bluuebunny/crossref_metadata_2025_split huggingface dataset:
A phase I/II study of lenvatinib (LEN) plus everolimus (EVE) in recurrent and refractory pediatric solid tumors, including CNS tumors.
Authors: Dela Cruz Filemon S. , Fox Elizabeth , Muscal Jodi Ann , Kirov Ivan , Geller James I. , DuBois Steven G. , Kim AeRang , Croop James , Laetsch Theodore Willis , Minard Charles G. , Liu Xiaowei , Weigel Brenda , Okpara Chinyere E. , Huang Jie , Dutta Lea , Aluri Jagadeesh , Glade Bender Julia Lynne 
Published: May 2020

10527 Background: Proangiogenic signaling pathways cooperate with mTOR-mediated regulation of cell growth and maintenance to drive development of many pediatric cancers. We report results of the phase 1 dose escalation for LEN + EVE in pediatric patients (pts) with recurrent solid and CNS tumors conducted by Children’s Oncology Group. Methods: Dose escalation was conducted using a rolling-6 design. Pts received LEN + EVE orally once daily in continuous 28-day cycles. Dose determination was based on toxicity (CTCAE v4.03) during cycle 1. Pharmacokinetics (PK) of plasma LEN and EVE were monitored. Results: 17 pts were enrolled (9 male; 8 female). Median (range) age was 10 (3–21) years; 8 pts had CNS tumors. 17 were evaluable for dose-limiting toxicity (DLT). Enrollment started at dose level 1 (DL 1; LEN 11 mg/m2 + EVE 3 mg/m2) and, after treatment of 3 pts, was initially de-escalated to DL –1 (LEN 8 mg/m2 + EVE 3 mg/m2) due to DLT of proteinuria in 1 pt and self-resolving headache in another who, on review, did not meet the definition of DLT. No pts enrolled at DL –1 (n = 5) experienced DLT. Overall, DLTs were observed in 2 of the first 6 patients enrolled at DL 1: the initial pt with proteinuria and 1 more pt with hypertriglyceridemia and hypercholesteremia. Because 2 pts had reversible DLT of different categories not related to Cmax or AUC, the DL 1 cohort was expanded to enroll an additional 6 pts, none of whom had DLT. Thus, 2/12 pts experienced DLT at DL 1. Overall, most common treatment-emergent adverse events (TEAEs; ≥ 50% of pts) were diarrhea, hypertension, hypertriglyceridemia, vomiting, abdominal pain, headache, and hypothyroidism. 47% of pts had ≥ 1 treatment-related TEAE grade ≥ 3; the most frequent was proteinuria (n = 2). On cycle 1 day 15, mean (SD) Cmax (ng/mL) for LEN at DL –1 and DL 1, respectively, was 314 (150) and 359 (270), and mean (SD) AUC0-8h (hr•ng/mL) for LEN was 1570 (935) and 1780 (1100). Taking all toxicities and PK into account, no further dose escalation was recommended. Best overall response in pts with measurable disease was 2/11 stable disease, 7/11 progressive disease, and 2/11 not evaluable. Conclusions: The recommended phase 2 dose of LEN + EVE in children with solid and CNS tumors was LEN 11 mg/m2 + EVE 3 mg/m2, with maximum daily doses capped at 18 mg and 5 mg, respectively. The toxicity profile was no more than additive to single-agent therapy. PK exposure was comparable with children on single-agent LEN and to adults receiving LEN + EVE. Enrollment to the phase 2 portion (Ewing sarcoma, high-grade glioma, and rhabdomyosarcoma strata) is ongoing. Clinical trial information: NCT03245151.
Change in cardiac function with CPX-351 in relapsed pediatric AML: A Children’s Oncology Group (COG) report from AAML1421.
