bluuebunny/crossref_metadata_2025 huggingface dataset:
Myeloperoxidase oxidation of methionine associates with early cystic fibrosis lung disease
Authors: Chandler Joshua D. , Margaroli Camilla , Horati Hamed , Kilgore Matthew B. , Veltman Mieke , Liu H. Ken , Taurone Alexander J. , Peng Limin , Guglani Lokesh , Uppal Karan , Go Young-Mi , Tiddens Harm A.W.M. , Scholte Bob J. , Tirouvanziam Rabindra , Jones Dean P. , Janssens Hettie M.
Published: September 2018

Cystic fibrosis (CF) lung disease progressively worsens from infancy to adulthood. Disease-driven changes in early CF airway fluid metabolites may identify therapeutic targets to curb progression.

CF patients aged 12–38 months (n=24; three out of 24 later denoted as CF screen positive, inconclusive diagnosis) received chest computed tomography scans, scored by the Perth–Rotterdam Annotated Grid Morphometric Analysis for CF (PRAGMA-CF) method to quantify total lung disease (PRAGMA-%Dis) and components such as bronchiectasis (PRAGMA-%Bx). Small molecules in bronchoalveolar lavage fluid (BALF) were measured with high-resolution accurate-mass metabolomics. Myeloperoxidase (MPO) was quantified by ELISA and activity assays.

Increased PRAGMA-%Dis was driven by bronchiectasis and correlated with airway neutrophils. PRAGMA-%Dis correlated with 104 metabolomic features (p<0.05, q<0.25). The most significant annotated feature was methionine sulfoxide (MetO), a product of methionine oxidation by MPO-derived oxidants. We confirmed the identity of MetO in BALF and used reference calibration to confirm correlation with PRAGMA-%Dis (Spearman's ρ=0.582, p=0.0029), extending to bronchiectasis (PRAGMA-%Bx; ρ=0.698, p=1.5×10−4), airway neutrophils (ρ=0.569, p=0.0046) and BALF MPO (ρ=0.803, p=3.9×10−6).

BALF MetO associates with structural lung damage, airway neutrophils and MPO in early CF. Further studies are needed to establish whether methionine oxidation directly contributes to early CF lung disease and explore potential therapeutic targets indicated by these findings.
Detection of mild cognitive impairment in middle-aged and older adults with obstructive sleep apnoea
Authors: Gagnon Katia , Baril Andrée-Ann , Montplaisir Jacques , Carrier Julie , Chami Sirin , Gauthier Serge , Lafond Chantal , Gagnon Jean-François , Gosselin Nadia
Published: September 2018

Obstructive sleep apnoea increases the risk for mild cognitive impairment and dementia. The present study aimed to characterise the ability of two cognitive screening tests, the Mini-Mental State Examination and the Montreal Cognitive Assessment, to detect mild cognitive impairment in adults aged 55–85 years with and without obstructive sleep apnoea.

We included 42 subjects with mild and 67 subjects with moderate-to-severe obstructive sleep apnoea. We compared them to 22 control subjects. Mild cognitive impairment was diagnosed by a comprehensive neuropsychological assessment. We used receiver operating characteristic curves to assess the ability of the two screening tests to detect mild cognitive impairment.

The two screening tests showed similar discriminative ability in control subjects. However, among the mild and the moderate-to-severe obstructive sleep apnoea groups, the Mini-Mental State Examination was not able to correctly identify subjects with mild cognitive impairment. The Montreal Cognitive Assessment's discriminant ability was acceptable in both sleep apnoea groups and was comparable to what was observed in controls.

The Mini-Mental State Examination should not be used to screen for cognitive impairment in patients with obstructive sleep apnoea. The Montreal Cognitive Assessment could be used in clinical settings. However, clinicians should refer patients for neuropsychological assessment when neurodegenerative processes are suspected.
Inhaled corticosteroids in COPD: friend or foe?
Authors: Agusti Alvar , Fabbri Leonardo M. , Singh Dave , Vestbo Jørgen , Celli Bartolome , Franssen Frits M.E. , Rabe Klaus F. , Papi Alberto
Published: September 2018

The efficacy, safety and positioning of inhaled corticosteroids (ICS) in the treatment of patients with chronic obstructive pulmonary disease (COPD) is much debated, since it can result in clear clinical benefits in some patients (“friend”) but can be ineffective or even associated with undesired side effects,e.g.pneumonia, in others (“foe”). After critically reviewing the evidence for and against ICS treatment in patients with COPD, we propose that: 1) ICS should not be used as a single, stand-alone therapy in COPD; 2) patients most likely to benefit from the addition of ICS to long-acting bronchodilators include those with history of multiple or severe exacerbations despite appropriate maintenance bronchodilator use, particularly if blood eosinophils are >300 cells·µL−1, and those with a history of and/or concomitant asthma; and 3) the risk of pneumonia in COPD patients using ICS is higher in those with older age, lower body mass index (BMI), greater overall fragility, receiving higher ICS doses and those with blood eosinophils <100 cells·µL−1. All these factors must be carefully considered and balanced in any individual COPD patient before adding ICS to her/his maintenance bronchodilator treatment. Further research is needed to clarify some of these issues and firmly establish these recommendations.
Microstructure and mechanical properties of aluminium-graphene composite powders produced by mechanical milling
Authors: Zhang Jiangshan , Chen Zhixin , Zhao Jingwei , Jiang Zhengyi
Published: September 2018

Background

Graphene has been reported to be a promising nanofiller in fabricating advanced metal matrix composites.

Methods

Graphene nanosheets (GNSs) have been incorporated into an aluminium matrix composite using mechanical milling and hot pressing in the current study.

Results

The SEM observation shows that aluminium particles are firstly flattened into flakes, and then fractured/ rewelded into equiaxed particles as the ball milling progresses. The crystalline size is decreased and the lattice strain is increased during the ball milling, which are also intensified by the added GNSs. The hardness of the composite is increased by 115.1% with the incorporation of 1.0 vol. % GNSs.

