bluuebunny/crossref_metadata_2025 huggingface dataset:
Mucosal melanoma staging and classification: Firstly established.
Authors: LIAN BIN , Cui Chuanliang , Song Xin , Zhang Xiaoshi , Wu Di , Si Lu , Chi Zhihong , Sheng Xinan , Zhou Li , Mao Lili , Tang Bixia , Wang Xuan , Li Si Ming , Yan Xieqiao , Balch Charles M. , Guo Jun
Published: May 2019

e21008

Background: Mucosal melanomas (MM) have a significantly worse survival outcome than cutaneous melanoma. The current staging rules for cutaneous melanoma do not apply to mucosal melanoma. Our previous studies have demonstrated mucosal melanomas arising from different anatomic sites can be staged and treated as a single disease entity. We are recommending a new evidence-based staging system for mucosal melanoma. Methods: The mucosal melanoma staging recommendations were made on the basis of a multivariate analysis of 543 patients with stages I, II, and III melanoma and 547 patients with stage IV melanoma to clarify TNM classifications and stage grouping criteria. Results: New staging definitions include the following: (1) in patients with localized melanoma, the depth of tumor invasion of the primary melanomas is the most dominant prognostic factor: T1 for tumor invading mucosa or submucosa; T2 for tumor invading the muscularis propria; T3 for tumor invading adventitia; T4 for tumor invading adjacent structures; (2) The dominant prognostic factor for regional nodal metastases is the number of metastatic nodes: N1 for 1 regional metastatic node; N2 for 2 or more regional metastatic nodes; (3) On the basis of a multivariate analysis of patients with distant metastases, the dominant component in defining the M category is the site of distant metastases (M1:lung only vs. M2:liver only vs. M3:brain only vs. M4:all other visceral metastatic sites). An elevated serum lactate dehydrogenase level would be designated in parenthesis. The staging grouping of mucosal melanoma can be defined as follow: (1) stage I: T1N0M0; (2) Stage II:T2-4N0M0; (3) Stage IIIA: T1-4N1M0, Stage IIIB: T1-4N2M0; (4) Stage IV: anyTanyNM1-4. Conclusions: Using an evidence-based approach, the proposed staging system of mucosal melanoma is the first to be established that reflects our improved understanding of this disease.
Local experience with ipilimumab and nivolumab in treatment of metastatic melanoma: From world standards to individualized approaches in real clinical practice.
Authors: Manikhas Georgy M. , Orlova Rashida , Zhukova Natalia V. , Antimonik Nina , Kutukova Svetlana I. , Beliak Natalia P. , Popova Natalia V.
Published: May 2019

e21023

Background: Ipilimumab (Ipi) is the first agent in metastatic melanoma treatment that achieved long-term efficacy in selected patients. Nivolumab (Nivo) is one of agents, PD-1 inhibitors, that change treatment paradigm of advanced melanoma due to improving OS for lots of patients. There is still needed to evaluate efficacy of this drugs in regular medical settings. Methods: 43 patients with advanced melanoma were treated in SPb Clinical Oncology Dispensary from 2014 till now: 16 male and 27 female, median age is 58y.o. (from 39 to 84). 31 patients received Ipi, 12 patients received Nivo. Almost of patients are progressed after 1-4 lines of previous systemic therapy before starting treatment with Ipi or Nivo. Initial performance status (PS) assessed by ECOG scale was following; 1 patient had PS = 0 by ECOG, 37 patients – PS = 1 by ECOG and 5 patients had PS = 2 status by ECOG. Adverse events (AEs) are collected according to CTC AE v4.03. Results: At the time of analysis median FU is 25.75 month (95% CI: 6,6-35.9). The most frequently reported AEs are: pruritis 20%, fatigue 10%, diarrhea 7%, hepatitis 4%. 6% of AEs are grade 3/4. There are no any infusion reactions to Ipi and Nivo. Ipilimumab: median PFS is 6.0 month (95% CI: 4.9;7.1), 19% of patients (n = 6) have no PD at the moment. Median OS is 12.0 months (95% CI: 9.7;14.3), 29% of patients are still alive (n = 9). 6-months OS is 81%, 1-year OS is 35%. Nivolumab: Only 3 from 12 patients have PD after Nivo on the time of analysis. Median PFS and OS is not reached: 10 patients are still alive. 1-year OS is 83,33%. 52% of patients have reported AEs. Conclusions: Efficacy and tolerability of Ipi and Nivo in our clinical practice is similar to data from international clinical studies. The treatment with Ipi and Nivo is not associated with drug related infusion reactions and immediate AEs and doesn’t require supervision of patients at in-patient departments.Ipi and Nivo treatment is safe, could be used on out patients’ basis in regular medical settings.
Outcomes of melanoma patients with brain metastases receiving immune checkpoint inhibitor (ICI) therapy.
Authors: Ardeshir-Larijani Fatemeh , Nelson Ariel Ann , Martin Petra , Mendiratta Prateek , Sloan Andrew E. , Choi Serah , Mansur David B. , Hoimes Christopher J.
Published: May 2019

