer centers. We observed and coded the interactions in three steps: 1) classification of all interactions as explicit offer, offer pending, trial discussed but not offered, or trial not discussed; 2) in interactions with no explicit offer, classification of patients who were informed their disease was stable or had progressed; 3) in interactions classified as cancer progressed but no trial offered, identification of factors discussed that may explain the lack of an offer. Results: Of the 50 interactions, 30% were classified as explicit offer; 6% as offer pending; 18% as trial discussed but not offered; and 40% as trial not discussed. Of the 35 interactions with no offer, 54% were with patients whose cancer had not progressed. In the 16 remaining interactions with patients with no offer and whose cancer had progressed, reasons for the lack of offer included: testing needed, no trial/study slot, and comorbidities; but in 25% of these, no reason was provided. Conclusions: Even in this highly selected population, few patients were offered a trial, often because they were ultimately ineligible. Findings support professional recommendations to broaden inclusion criteria to increase the pool of eligible patients. Findings also suggest trial accrual rates could be more accurately calculated by considering patients who are eligible to enroll, rather than all patients with cancer. In 40% of interactions, there was no mention of a trial, suggesting interventions should also be aimed at patient and physician attitudes and clinical communication. Clinical trial information: NCT 02906241.
Delay in time from diagnosis to treatment in metastatic melanoma, lung, and colon cancer.
Authors: Faisal Muhammad Salman , Khattab Ahmed , Jahangiri Vida , Shaikh Hira , Shaikh Soorih , Chaturvedi Abhishek , Raj Moses S. , Finley Gene Grant
Published: March 2020

e23186

Background: Delay in cancer treatment is anxiety provoking both for the patient and clinician. We conducted the study to evaluate the patterns of delay in treatment of patients with metastatic colon cancer, lung cancer and melanoma from diagnosis to the initiation of the treatment, and to identify the causes of delay. Methods: In this retrospective study, patients with metastatic colon cancer, lung cancer and melanoma diagnosed between 01/01/2016 to 12/31/2016 in a tertiary care network in the United States were studied. Data was collected from electronic health record (EHR) database, ‘Epic’. Variables such as demographic data, including patient age and gender, and type of cancer, and treatment received were analyzed. The causes of the delay were also evaluated when available. Results: Total number of patients in the study was 288. Mean age was 68.3 years (median 69 years) and 36% were alive at the time of data analysis. Male to female ratio was 1.4:1. 66.7% people had lung cancer, 30% had colon cancer and 3% had melanoma. 67 (23.6%) of total analyzed patients had denied definitive treatment and chose to undergo palliative management. Of the rest, most started treatment with chemotherapy (39.5%), followed by surgery (22.6%) and then radiation (14.6%). With the time of pathological diagnosis of the tumor taken as the date of diagnosis, mean delay from the day of diagnosis to the start of treatment in this study population observed was 27.7 days. 67 patients (23.3%) had a delay of more than 30 days, with the most common reason being systemic factors in 39 patients (58.2%), followed by patient factors in 23 patients (34.3%) and physician factors in 5 patients (7.5%). On logistic regression analysis, time from diagnosis to treatment didn’t predict mortality (OR = 0.99, 95% CI P = 0.10(0.97-1.002). Conclusions: Delay in treatment is common and the system factors one of the common reasons as exhibited by our study. Time from diagnosis to treatment didn’t predict mortality.
Simulated patient encounter to assess and improve fellows' ability to manage chemotherapy infusion reactions.
Authors: Zimmerman Danielle Elise
Published: March 2020