Conclusions

The local stress induced by the hard GNSs accelerates the milling process. The X-Ray diffraction patterns show that the intensity ratio of (111) to (200) can reflect the preferred orientation of the particle mixture, and the evolution of I(111)/I(200) agrees well with the observed results using SEM. The increased hardness is mainly attributed to the refined microstructure and Orowan strengthening.
Lorazepam as an adjuvant to haloperidol for agitated delirium at the end of life: A double-blind randomized controlled trial.
Authors: Hui David , Frisbee-Hume Susan , Wilson Annie , Dibaj Seyedeh , Nguyen Thuc , De La Cruz Maxine Grace Jaucian , Walker Paul , Delgado-Guay Marvin , Vidal Marieberta , Zhukovsky Donna S. , Epner Daniel E. , Reddy Akhila Sunkepally , Tanco Kimberson , Williams Janet L. , Hall Stacy , Liu Diane D , Hess Kenneth R. , Amin Sapna R. , Breitbart William , Bruera Eduardo
Published: September 2018

10003

Background: Agitated delirium is a highly distressing neuropsychiatric syndrome common in the last days of life. The use of benzodiazepines for agitated delirium is highly controversial. We compared the effect of lorazepam versus placebo as an adjuvant to haloperidol for persistent agitated delirium. Methods: In this double-blind trial, we randomly assigned patients with advanced cancer admitted to an acute palliative care unit with agitated delirium despite scheduled haloperidol to either lorazepam 3 mg IV or placebo, in addition to haloperidol 2 mg IV upon the onset of agitation. The primary outcome was the Richmond Agitation Sedation Scale (RASS) over the first 8 hours, ranging from -5 (unarousable) to +4 (combative). Secondary endpoints were rescue neuroleptic use, perceived comfort, delirium-related distress, adverse effects and overall survival. 26 patients per arm provided 80% power to detect a between arm difference of 0.5 effect size in mean RASS with a=5%. We used the Wilcoxon Rank Sum test for primary comparison. Results: 52 of 58 (90%) patients who received the medications completed 8 h of observation. RASS decreased significantly within 30 min of treatment in both arms (Table). The lorazepam arm was associated with significantly greater reduction of RASS (Table), less rescue neuroleptics (mean haloperidol equivalent dose 1 mg v. 3 mg, P=0.02), and greater comfort as perceived by blinded caregivers (84% v. 37%, P=0.007) and nurses (77% v. 30%, P=0.005) compared to placebo. We found no significant between-group differences in delirium-related distress, adverse effects and overall survival (median 68 v. 73 h, P=0.56). Conclusions: The combination of lorazepam/haloperidol resulted in rapid and significant reduction of agitation compared to haloperidol alone. Our study supports the judicious use of single dose lorazepam/haloperidol for persistent agitated delirium. Clinical trial information: NCT01670097. [Table: see text]
FDA analysis of enrollment of older adults in clinical trials for cancer drug registration: A 10-year experience by the U.S. Food and Drug Administration.
Authors: Singh Harpreet , Kanapuru Bindu , Smith Che , Fashoyin-Aje Lola A. , Myers Adrian , Kim Geoffrey , Pazdur Richard
Published: September 2018

10009

Background: Older adults are a growing segment of our oncology population, with an expected increase in cancer incidence of 67% from 2010 to 2030 in people age 65 and older. However, older adults have been proportionally underrepresented in clinical trials. We sought to analyze the age-related enrollment of cancer patients onto trials supporting registration of new drugs or new indications approved by the US Food and Drug Administration from 2005 to 2015. Methods: This study involved retrospective analyses of demographic data of cancer patients enrolled onto trials supporting registration from 2005-2015. The data on 224,766 cancer patients supporting 105 drug applications were analyzed according to age distributions of <65, 65-69, 70-74, 75-79, and ≥80 years. The rates of enrollment were compared with the corresponding rates in the US cancer population. The age distributions of the US cancer population were derived from the Surveillance, Epidemiology, and End Results Program of the National Cancer Institute for the year 2013 based on the 2010 US Census. Conclusions: Older adults were under-represented in the registration trials of new cancer therapies, especially those over age 75. Various strategies may be needed to evaluate cancer therapies for older adults in prospective clinical trials and to improve cancer care in adults over age 75. These include re-evaluating what may be considered restrictive eligibility criteria so as not to exclude older adults. Incorporating elements from geriatric assessment tools may help identify older adults most likely to benefit from treatment. More detailed labeling information that reflects the clinical experience with older adults could be considered. The FDA encourages drug sponsors as well as clinical trial cooperative groups to devise strategies to recruit patients that are reflective of their intended population. [Table: see text]
Impact of hearing and visual impairment in older adults with cancer.
Authors: Soto Perez De Celis Enrique , Sun Can-Lan , Tew William P. , Mohile Supriya Gupta , Gajra Ajeet , Klepin Heidi D. , Owusu Cynthia , Gross Cary Philip , Muss Hyman B. , Lichtman Stuart M. , Chapman Andrew E. , Cohen Harvey Jay , Dale William , Kim Heeyoung , Katheria Vani , Hurria Arti
Published: September 2018

10036

Background: Hearing and visual impairment increase the risk of psychological, functional, and cognitive deficits in older adults. However, little is known about their impact in older patients (pts) with cancer. Methods: This is a cross-sectional analysis of 2 prospective studies of pts ≥65 with cancer (Hurria et al. JCO 2011 & 2016) which identified risk factors for chemotherapy (CT) toxicity. Relationships between self-reported hearing/visual impairment (fair, poor or deaf/blind) and the need for assistance in instrumental activities of daily living (IADL, i.e. shopping), or activities of daily living (ADL, i.e. bathing); anxiety; depression and cognitive deficit (>11 on Blessed OMC test) were assessed (adjusted for age, sex, race, education, cancer type/stage, comorbidity, falls & medication). Results: Among 750 pts (median age 72, range 65-94) with solid tumors (28% lung, 27% GI, 30% breast/GYN; 58% stage IV), 28% (n = 213) reported 1 impairment (61% hearing, 39% visual) and 7% (n = 55) both. On multivariate analysis, impaired hearing was associated with IADL dependency, anxiety and depression. Visual impairment was associated with IADL dependency, ADL limitation and depression. Impairment in both was associated with IADL dependency, anxiety, depression and cognitive deficit. Conclusions: Older pts with cancer and hearing/visual impairment are at higher risk of functional, psychological and cognitive deficits. Interventions aimed at improving vision and hearing of older adults with cancer should be studied. [Table: see text]
Randomized trial of a smartphone mobile app for adherence to oral chemotherapy.
Authors: Greer Joseph , Jacobs Jamie M. , Pensak Nicole , Nisotel Lauren Ellen , Fishbein Joel , MacDonald James , Ream Molly , Fuh Charn-Xin , Buzaglo Joanne S , Muzikansky Alona , Lennes Inga Tolin , Safren Steven , Pirl William F. , Temel Jennifer S.
Published: September 2018