e21028

Background: The effect of ICI therapy on brain metastasis (mets) in melanoma patients has been described, however the impact of genomic alterations and local treatment (trt) including radiation therapy (RT) on CNS outcomes and overall survival (OS) has not yet been explored. Methods: Under institutional IRB approval, we reviewed our electronic medical record to identify patients (pts) with metastatic melanoma and brain mets who received trt with ICI. Trt history, CNS responses as indicated by the treating physician and available genomic data were recorded. OS was estimated using a multivariable Cox regression model adjusting for genomic alteration, age, ICI regimen and brain mets. Results: A total of 49 pts were identified (65% male). Thirty seven pts had testing for tumor genomic alterations (alt, hotspot and comprehensive genomic testing); BRAFV600E( 30%), cKIT(5%), NRAS(16%), no alt (38%). Prior to initiation of ICI, 78% had known CNS mets, of these, 61% received RT. There was no difference in median OS for pts who started RT prior to ICI compared to those without RT (mOS = 75.71 vs 49.4 weeks, p = 0.75). Median OS was improved for those pts who received RT > 90 days prior to initiation of ICI trt however this was not statistically significant (45.7 vs 136 weeks, p = 0.12) and HR = 0.45 (95% CI 0.08, 2.36). OS was not significantly different in pts with genomic alterations compared with those without alterations (p = 0.264). Of the pts with known brain mets at the time of ICI start, 34% had progressive disease at 3 months and 11% were felt to have pseudoprogression. 18% survived to undergo 6-month disease assessment, of these 12% had further progression. All pts with cKIT mutations survived to 6-month disease assessment. 75% of pts with known brain mets developed new lesions, 15% had increased mass size. Pts who developed new brain mets while on trt with ICI had worse survival than those with preexisting brain mets and developed new brain lesions (28 vs 58 weeks, p = 0.05). 6% of all pts developed CNS immune related adverse effects. Conclusions: Most patients with melanoma and known brain metastasis prior to ICI developed new brain lesions as a site of metastatic spread. The development of new brain mets was associated with worse outcomes. Neither genomic alterations nor RT prior to ICI start were associated with improved survival.
Patterns of major surgeries among patients diagnosed with cutaneous squamous cell carcinoma (CSCC).
Authors: Chen Chieh-I , Jalbert Jessica J , Andria Michael , Zhang Haixin Raymond , Ruiz Emily S
Published: May 2019

e21034

Background: CSCC is the second most common skin cancer. Most CSCC cases can be cured with surgical excision alone (5-year cure rate > 95%). We sought to evaluate patterns of major surgeries among patients with CSCC, overall and among those requiring systemic therapy. Methods: From Truven MarketScan claims data, we identified patient’s first CSCC diagnosis between 2013 and 2018 and required that they be continuously enrolled in their healthcare plan and have no CSCC diagnosis in the previous 12 months. Major surgeries included facial excisions over 3.1 cm, parotidectomy, removal of ear/eye/nose, amputations, craniectomy, excision of extracranial nerves, sentinel lymph node biopsy, lymphadenectomy, complex repairs of over 7.5 cm, integra, free flaps, and large grafts over 20 sq cm. Risk of a major surgery was assessed using Kaplan-Meier estimators for patients with CSCC overall and for those who received prior or concurrent systemic therapy, stratified by immune status. Results: A total of 240,122 patients with CSCC (mean age [SD]: 67.7 [12.9] years; male: 56.5%; immunocompromised: 12.4%) were identified with a mean (SD) follow-up of 1.34 (1.15) years. Risk of major surgery (95% confidence interval [CI]) at 1 and 2 years was 15.1% (14.9–15.2) and 18.6% (18.4–18.8), respectively. 782 patients received prior or concurrent systemic therapy, of which 22.4% (n = 175) were immunocompromised. Among those who received systemic therapy, 1- and 2-year risks (95% CI) were 8.4% (5.8–11.0) and 14.2% (10.0–18.2) for immunocompetent and 14.1% (7.7–20.0) and 19.3% (10.7–27.0) for immunocompromised patients, respectively. Conclusions: Over 2 years, approximately one in five patients with CSCC will undergo at least one major surgery. Prior or concurrent treatment with systemic therapy did not appreciably diminish the risk of requiring major surgery. For patients who received systemic therapy, the 1-year and 2-year risk of major surgery was higher for immunocompromised patients compared to immunocompetent patients.
Sustainable responses in metastatic melanoma patients with/without brain metastases after immunotherapy induced CR.
Authors: Dimitriou Florentia , Ramelyte Egle , Allayous Clara , Gérard Camille L. , Kähler Katharina C. , Toussaint Frédéric , Schäfer Sarah , Hassel Jessica Cecile , Heinzerling Lucie , Hauschild Axel , Michielin Olivier , Lebbe Celeste , Braun Ralph P , Dummer Reinhard , Mangana Joanna
Published: May 2019

e21042

Background: Immunotherapy (IT) has demonstrated an improved overall survival (OS) in advanced melanoma with 15% complete responses (CR) in treatment-naïve patients (pts) with brain metastases (met) in the anti-PD1/anti-CTLA4 combination. However, data on brain-met pts who discontinue treatment (EoT) after achieving a CR are lacking. Methods: Disease characteristics and clinical outcome were retrospectively collected from 6 centers on advanced melanoma pts treated with anti-PD1 or anti-PD1/anti-CTLA4. Pts were followed for at least 10 weeks (10.8 – 242). Off-treatment survival (OTS) was defined as time between last IT dose to disease progression or death. Results: Out of 890 pts, 62 achieved a CR; 40 pts stopped treatment due to CR, while 22 due to an adverse event (AE) (n = 19) or investigator decision (n = 3) with subsequent CR. 14 were treated with anti-PD1/anti-CTLA4 and 48 with anti-PD1. 24 had a BRAF mutation, of which 10 had previously received targeted therapy (TT). The median time to first CR was 31 weeks (6 – 138), median duration of response and OTS was 91.1 and 60.7 (10.6 – 242) weeks respectively. OTS was numerically longer for those pts with EoT after AE (85 weeks, 13-242) versus those with EoT due to CR (60 weeks, 11-130). Median OS was not reached. 6/62 (3%) progressed after EoT; 4 locoregionally while 2 were subsequently treated with IT. All pts were alive at last follow-up. 19 pts had brain mets. 8 were BRAF mutated. 10 were treatment naïve, 6 received previously anti-CTLA4, 1 chemotherapy and only 2 TT. Data on reasons for EoT and responses in brain mets are seen in the table. Conclusions: Early data suggest that OTS is numerically longer in patients with EoT due to AE with subsequent CR. EoT due to sustained CR is a feasible option also in brain mets. EoT due to AE with subsequent CR was a more frequent event in the combination treatment. [Table: see text]
Outcomes of melanoma soft parts/clear cell sarcoma (MSP/CCS) patients (pts) with immune and targeted therapies.
Authors: Jones Amy Little , Joon Aron , Haydu Lauren Elaine , Lazar Alexander J. , Tetzlaff Michael T. , Ravi Vinod , Davies Michael A.
Published: May 2019

