bluuebunny/crossref_metadata_2025_split huggingface dataset:
Naxitamab-based chemoimmunotherapy for resistant high-risk neuroblastoma: Preliminary results of HITS pilot/phase II study.
Authors: Mora Jaume , Kushner Brian H. , Flores Miguel Angel , Santa-María Vicente , Garraus Moira , Basu Ellen M. , Roberts Stephen S. , Castañeda Alicia , Gorostegui Maite , Cheung Nai-Kong V. , Modak Shakeel 
Published: May 2019

10025 Background: Chemoresistant and relapsed disease are major obstacles to curing high-risk neuroblastoma (HR-NB). Anti-GD2 monoclonal antibody (MoAb) is effective in preventing relapse after remission but responses in relapsed or progressive disease (PD) are rare. We investigated the combination of humanized anti-GD2 MoAb naxitamab, (previously termed Hu3F8), irinotecan, temozolomide and sargramostim (GM-CSF): a pilot HITS protocol against resistant HR-NB now expanded to a phase II study (NCT03189706). Methods: Salient eligibility criteria included evaluable or measurable chemoresistant disease. Prior anti-GD2 MoAb and/or irinotecan/temozolomide (I/T) therapy was permitted. Each cycle comprised of irinotecan 50 mg/m2/day intravenously (IV) plus temozolomide 150 mg/m2/day IV or orally (days 1-5); naxitamab 2.25 mg/kg/day IV over 30 minutes, days 2, 4, 8 and 10 (total 9 mg/kg or 270 mg/m2 per cycle), and GM-CSF 250 mg/m2/day subcutaneously, days 6-10. Toxicity was measured by CTCAE v4.0 and responses by modified International Neuroblastoma Response Criteria. Results: Forty-six (23 enrolled on protocol and 23 on compassionate-use basis) heavily prior-treated patients (median age at enrollment: 6.6 years; median number of prior relapses: 2) have received 175 (median 2; range 1-12) cycles to date. At enrollment, 7 patients had HR-NB refractory to induction chemotherapy while 39 had prior relapse. Toxicities included myelosuppression and diarrhea expected with I/T, and pain and hypertension expected with naxitamab. No other > grade 2 related toxicities occurred; treatment was outpatient. Early responses, assessed after 2 cycles, were documented in 18 (39%) patients and were complete (n = 9), partial (n = 8), and mixed (n = 1); 13 patients had stable disease. Responses were achieved in refractory (3/7;43%) and PD (15/39;38%) subgroups, in patients who had previously received I/T (12/34;35%) and/or anti-GD2 MoAb (14/36;39%), and in soft tissue (6/22; 27%) MIBG-avid skeletal sites (20/36;56%) and on bone marrow histology (9/12; 75%). Conclusions: High-dose naxitamab-based chemoimmunotherapy is safe and effective against chemoresistant HR-NB. This ongoing phase II study may define a broader role for naxitamab which was recently granted breakthrough designation by the FDA. Clinical trial information: NCT03189706.
The promoting resilience in stress management (PRISM) intervention for parents of children with cancer: A randomized controlled trial.
Authors: Taylor Mallory R. , Bradford Miranda C. , Junkins Courtney C. , Kross Erin K. , Curtis J. Randall , Yi-Frazier Joyce P. , Rosenberg Abby R. 