10055

Background: As patients with cancer are increasingly prescribed oral chemotherapy, they share greater responsibility for ensuring adherence and monitoring side effects. The aim of this study was to test the effect of a smartphone mobile app to improve adherence and symptom management in patients prescribed oral chemotherapy. Methods: From 2/15 to 12/16, 181 patients with diverse cancers prescribed oral chemotherapy were randomized to receive either the smartphone mobile app or standard care. The mobile app included a medication treatment plan with alerts, symptom reporting module, education library, and cancer-specific resources. The primary outcome was adherence, measured by electronic pill cap (MEMS) and self-report (Morisky Medication Adherence Scale; MMAS). To assess symptoms, mood, and satisfaction with care, participants completed the MD Anderson Symptom Inventory, Hospital Anxiety & Depression Scale (HADS); and Functional Assessment of Chronic Illness Therapy-Treatment Satisfaction (FACIT-TS) at baseline and 12 weeks. General linear models were used to assess intervention effects on patient outcomes. Results: Study groups did not differ across outcome measures from baseline to week 12. Secondary analyses showed that baseline adherence (MMAS) and anxiety (HADS) were moderators of intervention effects on adherence and treatment satisfaction. Among patients who reported adherence problems, those assigned to the mobile app had better average MEMS adherence (Mean Diff = 19.30, 95% CI = 0.09-38.51, p = .05) and satisfaction with clinician explanations per the FACIT-TS (Mean Diff = 1.69, 95% CI = 0.25-3.13, p = .02) compared to standard care. Also, among patients with higher anxiety, those in the mobile app group reported better adherence on the 12-week MMAS (95.2% vs. 68.0%, OR = 0.11, 95% CI = 0.01, 0.94, p = .04) and satisfaction with interpersonal treatment per the FACIT-TS (Mean Diff = 0.76, 95% CI = 0.13-1.39, p = .02) compared to standard care. Conclusions: Although potentially not for everyone taking oral chemotherapy, a smartphone mobile app to improve adherence and treatment satisfaction may be useful for patients with certain risk factors, such as those struggling with adherence or anxiety. Clinical trial information: NCT02157519.
Final results of a phase 2 study of talazoparib (TALA) following platinum or multiple cytotoxic regimens in advanced breast cancer patients (pts) with germline BRCA1/2 mutations (ABRAZO).
Authors: Turner Nicholas C. , Telli Melinda L. , Rugo Hope S. , Mailliez Audrey , Ettl Johannes , Grischke Eva-Maria , Mina Lida A. , Balmana Gelpi Judith , Fasching Peter A. , Hurvitz Sara A. , Wardley Andrew M. , Chappey Colombe , Verret Wendy , Hannah Alison L. , Robson Mark E.
Published: September 2018

1007

Background: TALA is a dual-mechanism PARP inhibitor that traps PARP on DNA. This study was designed to assess the activity of TALA in pts with g BRCA1/2mutation previously exposed to platinum or multiple prior cytotoxic regimens. Methods: ABRAZO (NCT02034916) is a 2-cohort, 2-stage phase 2 study of TALA (1 mg/d) following platinum-based therapy (Cohort 1 [C1]) or ≥ 3 platinum-free cytotoxic-based regimens (Cohort 2 [C2]) in pts with locally advanced or metastatic breast cancer (MBC) and g BRCA1/2mutation. Pts had ECOG PS ≤ 1 and measurable disease by RECIST v1.1. Five responses per cohort were required in ≤ 35 pts to progress to stage 2. The primary endpoint was confirmed ORR by independent radiology facility (IRF). Secondary endpoints: clinical benefit rate ≥ 24 weeks (CBR24), DOR, PFS, and OS. Results: From May 2014 to Feb 2016, 84 pts were enrolled (C1, n = 49; C2, n = 35). At data cutoff (1 Sep 2016), 9 pts continued on treatment. Both cohorts proceeded to stage 2 before enrollment closed. Median age was 50 (range, 31–75) years; 58% of pts had an ECOG PS of 0. TNBC/HR+ incidence in C1 and C2 was 59%/41% and 17%/83%, respectively. Median number of prior cytotoxic regimens administered for advanced disease was 2 in C1 and 4 in C2. ORR by IRF for BRCA1/BRCA2 was 24%/34%, and ORR by IRF for TNBC/HR+ was 26%/29%. Common all grade AEs: anemia (52%), fatigue (45%), nausea (42%), diarrhea (33%), thrombocytopenia (33%), and neutropenia (27%). Grade ≥ 3 AEs: anemia (35%), thrombocytopenia (19%), and neutropenia (15%). Nonhematological AEs grade ≥ 3 did not occur. AEs related to TALA led to drug discontinuation in 3 pts (4%); 4 AEs resulted in death, none related to TALA. Conclusions: TALA was well tolerated in MBC pts with a g BRCA1/2 mutation, exhibiting promising antitumor activity in C1 and C2. TALA vs physician’s choice of treatment in g BRCA1/2-mutated MBC is being evaluated in the phase 3 EMBRACA trial (NCT01945775). Clinical trial information: NCT02034916. [Table: see text]
The contribution of pre-existing cardiovascular (CV) risk factors to the risk of stroke or heart attack among non-Hodgkin lymphoma (NHL) survivors.
Authors: Salz Talya , Zabor Emily Craig , de Nully Brown Peter , Dalton Susanne Oksbjerg , Raghunathan Nirupa Jaya , Matasar Matthew J. , Steingart Richard , Hjalgrim Henrik , Svenssen Munksgaard Peter , Specht Lena , Vickers Andrew J. , Oeffinger Kevin C. , Johansen Christoffer
Published: September 2018