e21046

Background: Overall survival (OS) for pts with cutaneous melanoma has vastly improved with checkpoint inhibitors (CPI) and targeted therapy (TT), but less is known about outcomes of other rare tumors showing melanocytic differentiation. We examined outcomes for metastatic pts with MSP/CCS at MD Anderson (MDA) to characterize outcomes with contemporary therapies. Methods: Pts with MSP/CCS were identified in the MDA databases. Pts with < 2 visits to MDA or without molecular confirmation of dx were excluded. Log-rank testing was used to compare OS among distributions. Results: A total of 102 MSP/CCS pts were identified. Initial diagnosis was local disease 46%, regional metastases 34%, and systemic metastases 20%. Primary tumor site was lower extremity (LE) 48%, GI tract 29%, upper extremity (UE) 18%. 65 pts were diagnosed with metastatic disease (dz), including 32% with lung-only, 14% liver-only, and 51% with multiple metastatic sites. Median OS from diagnosis of distant metastatic dz was 22 mos (95% CI 16-34 mos). Primary tumor site (GI 46.4 vs. LE 19.1 vs. UE 14.7 mos; p = 0.018) and race (white 26.8 vs. black 6.5 mos, p = 0.019, HR 0.45) were significantly associated with OS from distant metastasis; sex, age, decade of diagnosis, size of primary, and prior treatment with neoadjuvant or adjuvant therapy were not. Treatments for metastatic dz included chemotherapy (n = 29), biochemotherapy (n = 11), biotherapy (n = 5), CPI (n = 11) and TT (n = 19). Median OS was 15.9 mos from start of CPI (range 10.7 to NR) and 16.9 mos from start of TT (range 7.8 to NR). Median OS from metastatic dz for pts not treated with CPI or TT was 17.1 mos (range 12.4 to 32.5), which was not significantly different versus CPI or TT. Duration of response was < 6 mos for 91% pts receiving CPI and 89% pts receiving TT. One pt had a durable response (41.8 mos) to anti-PD1 and one pt had a durable response (24.8 mos) to an AKT inhibitor. Conclusions: While rare responses to CPI and TT were observed, no significant difference was detected in OS compared to traditional therapies in pts with metastatic MSP/CCS. The development of more effective therapies remains an unmet need for this disease.
Mucosal melanoma of the female genital tract: Operation modalities.
Authors: Wang Xuan , Cui Chuanliang , Lian Bin , Zhou Li , Chi Zhihong , Si Lu , Sheng Xinan , Kong Yan , Mao Lili , Yan Xieqiao , Tang Bixia , Guo Jun
Published: May 2019

e21060

Background: Primary melanomas originating from the female genital tract are rare and aggressive. There are still no established guidelines for its primary surgery , so we analyzed the effect of the surgical approach on its relapse free survival (RFS) and overall survival (OS ) based on a phase 3 randomized trial (NCT03435302). Methods: Mucosal melanoma patients with female genital tract primary which were stageⅠ-Ⅲ and completely resected were enrolled as part of the multicenter, randomized, controlled, phase 3 trial for the comparison of adjuvant chemotherapy (TMZ plus DDP 6 cycles) vs. High-dose interferon group (HDI, 1 year).The RFS and OS was compared between local and extensive excision group. Results: Seventy eight female genital tract primary melanoma patients were enrolled from Feb 2014 to Jun 2016, Surgical approach was chosen by the surgeon, 39.2% (29/74) took local excision and 60.8% (45/74) extensive excision. The average age was 52.3 years. Of all these patients 46.2% were vulvar primary, 53.8% vaginal, and 85.3%stage I/II, 14.7% stage III. Primary ulceration was found in 68.1% lesions, 7 cases harbored with BRAF mutation. 57.7% patients randomized to adjuvant chemotherapy and 42.3% in HDI group. All these factors showed no difference in local excision and extensive excision group. At a median follow-up of 31.2 months (range: 5.3-60.0m), 64.4% got metastases and 23.1% showed local recurrence. RFS (8.0m vs. 11.4m, p = 0.523) and local recurrence rate (13.8% vs.31.1%, p = 0.105 ) did not show significant difference between local excision group and extensive excision group. OS in whole cohort was 28.9 months, it also did not show significant difference between two groups(local 25.5m vs. extensive 40.1m, p = 0.653). In univariate analysis there was also no relation between surgical approach and OS in this cohort. Conclusions: Based on this trial, for resectable female genital tract primary mucosal melanoma, there was no difference of local control rate, RFS and OS between local excision and extensive excision group. Local excision might be adequate for the primary leision. Still more prospective data are needed for this subtype of melanoma. Clinical trial information: NCT03435302.
Experiences of general practitioners and medical specialists with incurable cancer patients with a protracted disease trajectory: A focus group study.
Authors: Buiting Hilde M. , Botman Femke , van der Velden Lilly-Ann , Brom Linda , van Heest Florien , de Mol Pieter , Bakker Ton
Published: May 2019