Published: May 2019

10029 Background: Parents of children with cancer experience significant levels of distress, which may negatively impact surviving patients and family members. Positive psychology interventions have shown promise, but few address the well-being of parents. The objective of this study was to test the efficacy of a resilience intervention, Promoting Resilience in Stress Management-Parent (PRISM-P), among parents of children with cancer. Methods: This study was a phase 2, 1:1:1 RCT. Eligible participants were English-speaking parents of children 2-24 years-old receiving cancer-directed therapy at Seattle Children’s Hospital. PRISM-P is a skills-based program targeting resilience resources. Parents were randomized to usual care (UC), UC plus individual PRISM-P (1:1), or UC plus group PRISM-P (group). Parents completed surveys at baseline and 3 months measuring resilience (primary outcome, 10-item Connor Davidson Resilience Scale (CDRISC)) and other secondary outcomes including stress, social support, and benefit-finding. We performed an intention-to-treat analysis using unadjusted linear mixed-effects modeling to estimate PRISM effects on score change. With n = 25 per arm, we achieved 80% power to detect an effect size (CDRISC change) of 5.1 (Cohen’s d = 0.8) with a type 1 error rate of 0.05. Results: 107 parents enrolled. Of these, 94 (88%) completed baseline surveys and 77 (72%) completed 3 month surveys. Mean (SD) resilience score change in UC, 1:1 and group arms was -2 (3.5), 1 (5.3) and -1 (5.0), respectively. In mixed models, the estimated 1:1 PRISM benefit for resilience score change vs. UC was +2.8 (95% CI: 0.5,5.2, p = 0.02) while there was no evidence of a group benefit (beta 0.4, 95% CI: -2.1, 2.8, p = 0.76.). Models for secondary outcome score change found a PRISM advantage for benefit finding, where the 1:1 vs. UC difference was +0.5 (95% CI: 0.2, 0.8, p < 0.01) and the group vs. UC difference was +0.4 (0.0, 0.7, p = 0.05). Conclusions: Compared to UC, 1:1 PRISM-P was associated with improved resilience change, and both PRISM-P intervention arms were associated with greater benefit-finding. Future studies will explore larger scale efficacy and alternative delivery design. Clinical trial information: NCT02998086.
Poverty and survival in targeted immunotherapy clinical trials.
Authors: Bona Kira O'Neil , Li Yimei , Winestone Lena , Getz Kelly D. , Huang Yuan-Shung , Fisher Brian , Desai Ami Vijay , Richardson Troy , Hall Matt , Naranjo Arlene , Henderson Tara O. , Aplenc Richard , Bagatell Rochelle 
Published: May 2019

10034 Background: Whether precision medicine trials—which tailor medical treatment to a patient’s individual tumor characteristics—should include poverty as an outcome predictor is unknown. In Children’s Oncology Group (COG) trials ANBL0032 and ANBL0931, targeted immunotherapy resulted in the single greatest survival improvement for high-risk neuroblastoma (HR NBL) in decades. We utilized the ANBL0032/ANBL0931 cohort to investigate the hypothesis that poverty independently predicts inferior survival outcomes in targeted immunotherapy trials. Methods: We retrospectively analyzed outcome data for patients uniformly treated with immunotherapy on ANBL0032/ANBL0931 at Pediatric Health Information System-associated hospitals. Poverty exposure was a priori characterized at the neighborhood and household level. Neighborhood poverty was defined as living in a ZIP code with a median household income in the cohort’s lowest quartile ( < $35,916 vs. $46,324-$60,947). Household poverty was defined as Medicaid insurance (vs. private/other). Multivariable Cox regression evaluated associations between poverty exposures and event-free (EFS) and overall (OS) survival adjusting for demographic, clinical and tumor variables (ethnicity, hospital clustering, disease response, disease stage, MYCN status). Post-hoc analyses examined the joint effect of neighborhood and household poverty using a common reference. Results: Among 371 patients, 25% lived in high-poverty ZIP codes; 35% were Medicaid-insured; 14% were exposed to both. Only Medicaid was independently associated with inferior EFS (hazard ratio (HR) 1.90, 95% confidence interval (CI) 1.28-2.84, p = 0.001). OS was inferior in children with Medicaid (HR 2.79, 95%CI 1.63-4.79, p < 0.001) and less than complete disease response (HR 1.89, 95%CI 1.004-3.56, p = 0.049). In post-hoc analysis, joint poverty exposure had a more pronounced impact on EFS (HR 2.21, 95%CI 1.48 to 3.30, p < 0.001) and OS (HR 3.7, 95%CI 2.08-6.59, p < 0.001) than Medicaid alone. No other covariate remained significantly associated with survival. Conclusions: Poverty independently predicted inferior EFS and OS among a cohort of neuroblastoma patients uniformly treated with targeted immunotherapy. For the full potential of precision medicine to be realized, future clinical trials should systematically investigate and intervene upon poverty as a significant predictor of survival.
First experience of LOXO-292 in the management of pediatric patients with RET-altered cancers.