10082

Background: Increased risk of myocardial infarction (MI) and cerebrovascular accident (CVA) among NHL survivors is commonly attributed to NHL treatment. The extent to which pre-existing CV risk factors also contribute to increased risk is unknown. We investigated this association among an entire national population of NHL survivors who have a full range of important CV risk factors. Methods: Using Danish population-based registries, we identified all adults diagnosed with primary aggressive NHL from 2000-2010 and followed them for MI and CVA from 9 months after diagnosis through 2012. MI and CVA diagnoses were ascertained from the nationwide Hospital Discharge Register and Cause of Death Register. CV risk factors (hypertension, dyslipidemia, and diabetes), vascular disease, and intrinsic heart disease prevalent at NHL diagnosis were ascertained algorithmically using the National Prescription Register and the Hospital Discharge Register. Cumulative anthracycline dose was coded continuously. Receipt of radiation was coded dichotomously for both chest and neck. Controlling for age, sex, treatment, and CV diseases, we used Cox multivariate regression to test the association between pre-existing CV risk factors and subsequent CVA or MI. Results: Among 2604 patients with NHL, median age was 62, and median follow-up time was 2.4 years. Overall, 131 patients were diagnosed with MI or CVA. Before NHL diagnosis, 40% of patients had at ≥1 CV risk factor, 13% had vascular disease, and 6% had intrinsic heart disease. 90% of the patients were treated with anthracyclines, 9% had received chest radiation, and 15% had received neck radiation. Patients with ≥1 CV risk factor had an increased risk of MI or CVA compared to patients with none (HR = 1.5 [95% CI = 1.1-2.2). Prevalent vascular disease, prevalent intrinsic heart disease, and NHL treatment were not associated with MI or CVA (p’s > 0.05). Conclusions: In a large, well-characterized, and nationally representative cohort of NHL survivors, prevalent CV risk factors were associated with later CVA and MI. To prevent MI and CVA among survivors, decisions about post-treatment monitoring should take into account prevalent CV risk.
Abemaciclib for the treatment of brain metastases (BM) secondary to hormone receptor positive (HR+), HER2 negative breast cancer.
Authors: Tolaney Sara M. , Lin Nancy U. , Thornton Donald , Klise Suzanne , Costigan Timothy Michael , Turner P. Kellie , Anders Carey K.
Published: September 2018

1019

Background: Abemaciclib is an oral selective CDK4 and CDK6 inhibitor administered on a continuous dosing schedule, which has demonstrated clinical activity and an acceptable safety profile in patients (pts) with heavily pre-treated HR+ metastatic breast cancer (MBC). Abemaciclib has been shown preclinically to cross the blood-brain barrier, providing rationale for testing this agent in pts with BM. Furthermore, as previously presented, levels of abemaciclib similar to plasma were detected in resected BM in a subset of pts with HR+, HER2- MBC in this study. Methods: Study I3Y-MC-JPBO is an open-label, Phase 2, Simon 2-Stage trial evaluating the safety and efficacy of abemaciclib 200 mg BID in pts with new or progressive BM secondary to HR+ MBC, NSCLC, or melanoma. Eligible pts in Part B (the focus of this presentation) include pts with HR+, HER2- MBC who have ≥1 measurable brain lesion. The primary objective was objective intracranial (IC) response rate as defined by Response Assessment in Neuro-Oncology BM response criteria. Secondary objectives (IC related) include best overall response, duration of response, disease control rate, and clinical benefit rate. Exploratory objectives include assessment of drug concentrations in resected tumors. Safety, tolerability, and PK of abemaciclib were also assessed. Stage 1 includes 23 pts; if < 2 of the 23 pts respond to abemaciclib, futility is met. However, if ≥2 respond, 33 additional pts are to be enrolled to Stage 2. Results: This Stage 1 efficacy analysis included 23 pts; 32 pts were included in the safety analysis. Although 5 pts were considered nonevaluable, 2 pts (8.7%) had confirmed partial response (PR) (meeting the predefined threshold for advancement to Stage 2); enrollment is ongoing. At the time of the analysis, the 2 pts with PR had completed 14 and 15 cycles each (21d cycles) of therapy. The majority of adverse events were gastrointestinal in nature, consistent with previous studies of abemaciclib. Conclusions: This study has provided preliminary evidence that abemaciclib penetrated BM in pts with HR+, HER2- MBC and had antitumor activity in this population. Final results will be presented following Stage 2 analyses. Clinical trial information: NCT02308020.
Health-related quality of life from a phase 3 randomized trial of fulvestrant 500 mg vs anastrozole for hormone receptor-positive advanced breast cancer (FALCON).
Authors: Robertson John Forsyth Russell , Cheung Kwok-Leung , Noguchi Shinzaburo , Shao Zhimin , Degboe Arnold , Lichfield Jasmine , Thirlwell Jackie , Fazal Mehdi , Ellis Matthew J
Published: September 2018