e23010

Background: Advances in oncology have resulted in prolonged disease trajectories in patients with incurable cancer. In this disease-phase, patients are aware that cancer is incurable but they do not approach the last phase-of-life yet. We examined experiences and wishes of GPs and specialists concerning appropriate care-provision, delivered by GPs. Methods: We performed 6 focus groups in different regions in the Netherlands; 3 homogenous groups (N=15 GPs) and 3 heterogenous groups (N=23 GPs and medical specialists). Data were analysed with thematic content-analysis. Results: During the first focus-groups, the protracted disease phase was not acknowledged as a separate one; in the last focus-groups, however, this disease-phase received more attention. Physicians clearly distinghuished this trajectory from the palliative / terminal disease phase, partly because many patients did not experience severe physical problems. Most GPs preferred to be involved in the care of these patients as this would enable them to easily guide patients in their last phase-of-life. In these patients, GPs experienced difficulties in estimation of prognosis and advice of further treatment, partly because of insecurity of treatment side-effects of immunotherapy. Further, many physicians experienced difficulties in labeling this disease phase. ‘Stable’; ‘chronic’; and ‘Phase X’ were regularly mentioned. Medical specialists were more frequent involved with these patients but preferred to involve GPs as much as possible. They however also realised that this would become more difficult in future, given the growing group of patients in this disease phase. Conclusions: In the protracted disease phase, patients often do not experience severe physical symptoms. They often do not approach their patient for possible psycho-social problems. Apart from medical specialists, tools to easily communicate across specialties to optimise care need to be further explored.
Defining undertreatment and overtreatment in older patients with cancer: A scoping review of the literature.
Authors: DuMontier Clark , Loh Kah Poh , Bain Paul A , Silliman Rebecca A , Abel Gregory A. , Djulbegovic Benjamin , Driver Jane A. , Dale William
Published: May 2019

e23020

Background: The terms “undertreatment” and “overtreatment” are often used to describe the management of older adults with cancer. The aim of this scoping review was to explore the explicit and implicit definitions associated with the use of these terms. Methods: We searched PubMed (NCBI), Embase (Elsevier), and CINAHL (EBSCO) for titles and abstracts that included the terms "undertreatment" or "overtreatment" (overtreat OR undertreat OR over treat OR under treat) of older adults with cancer. We included all types of articles, cancers, and treatments. We excluded studies that only included patients younger than 60 years old or studies without a defined focus on older adults. CD and KL independently reviewed a subset of included articles to assess for inter-reviewer reliability. Results: We identified 224 primary and secondary research articles that used the terms “undertreatment” (192), “overtreatment” (72), or both (45) regarding the management of older adults with cancer. Only 14 (6.3%) articles provided an explicit definition; for the remaining articles, we derived the implicit definitions from the terms’ surrounding context. There was substantial agreement between CD and KL in their interpretation of definitions of these terms (kappa 0.81). “Undertreatment” was commonly used to imply less than “standard” therapy (130 articles, 67.7%), or less than “standard” therapy that contributed to worse outcomes (62, 32.3%). Many articles did not account for the underrepresentation of older adults in trials leading to “standard” therapy, and 24 primary studies performed no or limited adjustment for geriatric domains (e.g., function) in their analyses that suggested worse survival in older adults treated with substandard therapy. “Overtreatment” was commonly used to imply cancer treatment in an older adult whose cancer would not have caused symptoms in his/her remaining lifetime (31, 43.1%), or aggressive treatment in whom the harms of treatment outweigh its benefits (41, 56.9%). Conclusions: Nearly all articles used the terms “undertreatment” and/or “overtreatment” without an explicit definition, and we identified variability and limitations in the meanings implied by these terms.
Genetic variability of tramadol pharmacokinetic genes and pain treatment outcome after breast cancer surgery.
Authors: Besic Nikola , Goricar Katja , Jeriha Jakob , Dolzan Vita , Strazisar Branka
Published: May 2019

e23133

Background: Tramadol is a treatment of choice for pain management after axillary lymph node dissection in breast cancer patients. Tramadol is metabolized via CYP2D6 and UGT2B7, while ABCB1, ABCC2 and SLC22A1 are involved in transport of tramadol metabolites. Genetic variability of metabolizing enzymes or drug transporters may therefore affect efficacy and adverse effects of tramadol. The aim of this study was to evaluate the association of genetic variability in tramadol pharmacokinetics pathway on long-term outcome of tramadol pain treatment after breast cancer surgery. Methods: The study included 102 breast cancer patients treated with either 75 or 37.5 mg of tramadol for pain relief after breast cancer surgery including axillary lymph node dissection as part of a randomized clinical trial KCT 04/2015-DORETAonko/si at Institute of Oncology Ljubljana. All patients were genotyped for 14 polymorphisms in ABCB1, ABCC2, CYP2D6, SLC22A1 and UGT2B7 genes, as well as for CYP2D6 duplication and deletion. CYP2D6 phenotype was predicted from the genotype data and patients were categorized as poor (PM), intermediate, extensive or ultrarapid metabolizers. The association of genetic factors with pain one year after treatment was evaluated using logistic regression and Mann-Whitney test. Results: One year after treatment, 21 (20.8%) patients were still experiencing chronic and 25 (24.8%) neuropathic pain. CYP2D6 PMs were significantly more likely to experience chronic and neuropathic pain after tramadol treatment (OR = 5.96, 95% CI = 1.22-29.13, p = 0.027 and OR = 9.31, 95% CI = 1.65-50.59, p = 0.011, respectively), even after adjustment for tramadol dose (p = 0.032 and p = 0.016, respectively). PMs also had higher average pain intensity compared to others regardless of tramadol dose (p = 0.042). In patients receiving lower tramadol dose, ABCB1 rs1128503, rs2032582 and rs1045642 were associated with more chronic pain in the dominant model (p = 0.004, p = 0.004 and p = 0.047, respectively). Conclusions: Genetic variability in tramadol pharmacokinetics pathway may be associated with pain treatment outcome in breast cancer patients, therefore pharmacogenetic testing could enable more effective tramadol treatment. Clinical trial information: EudraCT 2015-000992-28.
HOME palliative care-Nepal: A cell-phone/website it system.
Authors: Paudel Bishnu D.
Published: May 2019