Authors: Gerdemann Ulrike , Lee Young Ah , Henry Dahlia , Smith Steven , Ortiz Michael Vincent , Rothenberg Stephen M. , Govinda Raju Sandya , Cox Michael Craig , Glade Bender Julia Lynne , Pappo Alberto S. , Frazier A. Lindsay , Kang Hyoung Jin 
Published: May 2019

10045 Background: Genomic alterations of RET kinase, including chromosomal fusions and activating point mutations, have been identified as oncogenic drivers in pediatric and adult cancers. Multikinase inhibitors have modest activity against RET-altered cancers and are associated with significant toxicity. LOXO-292 is a potent, ATP-competitive, small molecule RET inhibitor with high selectivity for RET, preclinical activity in the brain and excellent pharmacokinetic properties. In an ongoing phase 1/2 study of adult and adolescent patients with advanced RET-altered cancers, LOXO-292 demonstrated marked antitumor activity and was well tolerated. Methods: Pediatric patients with RET-altered cancers who were unable to access LOXO-292 through a phase 1/2 clinical trial were enrolled using FDA-allowed, IRB-approved single patient protocols . Patients received LOXO-292 (capsule/liquid formulation) orally, continuously, at a starting dose of 90 mg/m2 BID. Response was assessed locally by investigators. Results: As of January 31, 2019, 4 female patients aged 13 months–8 years were enrolled from the Republic of Korea (papillary thyroid cancer, n = 1) and the USA (infantile myofibroma/hemangiopericytoma, n = 1; congenital mesoblastic nephroma/infantile fibrosarcoma, n = 1; lipofibromatosis, n = 1). All tumors harbored RET gene fusions (5′ partners: CCDC6, MYH10, SPECC1L, and NCOA4, respectively), detected by next-generation sequencing. Previous therapies included surgery/iodine 131 (n = 1); vandetanib (n = 1); surgery/chemotherapy (n = 1); 1 patient was treatment-naïve. Duration of treatment ranged from 3–120 days and all patients remain on treatment. There were no dose modifications or discontinuations due to adverse events. There were no treatment-related adverse events ≥ grade 3. Two patients who were evaluable for response had partial responses (both ongoing, 1 confirmed, 1 pending confirmation). Conclusions: These preliminary data from a real-world setting suggest that LOXO-292 is effective and safe in pediatric patients whose tumors harbor RET gene fusions.
Capivasertib (AZD5363) plus fulvestrant versus placebo plus fulvestrant after relapse or progression on an aromatase inhibitor in metastatic ER-positive breast cancer (FAKTION): A randomized, double-blind, placebo-controlled, phase II trial.
Authors: Jones Robert Hugh , Carucci Margherita , Casbard Angela Claire , Butler Rachel , Alchami Fouad , Bale Catherine Jane , Bezecny Pavel , Joffe Johnathan , Moon Sarah , Twelves Chris , Venkitaraman Ramachandran , Waters Simon , Howell Sacha Jon 
Published: May 2019

1005 Background: The PI3K/AKT signalling pathway is frequently activated in patients (pts) with estrogen receptor (ER) positive breast cancer (ER+BC) and has been implicated in endocrine therapy resistance. Capivasertib (AZD5363) is a highly-selective, oral, small molecule AKT inhibitor. The FAKTION trial investigated the addition of capivasertib to fulvestrant for postmenopausal women with ER+ and HER2 negative BC after relapse or disease progression on an aromatase inhibitor (AI). Methods: FAKTION is an investigator-led, double-blind, placebo-controlled, randomised phase II trial. Patients were recruited from 21 UK sites and randomly assigned (1:1) to fulvestrant 500mg (day 1 and 15 of cycle 1 and day 1 only of subsequent 28 day cycles) with either capivasertib 400mg bd or placebo (4 days on/3 days off starting C1D15) until disease progression, unacceptable toxicity or withdrawal of consent. Allocation was balanced by minimisation according to PIK3CA mutation and PTEN expression status, measurable/non-measurable disease, and primary/secondary endocrine resistance. The primary endpoint was progression-free survival (PFS). The trial had 90% power to detect a hazard ratio of 0.65 at the one-sided 20% significance level. Secondary endpoints included overall survival (OS), objective response and clinical benefit rates, safety and the effect of PI3K/Akt pathway activation on PFS. Results: Between Mar 2015 and Mar 2018, 140 pts were randomised to fulvestrant + capivasertib (n = 69) or fulvestrant + placebo (n = 71). In the Intention-to-treat analysis, after 112 events, median PFS was 10.3 months (m) for capivasertib compared to 4.8m for placebo (Hazard Ratio (HR) 0.57; 95% CI: 0.39 to 0.84; one-sided p = 0.0017; two-sided 0.0035). Fifty-two deaths were reported. Median OS was 26.0m for capivasertib compared to 20.0m for placebo, with a survival difference starting to emerge after 12m (HR = 0.59; 95% CI: 0.34 to 1.05; two-sided p = 0.071). Toxicity data and subgroup analyses including relative capivasertib benefit by PI3K/Akt pathway alteration will be presented at the conference. Conclusions: The trial met its primary endpoint. Addition of capivasertib to fulvestrant for patients with endocrine resistant advanced breast cancer resulted in significantly longer PFS and an improvement in OS. The FAKTION results warrant further investigation of capivasertib for the treatment of ER positive breast cancer. Clinical trial information: NCT01992952.