Authors: Leger Kasey J. , Absalon Michael , Demissei Biniyam G , Gerbing Robert B , Alonzo Todd Allen , Hirsch Betsy A , Pollard Jessica Anne , Razzouk Bassem I. , Kolb E. Anders , Aplenc Richard , Ky Bonnie , Cooper Todd Michael 
Published: May 2020

10532 Background: Anthracyclines (AC) are highly effective in treating acute myeloid leukemia (AML), but limited by cardiotoxicity (CTX). CPX-351, a liposomal preparation of daunorubicin (DNR) and cytarabine, may provide therapeutic benefit with less CTX. We evaluated acute changes in cardiovascular (CV) function and biomarkers after 1 cycle of CPX-351 in children with relapsed AML within the phase 1/2 study, AAML1421. Methods: Patients (pts) received 135 units/m2/dose of CPX-351 on days 1, 3, and 5. Echocardiograms were centrally quantified at baseline (BL) and day 29 (end of cycle (EOC)). High sensitivity troponin (cTnT) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) were measured at BL and days 5, 8, 15, 22, and 29. Differences between BL and post-CPX-351 echo/biomarker measurements were analyzed using pre-specified Wilcoxon signed rank tests. The relationship between EOC ejection fraction (EF) and clinical variables was assessed using repeated measures linear regression. Results: In 32 included pts, the median AC exposure prior to study entry was 337 mg/m2 DNR equivalents. At baseline, markers of CV function and stress were abnormal (Table). Over 1 cycle, there was a statistically significant decrease in EF and circumferential strain (Table). NT-proBNP and cTnT did not increase significantly over time. In multivariable analysis, only increasing body surface area was significantly associated with lower EOC EF (b:-5.9, 95% CI -10.8,-0.9). Cancer therapy–related cardiac dysfunction, defined as ≥10% decline in EF to < 50%, occurred in 6/32 pts at EOC. Conclusions: In this single arm study of AC pre-treated children, baseline abnormalities in CV function were common. CPX-351 was associated with a statistically significant decline in CV function without a rise in cardiac biomarkers. Absent a comparator population, it is not known how these cardiac trends compare to non-liposomal AC or non-AC salvage regimens. The COG AAML1831 trial will determine if CPX-351 offers cardioprotection compared to standard AC in pts with de novo AML. Clinical trial information: NCT02642965. [Table: see text]
Risk factors in the HR-NBL-1/SIOPEN study in patients receiving dinutuximab beta (DB) based immunotherapy.
Authors: Ladenstein Ruth Lydia , Poetschger Ulrike , Valteau-Couanet Dominique , Gray Juliet , Luksch Roberto , Balwierz Walentyna , Castel Victoria , Ash Shifra , Beck Popovic Maja , Laureys Genevieve , Chan Godfrey Chi-Fung , Ruud Ellen , Vettenranta Kim , Owens Cormac , Schroeder Henrik , Ambros Peter F , Sarnacki Sabine , Boterberg Tom , Lode Holger N. 
Published: May 2020

10536 Background: We previously developed a risk factor model in HR-NBL1/SIOPEN patients treated without DB including age, LDH and metastatic site index (MSI). We tested if this score (Morgenstern, PBC 2018) would provide meaningful information in DB treated HR-NBL1/SIOPEN patients. Methods: High-risk patients (stage 4 ≥1yr.; stage 4 < 1yr. with MYCN amplification (MNA); stage 2, 3, 0-21y with MNA) received intensive induction, surgery, high dose therapy (HDT) and local radiotherapy (21Gy). Patients with a ≤9 months intervall till HDT/SCT, ≥ partial response prior and no progression received up to 5 cycles of 100mg/m2 DB: as short-term (STI: 5 days) or long-term infusion (LTI: 10 days ) ± 6 (STI) or 3 (LTI) x 106 IU/m2 subcutaneous interleukin 2 (scIL2 over 2 x 5 days) followed by 2 weeks of 160mg/m2 oral isotretinoin. Results: DB was used in 1018 patients [512 males; 89% Stage, 1% Stage 4s, 10% loc. MNA; 2.8 yrs median age at diagnosis] in 18 countries. STI was used in 61% patients, LTI in 39% and DB without scIL2 in 62% patients. 2-yrs. event-free (EFS)/overall survival (OS) was 0.65±0.02/0.78±0.01 and 5-yrs. EFS/OS of 0.56±0.02/0.63±0.02. 891/1018 patients were evaluable for risk factor analysis. EFS multivariate analysis included age, MSI, LDH ≥1250U/L, HDT typ, response prior DB, DB schedule and use of scIL2: only age > 1.5yrs.(p = 0.002) and MSI > 1 (p = 0.002) had independent prognostic prediction. If restricted to stage 4 only, LDH ≥1250U/L was also an independent factor (p = 0.049). Points were allocated in proportion to the log-cumulative hazard ratio (cHR): cHR for LDH > 1250U/L was 1.33 (score of 1), cHR for age > 5 years and metastatic site involvement (MSI) > 1 were 1.79 and 1.86 (scores of 2). Using the score (0 to 5) relevant risk groups can be identified: 5-yrs. EFS/OS for scores 0&1 are 0.80±0.06&0.77±0.04, score 2/3 are 0.58±0.03&0.57±0.04 and for scores 4/5 are 0.50±0.06&0.43±0.08. Conclusions: The score adds value in DB treatment groups as it differentiates prognostic subgroups facilitating decision making for future DB add on treatments. Clinical trial information: NCT01704716.