1048

Background: The Phase 3 randomized FALCON trial (NCT01602380) demonstrated improved progression-free survival with fulvestrant 500 mg (F) vs anastrozole 1 mg (A) in postmenopausal women with hormone receptor-positive (HR+) locally advanced or metastatic breast cancer (BC) without prior endocrine therapy (hazard ratio [HR] 0.797, 95% confidence interval [CI] 0.637-0.999; p = 0.0486; Robertson et al. Lancet 2016). Overall health-related quality of life (HRQoL) was maintained and similar for F and A. There was no evidence of a detriment with F vs A in time to deterioration for both Trial Outcome Index (TOI; HR 0.90, 95% CI 0.70-1.15; p = 0.4008) and Functional Assessment of Cancer Therapy for Breast Cancer (FACT-B) total score (HR 0.84, 95% CI 0.66-1.07; p = 0.1594). We present additional analyses of patient (pt)-reported HRQoL outcomes from FALCON. Methods: Women with HR+ BC were randomized 1:1 to F (Days 0, 14, 28, then every 28 days) or A (daily) until disease progression or discontinuation. HRQoL was assessed by FACT-B questionnaire (TOI [summary of physical and functional well-being and breast cancer subscale scores] and FACT-B total score) at randomization and every 12 weeks during treatment. HRQoL data post-treatment (with or without progression) were also collected. Results: 462 pts were randomized (F, n = 230; A, n = 232). Compliance to FACT-B during treatment ranged from 84.6-100.0%. Mean change from baseline in TOI (scale range 0-92) and FACT-B total score (scale range 0-144) remained broadly stable (approximately ±3 points to Week 132) and similar between arms during treatment. HRQoL was also maintained in FACT-B subscales. Approximately one third of pts had improved TOI (≥ +6 points) and FACT-B (≥ +8 points) total scores from baseline up to Week 144 of treatment with F (ranges 26.4-45.0%, and 20.0-35.8%, respectively) and A (ranges 18.6-32.9%, and 22.7-37.9%, respectively). Conclusions: Compliance to the FACT-B questionnaire on treatment with F and A for HR+ BC in the FALCON trial was good; mean change from baseline in TOI and FACT-B total score was maintained, and similar proportions of pts had improved TOI and FACT-B total score in both arms. Clinical trial information: NCT01602380.
Effect of chimeric antigen receptor-modified T (CAR-T) cells on responses in children with non-CNS extramedullary relapse of CD19+ acute lymphoblastic leukemia (ALL).
Authors: Talekar Mala Kiran , Maude Shannon L. , Hucks George E , Motley Laura S , Callahan Colleen , White Claire M , Baniewicz Diane , Barrett David Maxwell , Rheingold Susan R. , Lacey Simon F. , Levine Bruce L , Melenhorst Jan J. , Teachey David T. , June Carl H. , Grupp Stephan A.
Published: September 2018

10507

Background: Anti-CD19 CAR-T cell therapies have shown high efficacy in inducing durable marrow responses in patients with relapsed/refractory CD19+ ALL. We now report on outcome of 10 patients with extramedullary (EM) involvement of ALL treated with CAR-T, including 5 patients who had EM disease at time of infusion. Methods: We identified patients treated on pediatric phase 1/2a trials of murine (CTL019) or humanized (CTL119) anti-CD19 CAR-T cells for isolated EM or BM/EM relapse of ALL. EM relapse was defined as involvement of non-CNS site by imaging +/- pathology within 12 months (mos) of infusion. Post infusion, patients had diagnostic imaging done at 1, 3, 6, 9, and 12 mos. Results: Among 97 patients receiving CAR-T, ten (CTL019, n=6; CTL119, n=4) were identified who had EM involvement on average 2.3 mos (range 0-9 mos) prior to infusion; including 5/10 at time of infusion. Sites of EM relapses included testes, sinus, parotid, bone, uterus, kidney and skin, and 5 patients had multiple sites of EM involvement. Patients ranged from 2-4 relapses of their ALL pre-CAR-T. Two had isolated EM relapse (sites were parotid and multifocal bony lesions in one; testis and sinus in second). All 10 patients had undergone hematopoietic stem cell transplantation prior to EM relapse, 2 had received radiation directed to the EM site prior to CAR-T. Five patients evaluated by serial imaging had objective responses: 2 had resolution of EM disease by day 28; 2 had resolution by 3 mos; 1 had continued decrease in size of uterine mass at 3 and 6 mos and underwent hysterectomy at 8 mos with no evidence of disease on pathology. In the 4 patients with prior history of skin or testicular involvement, there was no evidence by exam at day 28. One patient had progressive EM disease within 2 weeks of CAR-T cell infusion and died at 6 weeks. Three relapsed with CD19+ disease [1 skin/medullary- died at 38 mos post CAR-T; 2 medullary (1 died at 17 mos, 1 alive at 28 mos)]. The remaining 6 are alive and well at median follow-up of 10 mos (range 3-16 mos) without recurrence of disease. Conclusions: Single agent CAR-T immunotherapy can induce potent and durable responses in patients with EM relapse of their ALL. Clinical trial information: NCT01626495, NCT02374333.
A pediatric phase I study of larotrectinib, a highly selective inhibitor of the tropomyosin receptor kinase (TRK) family.
Authors: Laetsch Theodore Willis , DuBois Steven G. , Nagasubramanian Ramamoorthy , Turpin Brian , Mascarenhas Leo , Federman Noah , Reynolds Mark , Smith Steven , Cruickshank Scott , Cox Michael Craig , Pappo Alberto S. , Hawkins Douglas S.
Published: September 2018

10510

Background: Larotrectinib is the first selective small-molecule inhibitor of TRKA, B, and C in clinical development. Data from the adult phase I trial demonstrate prolonged responses in patients (pts) with TRK fusions and a favorable tolerability profile. Methods: This multicenter, rolling 6 phase I study enrolled pts with refractory solid or CNS tumors aged ≥ 1 month – 21 years. Pts were dosed orally BID on a continuous 28-day schedule either by capsule or solution. Pharmacokinetic (PK)-directed intra-subject dose escalation was permitted, with exposures targeting the adult recommended Phase II dose (RP2D) of 100 mg BID. The primary objective was to define the MTD / RP2D; secondary objectives included PK and efficacy using RECIST v1.1. Results: As of December 31, 2016, 17 pts (12 with TRK fusions, 5 without TRK fusions) with a median age of 5.2 years (0.4 – 18.3) were enrolled to 3 dose levels. Pts were enrolled with fusions of all 3 NTRK genes: NTRK1 (n=6), NTRK2 (n=1), and NTRK3 (n=5) in heterogeneous tumor diagnoses: infantile fibrosarcoma (IFS) (n=6), other sarcoma (n=4), and papillary thyroid cancer (n=2). Most common AEs regardless of attribution were vomiting, diarrhea, and fatigue. While 8 (47%) pts experienced grade 3-4 AEs, none were attributed to larotrectinib. No DLTs were observed and an MTD was not established. Both formulations delivered dose-dependent PK comparable to the adult RP2D at dose level 3. 12 pts (10 with TRK fusions, 2 without TRK fusions) remain on treatment with median follow-up of 2.8 months (0.7 – 8.4). Among TRK fusion pts, the vast majority have achieved confirmed RECIST responses regardless of tumor diagnoses. No responses were seen in pts without TRK fusions (n=4). 5 pts discontinued therapy, including 2 with TRK fusions: 1 pt with IFS had sufficient response to allow tumor resection, and 1 pt with IFS progressed with a documented acquired resistance mutation. Conclusions: Larotrectinib has demonstrated a favorable tolerability profile and histology-independent efficacy in pediatric pts harboring TRK fusions. Updated safety and efficacy data will be presented, including the RP2D, response rate, duration of response, and use of larotrectinib in the pre-surgical setting. Clinical trial information: NCT02637687.
Phase 1/2 KEYNOTE-051 study of pembrolizumab (pembro) in pediatric patients (pts) with advanced melanoma or a PD-L1+ advanced, relapsed, or refractory solid tumor or lymphoma.
Authors: Geoerger Birgit , Kang Hyoung Jin , Yalon-Oren Michal , Marshall Lynley V. , Vezina Catherine , Pappo Alberto S. , Laetsch Theodore Willis , Petrilli Antonio Sergio , Handgretinger Rupert , Toporski Jacek , Glade-Bender Julia , Nicholls Wayne , Fox Elizabeth , DuBois Steven G. , Macy Margaret , Cohn Susan Lerner , Pathiraja Kumudu , Diede Scott J. , Ebbinghaus Scot , Pinto Navin R.
Published: September 2018