New insights in cisplatin and radiation-induced ototoxicity: A French Childhood Cancer Survivors Study (FCCSS).
Authors: Fresneau Brice , Santos Felicia , Allodji Rodrigue , Fayech Chiraz , Bolle Stephanie , Vu-Bezin Giao , Souchard Vincent , Haddy Nadia , Doz Francois P. , Berchery Delphine , Lemire Pierre , Journy Neige , Veres Cristina , Brugieres Laurence , Valteau-Couanet Dominique , Diallo Ibrahima , Dufour Christelle , De Vathaire Florent 
Published: May 2019

10061 Background: Platinum chemotherapy (CT) and cranial radiotherapy (RT) are risk factors of ototoxicity. Effects of RT dose at inner ear and of other CT were investigated. Methods: Of 7670 5-year childhood cancer survivors from the FCCSS treated before 20 years of age in 1942-2000 for solid cancer or lymphoma, 5243 with ototoxicity long-term follow-up data were included. Severe ototoxicity, defined as the need of hearing aids or Brock grade 3-4 hearing loss, was identified from self-administrated questionnaires, clinical visits and cohort linkage with the French Hospital Database and health insurance information system (SNIIRAM). The mean RT dose at inner ear was estimated using home-made software. Multivariable Cox models adjusted for gender, age at diagnosis, time period and social deprivation index was used to identify risk factors for severe ototoxicity. Results: After a mean follow-up of 30 years, 199 cases of severe ototoxicity were identified. Cumulative incidences at 30 and 50 years of age (30,50y-CumInc) were, 2.8% (95%CI = 2.4-3.3) and 5.5% (4.6-6.5), respectively. Mean RT dose at inner ear (Hazard Ratio HR = 1.6 (95%CI = 1.0-2.5), 4.5 (2.7-7.2), 5.7 (3.0-10.8) and 14.0 (9.2-21.2) for 0- < 5, 5- < 30, 30- < 40 and ≥40 Gy), as well as cisplatin (HR = 2.8, 95%CI = 1.9-4.0), melphalan (HR = 3.3, 95%CI = 1.9-5.7) and busulfan exposure (HR = 2.6, 95%CI = 1.6-4.4) were significantly associated with severe ototoxicity. Concerning melphalan (n = 199/5243 exposed), almost all cases were identified in neuroblostma patients (NBL), who also received cisplatin 200mg/m²/cycle (26/92 NBL, 30y-CumInc = 36.4% (95%CI = 25.9-48.4), vs. 3/107 non-NBL, 30y-CumInc = 1.6% (0.4-5.6)). Concerning busulfan (n = 131/5243 exposed), all cases were identified in NBL (n = 16/63, all treated with melphalan and cisplatin) and brain tumors (n = 13/28, all with RT at inner ear ≥5Gy). The 30y-CumInc in patients with RT at inner ear ≥5Gy was 7.4% (95%CI = 5.7-9.6) and 39.8% (22.5-60.0) respectively with and without busulfan. Conclusions: RT at inner ear has significant deleterious impact on audition, with cumulative incidence still worsening > 30years after RT, and with likely potentiation by busulfan. The deleterious effect of melphalan was related to previous treatment with cisplatin, either by interaction between these drugs, or by the high cisplatin dose by cycle used in NBL.