TPS10541

Background: Medical educators have adopted simulation-based exercises (SBEs) because studies of their use in the aviation industry and other technical fields have shown that they reduce human error. While use of simulation has increased in undergraduate and graduate medical education, it hasn’t been used as frequently in educating subspecialty fellows. Fewer than 5% of participants in a survey of different subspecialists indicated that simulations were part of their fellowship curriculum (1) even though simulation-based training is an ACGME program requirement (2). Chemotherapy infusion reactions (CIRs) occur with about 5% of all cytotoxic chemotherapies and even more frequently with biologics (3). These CIRs present significant morbidity and cost. HFS improves knowledge and confidence in medical trainees (4). Therefore, I designed a high fidelity simulation (HFS)-based curriculum to measure fellows’ current medical knowledge and provide a mechanism for gaining increased understanding and confidence. Across subspecialty graduation medical education, only one SBE with IRs has been performed, and that project aimed only to measure existing knowledge (5). This project aims to measure oncology fellows’ knowledge of and confidence in CIR management, measure attitudes regarding SBEs, measure improvement in knowledge following the SBEs, and assess for changes in behavior (management of CIRS) that may occur following these interventions. Methods: The HFS takes place in the VA Hospital Interdisciplinary Simulation and Education Center, which consists of a programmable mannequin that can “talk” through a speaker and convey physical exam signs in an “outpatient clinic.” Participants will interact with the mannequin, who will be a patient experiencing a paclitaxel infusion reaction. An evaluator will be grading the participant’s actions with an OSCE style checklist. Immediate debriefing will be followed by a didactic. Participants will complete post-intervention surveys regarding their confidence in and knowledge of management of CIRS. Participants will later be evaluated on their attitudes regarding the simulation, their knowledge of CIR management, and will also provide critique of the same interaction done by another provider. These HFS-based activities will allow evaluation of fellows’ current knowledge of and comfort with CIRS, fellows’ attitudes regarding the intervention, improvement in knowledge occurred following the intervention, and anticipated change in management.
A multicenter, randomized phase III study of asciminib (ABL001) versus bosutinib in patients (pts) with chronic myeloid leukemia in chronic phase (CML-CP) previously treated with ≥2 tyrosine kinase inhibitors (TKIs).
Authors: Mauro Michael J. , Hochhaus Andreas , Boquimpani Carla , Minami Yosuke , Allepuz Alex , Polydoros Fotis , Bédoucha Véronique , Aimone Paola , Réa Delphine
Published: March 2020

TPS7070

Background: There is a need for new treatment options for pts with CML who are intolerant/resistant to currently available BCR-ABL1 ATP-binding site targeted TKIs. Asciminib is a potent and specific BCR-ABL1 inhibitor with a novel allosteric mechanism of action targeting the ABL1 myristoyl pocket. This results in a mutation-driven resistance profile different from that of ATP binding-site TKIs, providing potential for both monotherapy and combination therapy with ATP-binding-site TKIs. In a phase 1 study (NCT02081378), asciminib showed clinical activity and good safety/tolerability in CML pts with resistance/intolerance to ≥2 TKIs and in pts with the T315I mutation. The recommended dose for asciminib monotherapy in CML pts without the T315I mutation was established as 40 mg BID. An ongoing phase 3 study (NCT03106779) is evaluating asciminib monotherapy vs bosutinib in pts with CML who have been treated with ≥2 prior ATP-binding-site TKIs. Methods: Eligible pts are adults with CML-CP who previously received ≥2 TKIs, with intolerance or failure to the most recent TKI. Treatment failure is defined per 2013 European LeukemiaNet (ELN) recommendations. Pts harboring T315I or V299L mutations are excluded. Pts are randomized 2:1 – stratified by baseline cytogenetic response status – to receive asciminib 40 mg BID or bosutinib 500 mg QD (planned enrollment: N = 222). Primary and key secondary objectives are to compare the rate of major molecular response ( BCR-ABL1IS≤0.1%) with asciminib vs bosutinib at 24 and 96 weeks, respectively. In a recent protocol amendment, the baseline BCR-ABL1IS threshold for enrollment was lowered from ≥1% to > 0.1% for pts with intolerance to the most recent TKI. This change was implemented to align with clinical practice and satisfy the treatment need to avoid waiting for an increase in BCR-ABL1IS levels to ≥1%. In addition, pts with documented bosutinib treatment failure as per ELN recommendations may switch to receive asciminib therapy at any time, as such pts may have limited treatment options outside of this study. This study is ongoing with 149 participating study sites in 30 countries. Clinical trial information: NCT03106779.
A phase I study of AMV564 in patients with intermediate or high-risk myelodysplastic syndromes.
Authors: Garcia-Manero Guillermo , Jacoby Meagan , Sallman David Andrew , Han Tae , Guenot Jeanmarie , Feldman Eric
Published: March 2020