Lung cancer as a subsequent neoplasm: A report from the Childhood Cancer Survivor Study (CCSS).
Authors: Ghosh Taumoha , Chen Yan , Dietz Andrew C , Armstrong Gregory T. , Howell Rebecca M. , Mulrooney Daniel A. , Turcotte Lucie Marie , Yuan Yan , Yasui Yutaka , Neglia Joseph Philip 
Published: May 2020

10551 Background: Lung cancer has been reported as a subsequent neoplasm (SN) in childhood cancer survivors. We aimed to assess the prevalence of and risk factors for lung cancer in the CCSS. Methods: Among 25,654 five-year survivors participating in the CCSS, lung cancer was self-reported and then confirmed by pathologic record review. Cancer treatment exposures were evaluated including chemotherapy and chest radiation by field size (none, small, large) and in a dose group (0-10 Gy, 10-30 Gy, 30-40 Gy, and > 40 Gy). Standardized incidence ratios (SIR) were calculated using rates from the Surveillance, Epidemiology, and End Results program. Hazard ratios (HR) were estimated for demographic and treatment variables using Cox proportional-hazards models. Results: Forty-two survivors developed subsequent malignant lung cancer (SIR 4.0, 95% CI 2.9-5.4), including 25 carcinomas, 7 mesotheliomas and 10 others. Two additional benign neoplasms were also identified. The cumulative incidence of lung SNs was 0.18% at 30 years (95% CI 0.10-0.25). Median time from primary diagnosis was 28 years (range 11-46); median age at diagnosis was 45 years of age (range 15-65). A multivariable model, including all covariates with a p-value < 0.2 in univariate analysis, showed significant associations between lung cancer and older age at diagnosis (HR 10.5, 95% CI 1.4-76.4, for 15-21 years vs. 0-4 years), as well as with primary diagnoses (relative to leukemia, HR 8.7, 95% CI 1.1-66.0, for Hodgkin lymphoma; HR 20.7, 95% CI 1.3-331.0 for neuroblastoma; and HR 21.4, 95% CI 2.3-202.7, for bone cancer). In a treatment model, maximum chest radiation dose (HR 4.1, 95% CI 1.4-11.7, for 30-40 Gy; and HR 8.1, 95% CI 3.0-22.2, for > 40 Gy, relative to 0-10Gy), but not sex, smoking status, or chemotherapy exposures, was associated with lung cancer. Notably, six survivors who developed lung cancer received no radiation and of these, five had a primary bone cancer. At the end of follow-up, 65.9% of survivors with lung cancer were deceased vs. 14.1% of survivors without lung cancer ( p < 0.001). Conclusions: Survivors of childhood cancer are at increased risk for developing lung cancer associated with exposure to high doses of chest radiotherapy. To our knowledge, this is the first study to describe associations with neuroblastoma and bone cancer. Future studies to understand additional treatment-related risk factors beyond chest radiotherapy dose are needed.
The efficacy of first-line chemotherapy in endocrine-resistant hormone receptor-positive (HR+), human epidermal growth factor receptor 2- negative (HER2-) metastatic breast cancer (MBC).
Authors: Chainitikun Sudpreeda , Long James , Rodriguez-Bautista Ruben , Iwase Toshiaki , Tripathy Debu , Fujii Takeo , Ueno Naoto T. 
Published: May 2020

1056 Background: Combinations of endocrine therapy (ET) and targeted therapy (CDK4/6 or mTOR inhibitors) are standard of care for HR+/HER2- MBC. When ET is not effective, chemotherapy is commonly used. However, clinical outcomes of chemotherapy in the endocrine-resistant setting are limited. We hypothesized that clinicopathological baseline and prior ET factors determine chemotherapy’s efficacy. We sought to identify predictive factors and the compare efficacies of chemotherapy agents in endocrine-resistant MBC. Methods: We conducted a retrospective study of patients with HR+/HER2- MBC who received chemotherapy after progression on ET with or without targeted therapy at MD Anderson Cancer Center from 1999-2017. We collected baseline clinicopathological and all treatment data. The primary endpoint was time to treatment failure (TTF) of first-line chemotherapy for MBC. We performed univariate and multivariate analyses using the Cox proportional hazard model. Kaplan-Meier methods were used to analyze TTF. Results: In the 1,258 patients analyzed, the mean age was 55.3 years (range 21-91). Forty-five patients (3.6%) had inflammatory breast cancer (IBC). Three hundred ninety patients (31%) received previous targeted therapy: 264 with CDK4/6 inhibitor, 205 with mTOR inhibitor, and 79 with both. The most frequent chemotherapy agents were capecitabine (48.9%) and taxanes (paclitaxel, nab-paclitaxel, or docetaxel; 28.6%). After adjustment for all factors in a multivariate model, IBC and prior exposure to a CDK4/6 inhibitor were significantly associated with shorter TTF. Previous treatment with a CDK4/6 inhibitor had the strongest negative effect on chemotherapy TTF regardless of ET duration (adjusted hazard ratio [HR] 1.84; 95%CI 1.49-2.27; p < 0.001). Capecitabine had significantly longer median TTF than taxanes regardless of whether patients had prior exposure to taxanes in (neo)adjuvant setting (6.1 vs 4.9 months; HR 0.64; 95%CI 0.55-0.75; p < 0.001). Conversely, the median TTF for taxanes was shorter in patients who received prior (neo)adjuvant taxanes than in those who did not (4.5 vs 5.1 months). Conclusions: Previous exposure to CDK4/6 inhibitor had a negative predictive effect for the efficacy of chemotherapy. Capecitabine had the best efficacy against endocrine-resistant breast cancer.