Biomarker analyses from JAVELIN Renal 101: Avelumab + axitinib (A+Ax) versus sunitinib (S) in advanced renal cell carcinoma (aRCC).
Authors: Choueiri Toni K. , Albiges Laurence , Haanen John B. A. G. , Larkin James M.G. , Uemura Motohide , Pal Sumanta K. , Gravis Gwenaelle , Campbell Matthew T , Penkov Konstantin , Lee Jae-Lyun , Ching Keith A. , Mu Xinmeng Jasmine , Wang Xiao , Zhang Weidong , Wang Jing , Chudnovsky Aleksander , di Pietro Alessandra , Robbins Paul B. , Motzer Robert J. 
Published: May 2019

101 Background: The phase 3 JAVELIN Renal 101 trial in previously untreated patients (pts) with aRCC demonstrated a progression-free survival (PFS) benefit and higher objective response rate with A+Ax vs S (Motzer, ESMO 2018; LBA6_PR). Here, we report outcomes from biomarker analyses of baseline tumor samples. Methods: We correlated efficacy with the results of molecular analyses of tissue samples from all 886 pts enrolled in JAVELIN Renal 101. Nephrectomy or tumor samples were characterized by immunohistochemistry (CD8 and PD-L1), whole-exome sequencing (WES), and RNAseq. WES and RNAseq were used to examine somatic mutations and analyze relevant gene expression signatures (GES) in relation to clinical outcomes. GES analyses included published and de novo signatures: effector T cell (Teff), angiogenesis (angio),T cell-inflamed (Tinf), and a novel immune-related signature incorporating pathway indicators for T- and NK-cell activation and IFNγ signaling, among others. Results: PD-L1 expression (≥1% immune cells) was associated with the longest PFS in the A+Ax arm and the shortest in the S arm (HR, 0.63; 95% CI, 0.49, 0.81). Significant treatment arm–specific differences in PFS were observed relative to wildtype when mutations in genes such as CD1631L, PTEN, or DNMT1 were present. Tumor mutational burden did not distinguish pts with respect to PFS. High-angio GES was associated with significantly improved PFS in the S arm but did not differentiate PFS in the A+Ax arm. In the low-angio subset, A+Ax improved PFS vs S. Pts with high Teff and Tinf in the A+Ax arm had longer PFS vs the S arm. In the A+Ax arm, PFS was enhanced in patients with immune GES–positive tumors vs those in the negative group (HR, 0.63; 95% CI, 0.46, 0.86; 2-sided p = 0.004), as well as in an independent dataset (JAVELIN Renal 100; Choueiri, Lancet Oncol, 2018) (HR, 0.46; 95% CI, 0.20, 1.05; 2-sided p = 0.064). Updated efficacy, including overall survival, will be presented. Conclusions: These findings define molecular features that differentiate therapy-specific outcomes in first-line aRCC and may inform personalized therapy strategies for pts with aRCC. Funding: Pfizer and Merck KGaA. Clinical trial information: NCT02684006.
Genomic markers of early progression on fulvestrant with or without palbociclib for ER+ advanced breast cancer in the PALOMA-3 trial.
Authors: O'Leary Ben , Cutts Ros , Huang Xin , Hrebien Sarah , Liu Yuan , Garcia-Murillas Isaac , Andre Fabrice , Loi Sherene , Loibl Sibylle , Cristofanilli Massimo , Bartlett Cynthia Huang , Turner Nicholas C. 