TPS7071

Background: The CD33 antigen is expressed on myeloblasts in approximately 75% of patients with myelodysplastic syndromes (MDS) and is also expressed on immunosuppressive myeloid-derived suppressor cells (MDSCs) that are prevalent in MDS. AMV564 is a novel bivalent, bispecific (2:2) T-cell engager that binds both CD33 and the invariant CD3ε on T-cells with strong avidity. AMV564 has significant cytotoxic activity against CD33-postive cells, including MDSCs, in animal models, in vitro studies, and in patients (Reusch et al. Clin Can Res 2016 and List et al. ASH 2017). Preliminary results from the phase 1 acute myeloid leukemia (AML) trial have demonstrated safety and activity in patients with AML arising from prior MDS (Westervelt et al. ASH 2018). Methods: AMV564-201 is an open label, phase 1, multicenter, dose-escalation with expansion trial of AMV564 in patients with intermediate-2 or high-risk MDS who are refractory to or relapsed from hypomethylating agents (HMAs) or intensive chemotherapy. The key objectives of the dose-escalation stage of the study are to characterize the safety and tolerability of AMV564, identify a maximum tolerated dose and/or a dose-schedule to evaluate in the dose expansion portion of the study. In the dose expansion stage of the study, the safety and tolerability of AMV564 will be further characterized in addition to a preliminary assessment of efficacy. Other objectives include characterization of AMV564 pharmacokinetics, pharmacodynamics, and immunogenic potential. Approximately 80 patients with intermediate-2 or high-risk MDS will be enrolled. The Dose Escalation Stage will include up to approximately 30 patients, depending on the dose at which the MTD is determined for each schedule, and approximately 50 additional patients will be enrolled in the Expansion Stage. AMV564 will be administered daily as a continuous intravenous (CIV) infusion over a period of 24 hours for 14 days in each cycle. Each cycle will be approximately 4 weeks. A lead-in dose regimen will be utilized for all patients treated at dose levels at or above 50 mcg/day. Patients will receive up to 4 cycles of AMV564 treatment at the assigned dose level. Clinical trial information: NCT03516591.
ALPINE: Phase III zanubrutinib (BGB-3111) versus ibrutinib in patients with relapsed/refractory (R/R) chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL).
Authors: Hillmen Peter , Brown Jennifer R. , Byrd John C. , Eichhorst Barbara , Lamanna Nicole , O'Brien Susan Mary , Qiu Lugui , Paik Jason C. , Hilger James D. , Huang Jane , Tam Constantine S.
Published: March 2020

TPS7572

Background: Inhibition of Bruton tyrosine kinase (BTK) has emerged as a strategy for targeting B-cell malignancies including CLL/SLL. Zanubrutinib, an investigational inhibitor of BTK, was specifically engineered to optimize selectivity, half-life and solubility in an effort to decrease toxicities and better penetrate tumor tissue. Early clinical data suggested that zanubrutinib treatment in patients with treatment-naïve (TN; n = 16) or R/R (n = 50) CLL/SLL induced deep responses: 94% overall response rate (ORR), including 6% and 2% complete response rates in TN and R/R CLL/SLL, respectively (ICML 2017). This study is designed to evaluate whether zanubrutinib monotherapy exhibits non-inferior and potentially superior efficacy based on the ORR vs ibrutinib monotherapy in patients with R/R CLL/SLL. Methods: This ongoing phase 3, randomized, open-label, global study (NCT03734016, BGB-3111-305) is comparing the efficacy and safety of zanubrutinib vs ibrutinib in adult patients with R/R CLL/SLL. Approximately 400 patients will be randomized, 1:1 to each arm and stratified by age (< 65 vs ≥ 65 years), refractory status (yes vs no), geographic region, and del(17p)/ TP53 mutation status (present vs absent). Key inclusion criteria include R/R CLL/SLL requiring treatment per iwCLL criteria, ECOG PS 0-2, and adequate hematologic function. The primary endpoint is ORR as determined by an independent review committee according to iwCLL guidelines, with modification for treatment-related lymphocytosis for patients with CLL and per 2014 Lugano Classification for patients with SLL. The study is powered to test the non-inferiority and superiority of the ORR for zanubrutinib vs ibrutinib. Secondary endpoints include progression-free survival, safety, duration of response, and overall survival. Recruitment is ongoing. Clinical trial information: NCT03734016.
Phase 1 study of AMG 119, a chimeric antigen receptor (CAR) T cell therapy targeting DLL3, in patients with relapsed/refractory small cell lung cancer (SCLC).
Authors: Byers Lauren Averett , Chiappori Alberto , Smit Marie-Anne Damiette
Published: March 2020