e23134

Background: Worldwide, major clinical barriers to effective palliative care are the absence of: 1. Current data on symptom type and intensity; 2. Immediately accessible information on practical, affordable, and effective interventions; and 3. Self-sustaining systems to facilitate currently limited physician engagement in continuing palliative care. In Nepal, essentially all families have a cell phone, the majority of which are Android smart phones. 80% of the population lives in rural settings. Methods: Following a cross sectional study in 383 Nepalis with advanced cancers using a cell-phone “app” on the Android platform with a validated 15-item symptom questionnaire, in which all approached patients agreed and were able to complete the instrument in under 3 minutes, we assembled a Nepali/US development team of clinicians and computer scientists to create a tele-home palliative care system centered on use of this app. Results: We have developed an internet website (homepalliativecareNepal.net) with patient/family and physician information pages, a guest health professional site, and a password-protected physician site with organized patient demographic and medical summary data, and telephone-submitted app-symptom reports, local clinical practice guidelines, and an intervention menu of 30 written and mini-video items and links (the majority non-pharmacologic) including start-up drug prescriptions (5), which can be personalized and directly sent to the patient by phone. The system is managed by a local organization that also ensures regular physician/clinic visits by the patient, or by a family member with a patient phone check-in, at least every two weeks, with creation of documentation of provided services. Conclusions: Our adaptable, patient-centered, IT-tools-facilitated, and economical system offers significant potential for addressing the need to engage all types of health care practitioners in palliative care in different cultural settings.
A phase I study of LOXO-292, a highly selective RET inhibitor, in pediatric patients with RET-altered cancers.
Authors: DuBois Steven G. , Albert Catherine Michelle , Mascarenhas Leo , Laetsch Theodore Willis , van Tilburg Cornelis Martinus , Potter Samara L , Turpin Brian , Glade Bender Julia Lynne , Spunt Sheri L. , Hladun Raquel , Casanova Michela , Ziegler David Simon , Morgenstern Daniel A. , Eary Todd , Ibabekci Shannon , Qamoos Hope , Rothenberg Stephen M. , Cox Michael Craig , Balis Frank M. , Pappo Alberto S.
Published: May 2019

TPS10066

Background: Genomic alterations in the RET kinase, including gene fusions and activating point mutations, are implicated in the pathogenesis of lung, thyroid, sarcoma and other cancers in both chidren and adults. Currently available multikinase inhibitors with anti-RET activity are non-selective and may be associated with less favorable toxicity profile. LOXO-292 is a novel, highly selective, ATP-competitive small molecule RET inhibitor. LOXO-292 has preclinical nanomolar potency against diverse RET alterations (e.g. fusions, activating mutations and anticipated acquired resistance mutations) and anti-tumor activity in the brain. LOXO-292 has demonstrated clinical activity in adult patients with RET-alterated solid tumors. Methods: LIBRETTO-121 (EudraCT 2019-000212-28) is an ongoing multicenter phase 1/2 dose escalation multicenter trial in patients 6 months-21 years of age with advanced, RET-altered solid and CNS tumors. Dose escalation follows a rolling 6 design starting at the equivalent of the adult recommended phase 2 dose. Enrollment began on 12 Feb 2019 and is ongoing. Key eligibility criteria include: solid or CNS tumor with a documented RET gene alteration refractory to standard therapy; age 6 months to 21 years of age; and adequate bone marrow, liver and kidney function. LOXO-292 is administered orally BID for continuous 28-day cycles. Both capsule and liquid suspension dosage forms are available. The primary objective of the phase 1 portion of the study is to determine safety and dose limiting toxicities. Key secondary objectives include characterization of pharmacokinetic properties, identification of the MTD and initial characterization of the anti-tumor activity of LOXO-292. Archival tissue will be used to further characterize molecular abnormalities. Clinical trial information: 2019-000212-28.
Phase 1/2 dose-escalation and expansion study investigating SAR439859 +/- palbociclib in postmenopausal women with estrogen receptor-positive (ER+)/HER2- metastatic breast cancer.
Authors: Bardia Aditya , Linden Hannah M. , Ulaner Gary A. , Chandarlapaty Sarat , Gosselin Alice , Celanovic Marina , Campone Mario
Published: May 2019