10525

Background: In phase 1 of the KEYNOTE-051 study (NCT02332668), the 2 mg/kg Q3W approved adult dose of pembro was also determined to be the pediatric recommended phase 2 dose. In phase 2, presented herein, we further evaluated this dose in pediatric pts with advanced cancer. Methods: Children aged 6 mo to < 18 y with advanced melanoma or a PD-L1+ advanced, relapsed or refractory solid tumor or lymphoma, measurable disease per RECIST v1.1, and performance score ≥50 using Lansky Play or Karnofsky scales received pembro 2 mg/kg Q3W for 35 cycles or until confirmed disease progression per immune-related RECIST by investigator review, intolerable toxicity, or pt/investigator decision to discontinue. Tumor imaging was performed every 8 wk for the first 6 mo, then every 12 wk thereafter. AEs were graded by NCI CTCAE v4.0. Key efficacy endpoints were ORR, disease control rate (DCR), and PFS per RECIST v1.1 by investigator and OS. Results: Of 369 pts prescreened, 364 were evaluable for PD-L1 expression; of these, 121 (33.2%) were PD-L1+. 66 pts were enrolled; median follow-up was 2.5 mo (range, 0.2-18). As of the data cutoff (Nov 7, 2016), 23 (34.8%) pts were still on treatment. Median age was 13 y (range, 1-17), 77.3% had metastatic disease, and 34.8% had ≥3 prior lines of therapy for recurrent/metastatic disease. Primary diagnoses were non-CNS solid tumors (n = 45), CNS tumors (n = 16), and lymphoma (n = 5). 5 (7.6%) pts had grade 3-4 treatment-related AEs (TRAEs), most commonly neutropenia (n = 2). No treatment-related deaths occurred; 1 pt discontinued for a TRAE (grade 3 AST increased). 1 pt each with Hodgkin lymphoma, adrenocortical carcinoma, mesothelioma, and glioblastoma had partial response for an ORR of 6.1% (95% CI, 1.7-14.8); 7 (10.6%) pts had stable disease for a DCR of 16.7% (95% CI, 8.6-27.9). Median PFS and OS were 1.8 mo and 9.2 mo, respectively; 12-mo PFS was 10.2% and OS was 40.5%. Potential effects of pembro on the developing immune system (eg, T and B cells, vaccinated antibodies) will also be presented. Conclusions: Pembro showed low toxicity and warrants further study to determine activity in select pediatric tumors. Enrollment in KEYNOTE-051 is ongoing. Clinical trial information: NCT02332668.
Risk stratification including FOXO1 fusion status (FOXO1) in patients with rhabdomyosarcoma (RMS) treated on six recent frontline trials: A report from the Children's Oncology Group (COG).
Authors: Hibbitts Emily , Hawkins Douglas S. , Arndt Carola A. S. , Chi Yueh-Yun
Published: September 2018

10528

Background: Clinical risk factors associated with outcome in children with either localized or metastatic RMS were identified by Meza et al. (2006) and Oberlin et al. (2008). We re-examined risk stratification by adding FOXO1 to traditional clinical prognostic factors in children with localized or metastatic RMS in a large cohort from COG frontline clinical trials. Methods: Data from six COG clinical trials (D9602, D9802, D9803, ARST0331, ARTS0431, ARST0531) accruing previously untreated patients with RMS from 1997 to 2013 yielded 1,853 eligible patients (two studies each for low, intermediate and high risk patients). Survival tree regression for event-free survival (EFS) and overall survival (OS) was conducted to determine prognostic impact of risk factors. Recursively, the factor most strongly associated with outcome was selected for branching and split using a goodness of fit measure. Factors included were age, FOXO1, group, histology, nodal status, number of metastatic sites, primary site, sex, tumor size, and presence of metastases in bone/bone marrow, soft tissue, effusions, lung, distant lymph nodes, and other sites. Results: 5-year overall EFS and OS was 0.67 (SE, 0.01) and 0.77 (SE, 0.01), respectively. Survival trees for EFS and OS found localized versus metastatic at the first split and included FOXO1 as a significant risk factor. Conclusions: FOXO1 improves risk stratification of patients with localized RMS, although histology and pattern of metastases are more predictive for patients with metastatic RMS. Our findings support incorporation of FOXO1 in risk stratified clinical trials. [Table: see text]
Blinatumomab use in pediatric patients (pts) with relapsed/refractory B-precursor acute lymphoblastic leukemia (r/r ALL) from an open-label, multicenter, expanded access study.
Authors: Locatelli Franco , Zugmaier Gerhard , Vora Ajay , Rossig Claudia , Peters Christina , Brethon Benoit , O'Brien Maureen Megan , Belton Laura , Handgretinger Rupert
Published: September 2018