Prevalence and characterization of dermatologic adverse events related to alpelisib (BYL719) in breast cancer patients.
Authors: Barrios M.S Dulce M. , Wang Diana G. , Blinder Victoria Susana , Bromberg Jacqueline , Drullinsky Pamela , Funt Samuel Aaron , Jhaveri Komal L. , Lake Diana , Lyons Tomas , Modi Shanu , Razavi Pedram , Sidel Michelle , Traina Tiffany A. , Vahdat Linda T. , Lacouture Mario E. 
Published: May 2020

1063 Background: Rash develops in approximately 50% of breast cancer patients receiving alpelisib, often requiring dose modifications. Herein, we describe the characteristics of alpelisib-related dermatologic adverse events (dAEs). Methods: A single center retrospective analysis was conducted via review of electronic medical records. We collected clinical, laboratory and management data relevant to patients treated with alpelisib for advanced breast cancer under four different randomized clinical trials or post approval by regulatory agencies from 6/1/2013 to 7/31/2019. Type and severity of dAEs was recorded using the Common Terminology Criteria for Adverse Events version 5.0 (CTCAE v5.0). Results: A total of 102 patients (mean age 56 years, range 27-83) receiving alpelisib from 200 to 350 mg daily, most frequently in combination with endocrine therapy (79, 77.5%) were included. We identified 41 (40.2%) patients with all-grade rash [CTCAE grade 1/2 = 22 (21.6%); CTCAE grade 3 = 19, (18.6%)] distributed primarily along the trunk (18, 78%) and developing, on average, within 12.8 +/- 1.5 days of treatment initiation (n = 38). Mean duration of rash was 7.1 +/- 3.8 days; and no grade 4 dAEs were observed. Of 29 patients with documented morphology of alpelisib-related dAEs, the majority (26, 89.7%) had maculopapular rash. Thirteen (68%) of 19 patients with any-grade rash and report of any associated symptoms had pruritus (7, 36%) or burning pain (6, 32%). All-grade dAEs correlated with an increase in serum eosinophils from 2.7% to 4.4% (p < 0.05), and prophylaxis with non-sedating antihistamines (n = 43) was correlated with a reduction of grade 1/2 rash onset (OR 0.39, p = 0.09). Sixteen (84.2%) of 19 patients with grade 3 dAEs had interruption of alpelisib, followed by management with antihistamines, topical and/or systemic corticosteroids. We did not observe rash recurrence in 12 (75%) of these 16 patients who re-initiated therapy; and the majority (9, 56.3%) were re-challenged without a dose reduction. Conclusions: Pruritus and increased blood eosinophils occur with maculopapular rash within the first two weeks of initiating alpelisib and persists for approximately seven days. To reduce onset of grade 1/2 rash, non-sedating antihistamines (i.e. cetirizine) are recommended during the first eight weeks. While grade 3 rash leads to interruption of alpelisib, dermatologic improvement is evident with systemic corticosteroids; and most patients can resume therapy at a maintained or reduced dose upon re-challenge.
Combination of fulvestrant and chemotherapy in ESR1 Y537S mutant breast cancer cells and potential synergy mechanism related to p53 wildtype.