TPS1105

Background: Endocrine therapy +/- cyclin-dependent kinase 4/6 inhibitors, such as palbociclib, is the standard of care for ER+/HER2- breast cancer. Tumors often become resistant to this combination but retain ER signaling dependence, allowing for sequential ER-directed therapy. Unlike other classes of endocrine therapy with one mode of action, selective ER degraders (SERDs) block signaling by both ER competitive antagonism and degradation, targeting resistance settings that other treatments cannot. SAR439859 is a potent, oral SERD with improved preclinical efficacy and pharmaceutical properties vs other SERDs. This study investigates SAR439859 +/- palbociclib in postmenopausal women with ER+/HER2- metastatic breast cancer. Methods: This prospective, open-label, non-randomized Phase 1/2 study (NCT03284957; TED14856) assesses SAR439859 single agent at dose levels increasing from 20 mg/day up to the maximum administered dose (Part A) followed by cohort expansion at the recommended dose (RD; Part B). The study will also assess two dose levels of SAR439859, in combination with palbociclib 125 mg/day (Days 1–21 in 28-day cycles; Part C) followed by cohort expansion (Part D). Postmenopausal women with ER+/HER2- metastatic breast cancer, who received ≥ 6 months of prior endocrine therapy, are eligible. Patients were permitted to have received ≤ 3 (Part A) or ≤ 1 (Parts B–D) prior chemotherapies for metastatic disease. Exclusion criteria include Eastern Cooperative Oncology Group performance status ≥ 2, concomitant illness (including those related to HIV or hepatitis and other cancers ≤ 3 years) and factors potentially affecting absorption of SAR439859 or palbociclib. Study endpoints include assessment of dose-limiting toxicities, determination of maximum tolerated dose and RD in dose escalation (Parts A and C), and objective response rate according to RECIST v1.1 in dose expansion (Parts B and D). 18FES-PET scan between Days 11–15 in Part A will assess ER availability. Safety, pharmacokinetics and response were evaluated for Parts A–D. Recruitment and screening are ongoing (Part A n = 16; B n = 18; C n = 2; D n = 0). Funding: Sanofi. Clinical trial information: NCT03284957.
NRG-BR002: A phase IIR/III trial of standard of care therapy with or without stereotactic body radiotherapy (SBRT) and/or surgical ablation for newly oligometastatic breast cancer (NCT02364557).
Authors: Chmura Steven J. , Winter Kathryn A. , Al-Hallaq Hania A , Borges Virginia F. , Jaskowiak Nora T. , Matuszak Martha , Milano Michael T. , Salama Joseph Kamel , Woodward Wendy A. , White Julia R.
Published: May 2019

TPS1117

Background: This is a randomized Phase II/III trial to evaluate if stereotactic body radiotherapy (SBRT) and/or surgical resection (SR) of all metastatic sites in newly oligo-metastatic breast cancer who have received up to 12 months of first line systemic therapy without progression will significantly improve median progression free survival (PFS). If this aim is met the trial continues as a phase III to evaluate if SBRT/SR improves 5 year overall survival. Secondary aims include local control in the metastatic site, new distant metastatic rate, and technical quality. Translational primary endpoint is to determine whether < 5 CTCs is an independent prognostic marker for improved PFS and OS. Methods: Women with pathologically confirmed metastatic breast cancer to ≤ 4 sites who have been diagnosed within 365 days with metastatic disease and the primary tumor site disease is controlled. CNS metastases are ineligible. ER/PR and HER-2 neu status is required. Site radiation credentialing with a facility questionnaire and pre-treatment review of first case is required. Randomization is to standard systemic therapy with local radiotherapy/ surgery for palliation when necessary versus ablative therapy of all metastases with SBRT and/or SR. For the phase IIR portion to detect a signal for improved median PFS from 10.5 months to 19 months with 95% power and a 1-sided alpha of 0.15 and accounting for ineligible/lost patients, 128 patients will be required. For the Phase III, an additional 232 patients will be required to definitively determine if ablative therapy improves 5-year overall survival from 28% to 42.5% (HR=0.67), with 85% power and a one-sided type I error of 0.025. For the translational research assuming a two-sided probability of type I error of 0.05, the number of patients accrued in the Phase II-R and Phase III portions will provide sufficient power of at least 91% and 93% to detect whether < 5 CTC’s is prognostic for PFS and OS, respectively. Present accrual (1-31-2019): 105. Contact Information: Protocol: CTSU member web site https://www.ctsu.org . Enrollment: OPEN at https://open.ctsu.org . Support: This project is supported by NRG Oncology grants U10CA180868 and U10CA180822 from the National Cancer Institute (NCI). Translational science is supported by the Ludwig Foundation for Cancer Research. Clinical trial information: NCT02364557.
Patient controlled analgesia (PCA) versus non-PCA intravenous hydromorphone titration for severe cancer pain: A randomized, controlled, multicenter, phase III trial, HMORCT09-1.
Authors: Lin Rongbo , Zhu Jinfeng , Feng Shuitu , Lin Sunzhi , Fu Jianqian , Yao Yongzhi , Hong Lixia , Xin Min , Chen Zhangshu , Cai Zhenyu , Li Chunxiang , Zhao Shen , Wu Qingyi , Yang Shangwang , Huang Cheng
Published: May 2019