TPS8576

Background: SCLC is an aggressive neuroendocrine tumor, with initial sensitivity to chemotherapy and radiotherapy often followed by chemoresistant disease progression. Notch signaling is a key regulator of neuroendocrine differentiation in SCLC, and delta-like ligand 3 (DLL3) is an inhibitory ligand of Notch receptors. DLL3 is expressed in most SCLC tumors but minimally expressed in normal tissues, suggesting that it may be a promising target for cancer immunotherapy. AMG 119 is an adoptive cellular therapy that consists of a patient’s autologous T cells that have been genetically modified ex vivo to express a transmembrane CAR that targets DLL3 and redirects cytotoxic T cell specificity to DLL3-positive cells. AMG 119 CAR T cells show potent killing of SCLC cells expressing DLL3 in vitro and inhibit tumor growth in an SCLC xenograft model in vivo. Methods: This phase 1 study will evaluate the safety and tolerability of AMG 119 administered as a single infusion in adult patients with relapsed/refractory SCLC who have progressed after at least 1 platinum-based chemotherapy regimen. The primary objectives are to evaluate safety and tolerability and determine the maximum tolerated cell dose (MTCD) or recommended phase 2 cell dose (RP2CD). Secondary objectives are to evaluate preliminary evidence of antitumor activity, expansion and persistence of AMG 119, and trafficking of AMG 119 to the tumor in post-treatment biopsy. Key inclusion criteria include histologically confirmed SCLC with radiographically documented disease progression or recurrence after at least 1 platinum-based regimen, ECOG performance status 0–1, at least 2 measurable lesions per modified RECIST 1.1, no untreated or symptomatic brain metastases, and adequate organ function. In the cell dose exploration phase, 3–4 patients will receive a single IV infusion of AMG 119 at each cell dose. Cell dose escalation/de-escalation decisions will be guided by a modified toxicity probability interval design. The dose expansion phase will seek to confirm the MTCD or RP2CD and obtain further safety and efficacy data. Clinical trial information: NCT03392064.
Phase 1 study of AMG 757, a half-life extended bispecific T cell engager (BiTE) antibody construct targeting DLL3, in patients with small cell lung cancer (SCLC).
Authors: Smit Marie-Anne Damiette , Borghaei Hossein , Owonikoko Taofeek Kunle , Hummel Horst-Dieter , Johnson Melissa Lynne , Champiat Stéphane , Salgia Ravi , Udagawa Hibiki , Boyer Michael J. , Govindan Ramaswamy
Published: March 2020

TPS8577

Background: SCLC is an aggressive neuroendocrine tumor; response to initial chemotherapy and radiotherapy is often followed by recurrence, rapid progression, and resistance to current therapies. Delta-like ligand 3 (DLL3) is an inhibitory ligand of Notch receptors that is expressed in most SCLC tumors but minimally expressed in normal tissues. DLL3 may therefore be a promising target for T cell–redirecting immunotherapy. AMG 757 is a half-life extended BiTE antibody construct that is designed to transiently connect DLL3-positive cells to CD3-positive T cells and induce T cell–mediated cell lysis and concomitant T cell proliferation. AMG 757 induces potent killing of SCLC cell lines in vitro and inhibits tumor growth in the SHP-77 human SCLC xenograft model in vivo. AMG 757 was well tolerated in a preclinical multi-dose toxicology study in cynomolgus monkeys, with no evidence of tissue damage at weekly doses up to 4.5 mg/kg. Methods: NCT03319940 is an open-label, ascending, multiple dose, phase 1 study evaluating AMG 757. The study will initially enroll adult patients with relapsed/refractory SCLC who have progressed after at least 1 platinum-based chemotherapy regimen. Additional inclusion criteria include ECOG performance status 0–2, at least 2 measurable lesions per modified RECIST 1.1, no untreated or symptomatic brain metastases, and adequate organ function. Primary objectives are to evaluate safety and tolerability and to determine the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D). Secondary objectives are to characterize pharmacokinetics (PK) and evaluate preliminary antitumor activity. In the dose exploration phase, patients will be monitored for dose-limiting toxicities during the first 28 days. A Bayesian logistic regression model will be used to inform dose escalation/de-escalation decisions. The dose expansion phase will confirm the MTD or RP2D and collect further safety and efficacy data. AMG 757 will be administered as a short-term intravenous infusion once every 2 weeks. Alternative dosing schedules may be explored based on emerging PK and safety data. Clinical trial information: NCT03319940.