Phase II Study of Sequential Gemcitabine Followed by Docetaxel for Recurrent Ewing Sarcoma, Osteosarcoma, or Unresectable or Locally Recurrent Chondrosarcoma: Results of Sarcoma Alliance for Research Through Collaboration Study 003

Background.Gemcitabine and docetaxel have a broad spectrum of clinical activity in patients with carcinoma. The Sarcoma Alliance for Research Through Collaboration conducted a phase II trial of gemcitabine in combination with docetaxel in children and adults with recurrent Ewing sarcoma (EWS), osteosarcoma (OS), or unresectable or recurrent chondrosarcoma. The primary objective was to determine the objective response rate using Response Evaluation Criteria in Solid Tumors (RECIST).Methods.Gemcitabine (675 mg/m2 i.v. over 90 minutes on days 1 and 8) was administered in combination with docetaxel (75 mg/m2 i.v. over 1 hour on day 8) every 21 days. All patients received filgrastim or pegfilgrastim. A Bayesian formulation was used to determine the probability of achieving the target response rate for each subtype—0.35 for EWS and OS or 0.20 for chondrosarcoma. If the probability of achieving the target response rate was <0.05, the combination was considered inactive. Toxicity was graded according to Common Terminology Criteria for Adverse Events (CTCAE), version 3.0.Results.Fifty‐three eligible patients were enrolled in the three subtype groups—OS (n = 14), EWS (n = 14), and chondrosarcoma (n = 25). Toxicities included neutropenia, thrombocytopenia, fatigue, dyspnea, bronchospasm, edema, neuropathy, and liver function abnormalities. Dose modification for toxicity was required for eight patients during cycle 1 and 16 patients in subsequent cycles. Seven patients withdrew from therapy as a result of toxicity. No complete responses were observed. Partial responses were observed in OS (n = 1), EWS (n = 2), and chondrosarcoma (n = 2) patients.Conclusion.Gemcitabine in combination with docetaxel was associated with a probability of reaching the target 35% response rate of <5% in OS patients and 5.6% in EWS patients; the probability of reaching a 20% response rate in chondrosarcoma patients was 14%.摘要背景. 吉西他滨与多西他赛对癌症患者有广谱的临床疗效。 肉瘤研究联盟协作组在复发的尤文肉瘤 （EWS）、 骨肉瘤 （OS）、 不可切除或复发的软骨肉瘤成人和儿童患者中开展了吉西他滨联合多西他赛的 II 期试验。 主要目的为通过实体瘤疗效评估标准 （RECIST） 确定客观缓解率。方法. 吉西他滨 （675 mg/m2， 静脉滴注 90 分钟以上， 第 1 和 8 天） 联合多西他赛 （75 mg/m2， 静脉滴注 1 小时以上， 第 8 天） 每 21 天给药 1 次。 全部患者均同时接受非格司亭或乙二醇化非格司亭。 利用贝叶斯公式来确定各个亚型达到目标缓解率的概率——EWS 和 OS 为 0.35， 软骨肉瘤为 0.20。 如果达到目标缓解率的概率 < 0.05， 则认为联合方案无效。 毒性反应根据不良事件通用术语标准 （CTCAE） 3.0 版来分级。结果. 53 例合格患者入组 3 个亚型组 ： OS （n=14）、 EWS （n=14）、 软骨肉瘤 （n=25）。 毒性反应包括中性粒细胞减少、 血小板减少、 乏力、 呼吸困难、 支气管痉挛、 水肿、 神经病变以及肝功能异常。 第 1 个周期有 8 例患者、 其后周期有 16 例患者因毒性反应而需要剂量调整。 7 例患者因毒性反应而撤出治疗。 未观察到完全缓解。 OS （n=1）、 EWS （n=2） 和软骨肉瘤 （n=2） 组均有患者达到部分缓解。结论. 吉西他滨联合多西他赛在 < 5% 的 OS 患者、 5.6% 的 EWS 患者中达到目标缓解率的概率为 35%； 14% 软骨肉瘤患者中达到目标缓解率的概率为 20%。讨论. 贝叶斯公式能够评估各个亚型在分别进行缓解率评估后预测达到目标缓解率的概率。 通过多角度来看这些数据， 在考量达到目标缓解率的概率以及入组率之后即能发现本研究设计方案阻碍了研究的继续开展。 因为这一设计方案并未设定判断治疗为 “有效” 的规则， 所以并不适合与标准的分 2 阶段进行的 II 期试验设计直接比较。 关闭 EWS 和软骨肉瘤亚组的决定， 某种程度上是基于入组缓慢， 另外达到目标缓解率的概率较低也支持这一决定。 入组率而不是统计设计， 对试验周期有显著影响。The Oncologist 2012;17:321‐e329Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/139909/1/onco0321-sup-0002.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/139909/2/onco0321-sup-0001.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/139909/3/onco0321.pd

TThe ENCCA-WP7/EuroSarc/EEC/PROVABES/EURAMOS 3rd European Bone Sarcoma Networking Meeting/Joint Workshop of EU Bone Sarcoma Translational Research Networks; Vienna, Austria, September 24–25, 2015. Workshop Report