TPS11635

Background: The opioid dose for an individual with cancer pain to provide adequate relief of pain with an acceptable degree of side effects is variable. Opioid titration is a process to obtain the tailored dose. Conventional titration is administered by a clinician or nurse. PCA is that patients control cancer pain by self-administration of intravenous opioids using programmable pump. The aim of our study is to evaluate the efficacy of PCA titration versus conventional titration intravenously for severe cancer pain (10-point numerical rating scale, NRS ≥ 7). Injectable Hydromorphone was selected as pharmaceutical analgesics, which works as well as morphine and oxycodone and had similar side effects. Methods: This is currently enrolling patients (n=230) with severe cancer pain during previous 24 hours. Patients are randomized 1:1 and stratified by opioid intolerance or opioid tolerance into PCA or non-PCA titration. PCA titration using programmable pump: bolus hydromorphone at 0.5mg (for opioid intolerance) or hydromorphone dose equivalent to 10% to 20% of the total opioid taken in the previous 24 hours with a lockout time 15 minutes (for opioid tolerance) was administered by the patients educated. No basal infusion was set in the pump. Non-PCA titration administered by a nurse or clinician: Initial hydromorphone doses were same with PCA titration. Reassess pain at 15 minutes. Increased dose of hydromorphone by 50%-100% if pain unchanged or increased, or repeat same dose if pain decreased to NRS 4-6, or continue at current effective dose as needed over initial 24 hours. The primary endpoint is the time needed to successful titration was defined the time from the first dose of hydromorphone after randomization to achieve satisfied pain control. The satisfied pain control was defined NRS pain score ≤ 3 at rest in at least 2 consecutive assessment (15 minutes interval). The time needed to successful titration was extended to achieve satisfied pain control again if NRS pain score ≥ 7 after satisfied pain control within 24 hours. The failure of successful titration was defined that satisfied pain control does not achieve within 24 hours. Secondary endpoints include the percentage of patients titrated successfully, the mean NRS pain score of 24 hours, the total dose of hydromorphone titrated, and adverse events. Clinical trial information: NCT03375515.
Omega-3 fatty acids and ERPR(-) and HER2/neu(+/-) breast cancer prevention.
Authors: Kalu Chidimma , Woelke Sarah , Zhang Jianying , Belury Martha , Shen Rulong , Clinton Steven K. , Yee Lisa
Published: May 2019

TPS1589

Background: The most aggressive breast cancer subtypes tend to be estrogen and progesterone receptor negative (ERPR(-)) and human epidermal growth factor receptor type 2 positive (HER2(+)). Women with these breast cancer subtypes (triple negative, ERPR(-)HER2(+)) tend to experience worse clinical outcomes and have a relatively higher risk of recurrence. Our previous research demonstrated that dietary omega-3 (n-3) fatty acids can significantly inhibit ERPR(-) HER2(+) tumorigenesis in MMTV-HER2/neu transgenic mice fed fish oil vs corn oil-based diets. The fish oil diet group developed 30% fewer breast tumors, had lower Ki67 expression, and experienced less mammary atypia relative to the corn oil diet group. Other studies involving diet, nutrition and breast cancer point to the potentially protective effect of an anti-inflammatory diet on the risk of developing ER(-) and HER2(+) breast cancer, further supporting the evidence that the ERPR(-), HER2(±) subtypes may be highly responsive to this bioactive nutrient. Methods: This is a double-blinded, randomized clinical trial of high dose (~5.4 g EPA+DHA) vs low dose (~0.9 g EPA+DHA in fatty acid mix of the typical American diet) of n-3 fatty acids in breast cancer survivors of ERPR(-), HER2(±) breast cancer. Eligible participants will take 5 capsules/day for 12 months, with cellular samples of breast epithelial and/or adipose tissue obtained by fine needle aspirations of the contralateral breast. The study aims to determine whether n-3 fatty acid supplementation will modify fatty acid metabolite content in breast adipose tissue, modulate cytomorphology and/or cell proliferation in breast epithelial cells, affect DNA methylation patterns, and modulate pro- vs anti-inflammatory gene expression patterns in breast adipose tissue. Correlative aims will evaluate possible associations between factors such as breast adipose tissue, red cell membrane fatty acid profiles, BMI, and reported dietary intake. Sample size of 40 participants per arm was calculated to provide at least 80% power to detect a statistically significant difference for each primary endpoint. This study focuses on women survivors of high risk breast cancer subtypes, specifically triple negative or ERPR(-)HER2(+) disease, who are currently without long term adjuvant options. Eligibility criteria include prior diagnosis of ERPR(-) stage 0 to III breast cancer, ≤5 years from completion of standard therapy.The study was closed to accrual in November 2018; less than 9 months of follow-up remain for active study participants. Clinical trial information: NCT02295059.
EORTC 1709/CCTG CE.8: A phase III trial of marizomib in combination with standard temozolomide-based radiochemotherapy versus standard temozolomide-based radiochemotherapy alone in patients with newly diagnosed glioblastoma.
Authors: Roth Patrick , Reijneveld Jaap C. , Gorlia Thierry , Dhermain Frederic , De Vos Filip Yves Francine Leon , Vanlancker Maureen , O'Callaghan Christopher J. , Le Rhun Emilie , Van Den Bent Martin J. , Mason Warren P. , Weller Michael
Published: May 2019