10530

Background:Blinatumomab (blin), a bispecific T-cell engaging antibody construct, has shown antileukemia activity and tolerability in pts with r/r ALL. We further evaluated safety and efficacy of blin in the first 40 pediatric pts with r/r ALL enrolled in an expanded access study (NCT02187354). Methods: Eligible pts (28 d to < 18 yrs) had ≥ 5% blasts and r/r ALL (refractory, ≥ 2 relapses or relapse after transplant [HCT]). Blin was dosed by continuous infusion (4 wks on/2 wks off) for up to 5 cycles (≥ 5 to < 25% blasts: 15 µg/m2/d; ≥ 25% blasts: 5 µg/m2/d on d1−7 in cycle 1, then 15 µg/m2/d). The primary endpoint was incidence of treatment-emergent (TE) and treatment-related (TR) adverse events (AEs); key efficacy endpoints were complete response (CR) and minimal residual disease (MRD, by PCR or flow cytometry) in the first 2 cycles, relapse-free survival, overall survival and HCT rate. Results: Of the first40 treated pts (median age, 9 [range, 1−17] yrs), 24 (60%) had ≥ 2 relapses, 20 (50%) relapsed after HCT and 5 (13%) were primary refractory; 18 (45%) had ≥ 50% blasts and 21 (53%) had prior HCT. Safety and key efficacy outcomes are shown in the table, including 63% CR in the first 2 cycles. There were 8 relapses and 20 deaths after treatment. Regardless of causality, the most frequent TEAEs were pyrexia (78%), cytokine release syndrome (CRS; 23%) vomiting (23%) and anemia (20%); all 9 CRS events were grade (gr) 1 or 2 and 1 tumor lysis syndrome was gr 3. 10 (25%) pts interrupted treatment and 2 (5%) discontinued due to TRAEs; 13 (33%) pts had gr ≥ 3 TRAEs, including 2 of 3 neurologic events (depressed level of consciousness and headache; both gr 3); 2 fatal AEs were considered unrelated to blin. Conclusions:Here single-agent blin showed antileukemia activity in pediatric pts with high-risk r/r ALL including t(17;19) and AEs consistent with those previously reported for r/r ALL. Clinical trial information: NCT02187354. [Table: see text]
Early response rates and Curie scores at end of induction: An update from a phase II study of an anti-GD2 monoclonal antibody (mAb) with chemotherapy (CT) in newly diagnosed patients (pts) with high-risk (HR) neuroblastoma (NB).
Authors: Furman Wayne Lee , Shulkin Barry L. , Federico Sara Michele , McCarville Mary B , Davidoff Andrew M. , Krasin Matthew J. , Wu Jianrong , Brennan Rachel Christine , Bishop Michael William , Helmig Sara E. , Navid Fariba , Santana Victor M. , Anthony Gwendolyn , Hank Jacquelyn A , Gillies Stephen D , Sondel Paul M. , Leung Wing H. , Pappo Alberto S.
Published: September 2018

10534

Background: We are conducting a Phase II trial of the anti-GD2 mAb hu14.18K322A given concomitantly with CT in newly diagnosed pts with HR NB. Our primary objective is to compare the response rate (RR; defined as ≥ PR) after two courses of CT with cyclophosphamide (CTX)/topotecan (TPT) and hu14.18K322A with GM-CSF and IL-2 to the RR reported by Park et al. (JCO 29:4351, 2011), using identical CT with GCSF only, in a two-stage group sequential design. Semiquantitative MIBG scoring (Curie; CS) has been shown to be a prognostic indicator of outcome in pts with HR NB (Yanik et al, J Nucl Med, 2013), particularly, those with CS > 2 at end of induction (EoI) CT have inferior outcomes. Here we update the RR and report the CS at EoI CT. Methods: Pts received induction CT (6 cycles) as described by Park et al, with the addition of hu14.18K332A (on d 2-5; 40mg/m2/d x 4d), daily sc GM-CSF and sc IL-2 (1 x 106 IU/m2/dose) qod x 6. 123I-MIBG scans and scoring (CS) were obtained on all pts at diagnosis, after second course of CT and at EoI. Results: 42 evaluable pts completed the first two courses of CT (24 male, median age 2.9 yrs (range 6 m -15.2 yrs), 36 INSS 4, 19 MYCNamplified); 40/42 evaluable pts had measurable reductions in primary tumor volume after two courses of CT (median 79%, average 69%, range +5 – 100%). Responses (≥ PR) after two courses were seen in 32/42 (76.2%; 95% CI 61.3 – 87.9%); No mAb dose-reductions were made but 20/43 (47%) pts had infusion times extended. The development of human anti-human antibody reactivity (HAHA) to hu14.18K322A in the first 22 pts is minimal. Of the 36 INSS 4 pts, 1 withdrew prior to EoI and 2 are too early. The median CS at diagnosis for the 33 stage 4 pts who have completed induction CT was 18 (range 1 – 28). At EoI the median CS was 0 (range 0 -23); 29/33 INSS 4 pts had EoI CS ≤ 2. Conclusions: The addition of hu14.18K322A to two courses of CTX/TPT significantly improves the RR compared to two courses of CTX/TPT alone (32/42 vs 12/30 as reported by Park et al,; P = 0.000004). The improved median CS of the stage 4 patients from 18 at diagnosis to 0 at EoI suggest the improvement in early RR may translate into improved EFS as well. Clinical trial information: NCT01857934.
ADVL1522: A phase 2 study of IMGN901 (lorvotuzumab mertansine; IND# 126953, NSC# 783609) in children with relapsed or refractory Wilms tumor, rhabdomyosarcoma, neuroblastoma, pleuropulmonary blastoma, malignant peripheral nerve sheath tumor (MPNST), and synovial sarcoma: A Children's Oncology Group study.
Authors: Geller James I. , Pressey Joseph Gerald , Smith Malcolm A. , Kudgus Rachel A. , Schoon Renee , McGovern Renee M. , Cajaiba Mariana , Reid Joel M. , Hall David , Barkauskas Donald A. , Dome Jeffrey , Fox Elizabeth , Weigel Brenda
Published: September 2018