This report summarizes the results of the 3rd Joint ENCCA-WP7, EuroSarc, EEC, PROVABES, and EURAMOS European Bone Sarcoma Network Meeting, which was held at the Children's Cancer Research Institute in Vienna, Austria on September 24-25, 2015. The joint bone sarcoma network meetings bring together European bone sarcoma researchers to present and discuss current knowledge on bone sarcoma biology, genetics, immunology, as well as results from preclinical investigations and clinical trials, to generate novel hypotheses for collaborative biological and clinical investigations. The ultimate goal is to further improve therapy and outcome in patients with bone sarcomas

X-ray screening identifies active site and allosteric inhibitors of SARS-CoV-2 main protease

The coronavirus disease (COVID-19) caused by SARS-CoV-2 is creating tremendous human suffering. To date, no effective drug is available to directly treat the disease. In a search for a drug against COVID-19, we have performed a high-throughput X-ray crystallographic screen of two repurposing drug libraries against the SARS-CoV-2 main protease (M^(pro)), which is essential for viral replication. In contrast to commonly applied X-ray fragment screening experiments with molecules of low complexity, our screen tested already approved drugs and drugs in clinical trials. From the three-dimensional protein structures, we identified 37 compounds that bind to M^(pro). In subsequent cell-based viral reduction assays, one peptidomimetic and six non-peptidic compounds showed antiviral activity at non-toxic concentrations. We identified two allosteric binding sites representing attractive targets for drug development against SARS-CoV-2

Burden of chronic diseases among sarcoma survivors treated with anthracycline chemotherapy: results from an observational study

Aim: Cardiovascular disease is a leading cause of mortality among long-term cancer survivors treated with large total doses of doxorubicin. An increase in coronary artery disease (CAD) among childhood cancer survivors by age 45 has been observed and is driven by primarily anthracycline chemotherapy and to a lesser extent chest radiation that includes the heart in the radiation field. The risk factors and associated chronic diseases (hypertension, etc.) are well known for CAD and can be often prevented or treated, thus reducing the risk of CAD in these patients. We piloted a risk-based survivorship clinic in an academic medical center to characterize the distribution of risk factors for CAD and improve the quality of life in a population of sarcoma survivors treated with doxorubicin.Methods: We followed a prospective cohort of sixty-one survivors of bone and soft tissue sarcoma treated with doxorubicin chemotherapy (&gt; 400 mg/m2) and at least 2 years post-therapy attending the sarcoma survivorship clinic. We collected clinical, demographic data, and patient reported outcomes via PROMIS questionnaires annually.Results: We demonstrated a high burden of chronic diseases in this population. Among six chronic conditions that are known risk factors for CAD (hypertension, diabetes, obesity, chronic inflammation, kidney disease and dyslipidemia), more than one-fourth (26%, 16/61) of patients had three or more of these risk factors at baseline visit, and 49% (30/61) had two or more.Conclusion: The results of this pilot study support the presence of modifiable CAD risk factors in this population of sarcoma survivors. Evidence-based guidelines for high-risk survivors of rare cancers are needed

Subgroup analysis of older patients treated within the randomized phase 3 doxorubicin versus doxorubicin plus evofosfamide (SARC021) trial.

BACKGROUND: More than half of patients with soft tissue sarcoma (STS) are aged ≥65 years (older), however contemporary data on the efficacy/safety of anthracycline chemotherapy in older patients with STS are lacking. METHODS: SARC021 randomized patients to receive first-line doxorubicin or doxorubicin plus evofosfamide. The main aim of this study was to compare the outcome and safety of first-line anthracycline-based therapy in older patients compared with those <65 years. IRB approval was obtained at all participating sites and this research meets requirements for protection of human subjects. RESULTS: Of 640 patients, 209 (33%) were older, with a median age 70 (range 65-89) years. The median overall survival (OS) was 16.7 months (95%CI: 13.2-20.0) in older patients compared to 20.1 months (95%CI: 16.9-23.2) in those aged <65 years (n = 431), HR 1.21 (95%CI: 0.99-1.48), p = .057. The median progression-free survival (PFS) in older patients was 6.3 months (95%CI: 5.8-7.2) compared to 6.0 (95%CI: 5.1-6.4) in those <65 years, HR 0.86 (95%CI: 0.70-1.05), p = .14. Older patients had significantly more hematological (141 [67%] versus 208 [48%], p < .0001), non-hematological (131 [63%] versus 215 [50%], p = .0097) and ≥ Grade 3 adverse events (178 [85%] versus 299 [69%], p = .0002), compared to younger patients. More older patients (30, 14%) stopped treatment due to adverse events compared to younger patients (22, 5%), p = .0001. CONCLUSIONS: The efficacy of first-line anthracycline-based chemotherapy did not differ significantly between older and younger advanced sarcoma patients. Significantly more older patients stopped chemotherapy due to adverse events. These results provide a benchmark for daily clinical practice and future trials in older patients.status: publishe