Authors: Ma Wen , Hermida-Prado Francisco , Guarducci Cristina , Feit Avery , Nardone Agostina , Cohen Gabriella , Pan Wenting , Wei Hongliang , Li Nanlin , Brown Myles , Jeseslsohn Rinath 
Published: May 2020

1065 Background: The acquisition of ligand-independent ESR1 mutations during endocrine therapy in metastatic ER+ breast cancer is a common mechanism of resistance to endocrine treatment, particularly aromatase inhibitors, and found in more than 30% of patients with metastatic ER+ breast cancer. Our recent work showed that the ER mutations confer resistance to currently available endocrine treatments while promoting an aberrant ER transcriptional activity that drives metastases. These results underscore the importance of targeting the ESR1 mutations even after the development of endocrine resistance. We hypothesized that during chemotherapy treatment, the ESR1 mutations remain an important driver of tumor growth and metastases and therefore drugs targeting the ESR1 mutation could enhance the efficacy of chemotherapy. In this study we investigated the combination of chemotherapy with the selective estrogen receptor degrader in the presence of WT and mutant ER. Methods: We performed synergy studies testing the combination of fulvestrant with chemotherapy treatments commonly used in ER+ metastatic breast cancer including 5FU (representing capecitabine), adriamycin and paclitaxel using MCF7 and T47D breast cancer cell lines engineered to express doxycycline inducible Y537S-ESR1 mutation. Results: We found that in MCF7 cells the combination of chemotherapy and fulvestrant was synergistic and the synergy was augmented with the induction of the Y537S mutation. In contrast, there was no synergy in T47D cells that harbor a P53 mutation. We confirmed that the synergistic activity of fulvestrant with chemotherapy is dependent on P53 by generating P53 knock-out MCF7 cells using CRISPR-cas9. Additionally, cell cycle and apoptosis analyses showed that the synergistic activity was mainly due to increased effects on G1 arrest rather than apoptosis. Conclusions: Our study indicates that chemotherapy and fulvestrant are synergistic in ER+ breast cancer and the synergy is increased in the presence of the Y537S ESR1 mutation and is dependent on P53 activity. These results support a clinical trial testing the addition of fulvestrant or other novel selective estrogen receptor degraders in patients with metastatic ER+ breast cancer who are starting chemotherapy treatment.
PIK3CA mutation status and progression-free survival in advanced hormone receptor positive (HR+)/ human endocrine receptor negative (HER2–) metastatic breast cancer (mBC): A meta-analysis of published clinical trials.
Authors: Signorovitch James , Andre Fabrice , Wang Ruchuan , Lorenzo Ines , Ridolfi Antonia , Park Jinhee , Fillbrunn Mirko , Dua Akanksha , Rugo Hope S. 
Published: May 2020

1069 Background: Approximately 40% of HR+/HER2- mBC patients harbor PIK3CA mutation. Associations between PIK3CA mutation status and clinical outcomes among patients with HR+/HER2- mBC have been heterogeneous across clinical trials. We synthesized available evidence from clinical trials to estimate the association between PIK3CA status and progression-free survival (PFS) using a meta-analysis adjusting for study design differences. Methods: Randomized clinical trials reporting PFS stratified by PIK3CA status in HR+/HER2- mBC were identified via a systematic literature review. Trial arms receiving PIK3CA targeted therapies were excluded. Median PFS, 6-, 12- and 18-month PFS rates, and data on trial design features were extracted. Associations between PIK3CA status and PFS were estimated adjusting for study follow-up duration, PIK3CA testing method (ctDNA vs tissue ) and study treatment using multi-level random effects meta-regression. Results: The analyzed data included 3,238 patients from 33 study arms across 11 trials ( PIK3CA mutated (MT): 1,386, wild type (WT): 1,852). PIK3CA mutation was overall associated with shorter median PFS (difference [95% CI] (months): -2.15 [-4.14, -0.15]) with substantial heterogeneity across studies ( I2 = 98.34%). The direction of this association was robust to adjustment for study treatment (-1.27 [-2.22, -0.32]). The association was stronger for ctDNA testing (-2.16 [-3.65, -0.66]; N (total patients): 1,876) than for tissue testing (-0.65 [-2.2, 0.91]; N: 998). Findings were similar for 6-month PFS rates (absolute rate difference -9.17% [-14.22, -4.12], N: 3,179; MT: 1,366, WT: 1,813). Associations were directionally consistent but not statistically significant at 12 months (N = 2,487; MT: 1,056, WT: 1,431) and 18 months (N = 1,745; MT: 811, WT: 934), potentially due to the decreasing precision towards the tails of the PFS curves and significant heterogeneity across studies. Conclusions: Pooling evidence across multiple studies, PIK3CA mutation was associated with shorter PFS, especially when ctDNA testing was used. These findings suggest a negative prognostic value of PIK3CA mutation in patients with HR+/HER2- mBC.