10537

Background: Lorvotuzumab mertansine (IMGN901; LM) is an antibody-drug conjugate, linking anti-mitotic agent (DM1) to an anti-CD56 antibody. Preclinical data show effects in Wilms tumor (WT), rhabdomyosarcoma (RMS), and neuroblastoma (NBL). Synovial sarcoma (SS), MPNST and pleuropulmonary blastoma (PPB) also express CD56. A phase 2 trial assessing the efficacy and tolerability of LM administered at the adult recommended phase 2 dose (RP2D) was conducted in children with relapsed tumors. Methods: LM (110 mg/m2/dose) was administered IV on days (d) 1 and 8 of 21 d cycles, with dexamethasone pre-medication. The tolerability of LM was assessed in 6 patients prior to trial activation group-wide. Dose limiting toxicity (DLT) was assessed using CTCAE. Response was assessed by RECIST. Pharmacokinetics (PK) were obtained during cycle 1. Peripheral blood CD56-positive cells were measured d1 and d8 pre-dose. Tumor CD56 expression by immunohistochemistry in archival tissue was scored (0-3+). Results: Sixty-two patients were enrolled. The median (range) age was 14.3 y (2.8–29.9); 35 were male. Diagnoses included WT (17), RMS (17), NBL (12), SS (10), MPNST (5) and PPB (1). One patient was ineligible due to lack of measurable disease. Of 61 eligible patients, 47 were evaluable for toxicity, 50 for response, 50 for tumor CD56 expression; and 18 consented to optional PK. Five patients experienced 9 DLTs: hyperglycemia (1), colonic fistula (1) with perforation (1), nausea (1) with vomiting (1), increased ALT (2 in cycle 1; 1 in cycle 2 with increased AST (1)). Non-dose limiting toxicities (Grade ≥3) attributed to LM included lymphopenia, anemia, vomiting, dehydration, hypokalemia, hyperuricemia, hypophosphatemia. Mean DM1 Cmax, t1/2 and AUC0-∞values were 922 ng/ml, 33 h and 27400 ng/ml*h, respectively. Tumor CD56 expression was 0 (8%), 1+(4%), 2+(12%), 3+(76%). LM and CD56 antibody PK, and response, will be reported. Conclusions: LM (110 mg/m2) is tolerated in children at the adult RP2D. Clinical trial information: NCT 02452554.
Role of radiotherapy to primary/metastatic sites in pediatric patients with metastatic rhabdomyosarcoma in the BERNIE study.
Authors: Cameron Alison , Chisholm Julia , Elze Markus C. , Casanova Michela , Geoerger Birgit , Gaze Mark , Oberlin Odile , Bachir Jeanette , Fürst-Recktenwald Sabine , Merks Johannes H.M.
Published: September 2018

10541

Background: Local control is a key part of treatment of local/locoregional rhabdomyosarcoma (RMS) and often involves radiotherapy (RT) with/without surgery. The role of RT in metastatic RMS is uncertain, with little published evidence to guide clinicians. We analyzed data from the BERNIE trial to assess the benefit of RT for patients (pts) with metastatic RMS. Methods: In the BERNIE study (NCT00643565) pts aged ≥6 months to <18yrs with metastatic RMS and non-RMS soft tissue sarcoma were randomized to receive chemotherapy (CT) with/without bevacizumab (BEV), surgery, and/or RT (at cycle 6–9) then maintenance CT. RT was recommended for all sites of metastases if feasible (investigator discretion allowed, resulting in variability in actual RT given). Pts were categorized into those receiving: RT all sites, partial RT, no RT. Event-free survival (EFS) and overall survival (OS) were calculated using Cox proportional hazards models and a landmark approach: only pts who were event free at day 221 (i.e. end of cycle 9 + 1 month) were included (EFS, n=85; OS, n=97). Variables adjusted were: treatment (as randomized), disease type (alveolar/embryonal/other), risk group, age >10yrs, metastatic lesion count (1, 2–3, 4+). The analysis was non-randomized, exploratory and post hoc. Results: Of 102 pts with RMS, 22 received no RT, 49 partial RT, and 31 RT to all sites. Baseline characteristics were mostly balanced, and comparable proportions of pts received BEV. Better OS was observed in the RT group (Table) (comparable with unadjusted results). A non-significant EFS improvement was observed for the RT groups. Conclusions: Partial RT and RT to all sites of disease in metastatic RMS was associated with significant OS benefits, albeit in small pt numbers. This should be confirmed in a prospective randomized trial. Clinical trial information: NCT00643565. [Table: see text]
Phase I study of talazoparib and irinotecan in children and young adults with recurrent/refractory solid tumors.
Authors: Federico Sara Michele , Stewart Elizabeth , Coleman Jamie L. , Bishop Michael William , Santana Victor M. , Lam Catherine , Hawkins Dana , Wu Jianrong , Mao Shenghua , Goshorn David Ross , Pappo Alberto S. , Dyer Michael A.
Published: September 2018

10542

Background: Poly (ADP-ribose) Polymerase inhibitors (PARPi) target tumors with deficiencies in DNA repair mechanisms. Talazoparib (TAL), a potent PARP inhibitor, demonstrated significant efficacy in a Ewing sarcoma model when combined with DNA-damaging irinotecan (IRN). We performed a phase I trial to determine the maximum tolerated doses (MTDs) of TAL and IRN in pediatric patients with solid tumors. Methods: Cohorts of 3-6 eligible patients (pts) with recurrent/refractory solid tumors received escalating doses of oral (PO) TAL and intravenous (IV) IRN in a 3+3 design (Table 1). Each course was 21 days. Serum for TAL and IRN pharmacokinetics (PK) were obtained. Toxicities were assessed using CTCAE v.4 and responses were evaluated by RECIST v.1.1. Results: Twenty-four pts (9 male; median age, 11 years; 18 recurrent) received a median of 2 courses (range, 1-18). Fifteen pts had prior exposure to IRN. Table 1 summarizes the dose-limiting toxicities (DLTs) in course 1. The most common grade 3 or higher non-hematologic and hematologic toxicities in 82 evaluable courses were febrile neutropenia (5), elevated gamma-glutamyltransferase (GGT, 4), neutropenia (22) and lymphopenia (17). Two of 22 evaluable patients had a response (CR Ewing sarcoma, 18 courses; PR synovial sarcoma, 10 courses) and 9 had disease stabilization, median 4 courses (range, 4-10). Results of PK tests will be presented. Conclusions: The recommended phase II doses are TAL 600mcg/m2 (max 1000mcg/dose) days 1-6 and IRN 40mg/m2/day days 2-6. This regimen is feasible with evidence of anti-tumor activity and warrants further investigation. Clinical trial information: NCT02392793. [Table: see text]