TPS2072

Background: The standard treatment for patients with newly diagnosed glioblastoma comprises maximum safe surgery, radiotherapy (RT), and concomitant and up to six cycles of maintenance temozolomide (TMZ) chemotherapy (TMZ/RT→TMZ). Despite this intense therapy, the prognosis remains poor and there is an urgent need to develop new therapeutic options. Marizomib is a novel, irreversible and brain-penetrant pan-proteasome inhibitor. Following its successful assessment in phase I trials in patients with newly diagnosed as well as recurrent glioblastoma, marizomib is now being investigated in a phase III trial. Methods: EORTC 1709/CCTG CE.8 is a multicenter, randomized, controlled, open label phase III superiority trial. Eligibility criteria include histologically confirmed newly diagnosed glioblastoma and a performance status ≥70. Approximately a total of 750 patients will be enrolled and randomized 1:1. Stratification factors include institution, age, Karnofsky performance status and extent of surgery. The primary objective of this study is to compare overall survival in patients receiving marizomib in addition to standard of care (TMZ/RT→TMZ) with patients receiving standard treatment only. The testing strategy specifies the determination of this objective in both the intent-to-treat population and the subgroup of patients with tumors harboring an unmethylated MGMT promoter. Secondary endpoints include progression-free survival, safety, neurocognitive function and quality of life. The study is accompanied by a translational research program. The study will be opened at 50 EORTC sites in Europe and done as an intergroup collaboration with the Canadian Cancer Trials Group (CCTG) with 25 sites in Canada and additional sites in the US. Patient enrolment started in June 2018 and as of January 29, 2019, a total of 85 patients have been randomized. An update on the enrolment status will be provided at the ASCO conference. Clinical trial information: NCT03345095.
A phase I/II study of nivolumab plus or minus ipilimumab in combination with multifraction stereotactic radiosurgery for recurrent high-grade radiation-relapsed meningioma.
Authors: Huang Jiayi , Campian Jian Li , Gao Feng , Johanns Tanner Michael , Desjardins Annick , Wang-Gillam Andrea , Rubin Josh
Published: May 2019

TPS2073

Background: There is currently lack of effective therapy for meningiomas that have relapsed despite surgery and radiation therapy (RT). Reirradiation have been used in selected cases, but the long-term clinical outcomes remained poor, especially for high-grade meningiomas. Preclinical data have suggested synergy between hypofractionated radiosurgery with immune checkpoint inhibitors such as PD1 and CTLA4 inhibitors. The purpose of this study is to evaluate feasibility and preliminary clinical efficacy of combining reirradiation using hypofractionated radiosurgery with concurrent nivolumab (PD1 inhibitor) plus or minus ipilimumab (CTLA4 inhibitor) for recurrent high-grade meningiomas. Methods: During the phase I portion, eligible patients will be treated according to treatment-escalation schema following the modified 3+3 design (Table). The maximum tolerated combination (MTC) will be the regimen at which ≤1/6 patients experience dose-limiting toxicity within 8 weeks of the start of study therapy. During the phase II portion, a total of 24 evaluable patients will be enrolled at the MTC using Simon’s MiniMax two-stage design. Key eligibility criteria include patients with recurrent grade II-III meningiomas after prior RT; age ≥ 18 years; ECOG score ≤ 2; measurable disease but ≤ 5 cm (or 20 cm3); prior radiation dose ≤ 70 Gy with at least 6 months interval; normal organ function; no active autoimmunity. The primary endpoints are to determine the MTC (phase I) and the objective response rate of the MTC (phase II). Secondary endpoints include safety, duration of response, progression-free survival, overall survival. Exploratory endpoints include developing an immune or molecular signature for predicting treatment response and resistance. The trial is actively enrolling and funded by the National Cancer Institute Experimental Therapeutics Clinical Trials Network (NCI-ETCTN). Treatment Escalation Schema. Clinical trial information: NCT03604978. [Table: see text]
A phase III trial-in-progress comparing tislelizumab plus chemotherapy with placebo plus chemotherapy as first-line therapy in patients with locally advanced unresectable or metastatic gastric or gastroesophageal junction (G/GEJ) adenocarcinoma.
Authors: Xu Rui-hua , Arkenau Hendrik-Tobias , Bang Yung-Jue , Denlinger Crystal S. , Kato Ken , Tabernero Josep , Wang Jin , Li Jiang , Castro Henry , Moehler Markus Hermann
Published: May 2019

TPS2655

Background: In patients (pts) with locally advanced or metastatic G/GEJ cancer, fluoropyrimidine- and platinum (plt)-based combination chemotherapy is first-line standard of care. Despite improvement in chemotherapy regimens, outcomes are poor and survival remains low. Tislelizumab, an investigational anti-PD-1 antibody, was engineered to minimize binding of FcγR on macrophages in order to abrogate antibody-dependent phagocytosis, a mechanism of T-cell clearance and potential resistance to anti-PD-1 therapy. Previous reports suggested tislelizumab, as a single agent and in combination with chemotherapy, was generally well tolerated and had antitumor activity in pts with advanced solid tumors, including G/GEJ cancer. Methods: This global, double-blind, randomized, phase 3 study (NCT03777657) is designed to compare plt/fluoropyrimidine + tislelizumab versus plt/fluoropyrimidine + placebo as first-line therapy for pts with locally advanced or metastatic G/GEJ cancer. Approximately 720 pts from 160 centers will be randomized 1:1 to receive tislelizumab (200 mg IV Q3W) or placebo (IV Q3W) in combination with chemotherapy. Oxaliplatin (130 mg/m² IV Q3W) plus capecitabine (1000 mg/m2 orally twice daily for 2 weeks) or cisplatin (80 mg/m² IV Q3W) plus 5-fluorouracil (800 mg/m2/day IV on Days 1–5 Q3W) will be used as backbone chemotherapy on an individual basis. Chemotherapy will be administered for up to 6 cycles; capecitabine maintenance therapy is optional for pts who received capecitabine and oxaliplatin. PD-L1 expression will be assessed using the VENTANA PD-L1 (SP263) assay. Progression-free survival and overall survival are primary endpoints in the intent-to-treat and PD-L1-positive analysis sets of the study. Secondary endpoints include overall response rate, duration of response, quality-of-life outcomes, and the safety/tolerability profile of combination therapy. Exploratory endpoints include disease control rate, time to response, and an analysis of potential predictive biomarkers including, but not limited to, PD-L1 expression. Clinical trial information: NCT03777657.