Published: May 2019

1010 Background: Markers of early progression on endocrine therapy in combination with CDK4/6 inhibitors remain limited despite the key role of these combinations in treating of ER+ advanced breast cancer (ABC). We investigated genomic aberrations in patients treated with fulvestrant, with and without palbociclib, with a circulating tumor DNA analysis of baseline plasma in the PALOMA-3 trial. Methods: PALOMA-3 was a phase III trial that randomized 521 patients with ER+/HER2- ABC 2:1 to palbociclib plus fulvestrant (P+F) or placebo plus fulvestrant (F). Using baseline plasma samples, somatic mutations were assessed with a 17 gene panel. Copy number aberrations (CNA) were characterized with a 14 gene panel including ~800 SNPs in 8 commonly altered regions for estimation of tumor purity, the percentage of plasma DNA that was derived from tumor cells. Results for mutations and CNAs were available in 310 pts (203 P+F, 107 F) and were associated with clinical characteristics and progression free survival (PFS) using univariable and multivariable Cox proportional hazards models, including tumor purity and treatment as variables. Results: In the multivariable analysis of the whole cohort, higher baseline tumor purity in plasma was associated with worse PFS (HR 1.20, 95% CI 1.09 – 1.32, p = 0.0001, HR per 10% increase in purity). Baseline TP53 mutation was also associated with shorter PFS (HR 1.84, 95%CI 1.27 – 2.65, p = 0.0011), as was baseline FGFR1 amplification (HR 2.91, 95%CI 1.61 – 5.25, p = 0.0004). PIK3CA and ESR1 mutations had no significant association with PFS in the multivariable model. Palbociclib treatment effect was comparable with the overall trial result (HR 0.43, 95%CI 0.32 - 0.57, p < 0.0001). TP53 mutations were significantly associated with visceral (q = 0.046) and soft tissue/LN metastases (q = 0.042) and the number of disease sites (q = 0.0086) after correction for multiple testing. Conclusions: TP53 mutation, FGFR1 amplification , and tumor purity in plasma identified patients at risk of early progression In PALOMA-3. If validated these results could inform future clinical trials of CDK4/6 inhibitors combinations.
Pembrolizumab (P) in patients (pts) with metastatic breast cancer (MBC) with high tumor mutational burden (HTMB): Results from the Targeted Agent and Profiling Utilization Registry (TAPUR) Study.
Authors: Alva Ajjai Shivaram , Mangat Pam K. , Garrett-Mayer Elizabeth , Halabi Susan , Alvarez Ricardo H. , Calfa Carmen Julia , Khalil Maged F. , Ahn Eugene R , Cannon Timothy Lewis , Crilley Pamela A. , Fisher Julie Gottlieb , Haslem Derrick S. , Shrestha Sagun , Antonelli Kaitlyn R. , Butler Nicole L. , Warren Sasha L. , Rygiel Andrew Lawrence , Ranasinghe Shamika , Bruinooge Suanna S. , Schilsky Richard L. 
Published: May 2019

1014 Background: TAPUR is a phase II basket study evaluating the anti-tumor activity of commercially available targeted agents in pts with advanced cancers with specific genomic alterations. P is an immune checkpoint inhibitor and HTMB is an emerging predictive biomarker for checkpoint inhibitor therapy. Results in a cohort of MBC pts with HTMB treated with P are reported. Methods: Eligible pts had advanced cancer, no standard treatment options, ECOG PS 0-1, measurable disease and acceptable organ function. Genomic testing was performed using commercially available tests selected by sites. Pts matched to P had HTMB defined as ≥9 mutations/megabase (Muts/Mb) by a FoundationOne test (n=20) or approved by the TAPUR Molecular Tumor Board for other tests (n=8). A Simon two-stage design was used to test a null rate of 15% vs. 35% (power = 0.85; α = 0.10). If ≥2 of 10 pts in stage 1 have disease control (DC) (objective response (OR) or stable disease at 16 weeks (wks) (SD16+)), an additional 18 pts are enrolled. If ≥7 of 28 pts have DC, the drug is considered worthy of further study. Secondary endpoints are progression-free survival (PFS), overall survival (OS) and safety. Results: Twenty-eight female MBC pts were enrolled from October 2016 to July 2018. Pts received P at 2 mg/kg (n=8) or 200 mg (n=20) IV over 30 minutes, every 3 wks. HTMB ranged from 9 to 37 Muts/Mb. Demographics and outcomes are summarized in Table (N=28). No relationship was observed between #Muts/Mb and PFS or OS. Two grade 3 AEs (weight loss and hypoalbuminemia) and 1 grade 2 SAE (urinary tract infection) were reported as at least possibly related to P. Conclusions: P demonstrated anti-tumor activity in heavily pre-treated MBC pts with HTMB . Additional study of P is warranted in MBC pts with HTMB. Clinical trial information: NCT02693535. [Table: see text]