Objectives To assess whether late surfactant treatment of extremely low gestational age newborn (ELGAN) infants requiring ventilation at 7–14 days, who often have surfactant deficiency and dysfunction, safely improves survival without bronchopulmonary dysplasia (BPD). Study design ELGAN infants (≤ 28 0/7 weeks) who required mechanical ventilation at 7–14 days were enrolled in a randomized, masked controlled trial at 25 US centers. All infants received inhaled nitric oxide (INO) and either surfactant (calfactant/Infasurf®) or sham instillation every 1–3 days to a maximum of 5 doses while intubated. The primary outcome was survival at 36 weeks postmenstrual age (PMA) without BPD, evaluated by physiologic oxygen/flow reduction. Results Between January 2010 and September 2013, 511 infants were enrolled. There were no differences between treatment groups in mean birth weight (701±164 g), gestational age (25.2±1.2 weeks), percentage <26 weeks (70.6%), race, sex, severity of lung disease at enrollment, or co-morbidities of prematurity. Survival without BPD was not different between treated vs. controls at 36 weeks PMA (31.3% vs. 31.7%; relative benefit 0.98 (95% CI: 0.75, 1.28 p=0.89) or 40 weeks (58.7% vs. 54.1%; relative benefit 1.08:0.92, 1.27 p=0.33). There were no differences between groups in serious adverse events, co-morbidities of prematurity, nor in the severity of lung disease to 36 weeks. Conclusions Late treatment with up to 5 doses of surfactant in ventilated premature infants receiving iNO was well tolerated but did not improve survival without BPD at 36 or 40 weeks. Pulmonary and neurodevelopmental assessments are ongoing.
This study provides preliminary information that eltrombopag does increase platelets in patients receiving chemotherapy for advanced solid tumors. Further investigation is needed to identify the optimal dose(s) and schedule of eltrombopag in patients receiving myelosuppressive chemotherapy.
PURPOSE Tissue-based comprehensive genomic profiling (CGP) is increasingly used for treatment selection in patients with advanced cancer; however, tissue availability may limit widespread implementation. Here, we established real-world CGP tissue availability and assessed CGP performance on consecutively received samples. MATERIALS AND METHODS We conducted a post hoc, nonprespecified analysis of 32,048 consecutive tumor tissue samples received for StrataNGS, a multiplex polymerase chain reaction (PCR)–based comprehensive genomic profiling (PCR-CGP) test, as part of an ongoing observational trial ( NCT03061305 ). Sample characteristics and PCR-CGP performance were assessed across all tested samples, including exception samples not meeting minimum input quality control (QC) requirements (< 20% tumor content [TC], < 2 mm2 tumor surface area [TSA], DNA or RNA yield < 1 ng/µL, or specimen age > 5 years). Tests reporting ≥ 1 prioritized alteration or meeting TC and sequencing QC were considered successful. For prostate carcinoma and lung adenocarcinoma, tests reporting ≥ 1 actionable or informative alteration or meeting TC and sequencing QC were considered actionable. RESULTS Among 31,165 (97.2%) samples where PCR-CGP was attempted, 10.7% had < 20% TC and 59.2% were small (< 25 mm2 tumor surface area). Of 31,101 samples evaluable for input requirements, 8,089 (26.0%) were exceptions not meeting requirements. However, 94.2% of the 31,101 tested samples were successfully reported, including 80.5% of exception samples. Positive predictive value of PCR-CGP for ERBB2 amplification in exceptions and/or sequencing QC-failure breast cancer samples was 96.7%. Importantly, 84.0% of tested prostate carcinomas and 87.9% of lung adenocarcinomas yielded results informing treatment selection. CONCLUSION Most real-world tissue samples from patients with advanced cancer desiring CGP are limited, requiring optimized CGP approaches to produce meaningful results. An optimized PCR-CGP test, coupled with an inclusive exception testing policy, delivered reportable results for > 94% of samples, potentially expanding the proportion of CGP-testable patients and impact of biomarker-guided therapies.
Background: Neratinib is an irreversible pan-HER tyrosine kinase inhibitor. Results from the randomized, placebo-controlled, Phase III ExteNET study demonstrated that neratinib significantly improves 24-month iDFS in patients (pts) with trastuzumab-treated early-stage HER2+ breast cancer (HR 0.67; 95% CI 0.50–0.91; p=0.009) [Chan et al. Lancet Oncol 2016]. In ExteNET, loperamide prophylaxis was not mandated, and diarrhea was the most commonly observed toxicity (grade 3, 39.8%). To reduce neratinib-associated diarrhea, high-dose loperamide prophylaxis given with the first 1–2 cycles of neratinib has been incorporated into all neratinib clinical trials; available data suggest that loperamide prophylaxis reduces the incidence and median cumulative duration of higher-grade neratinib-related diarrhea. CONTROL is an international, open-label, sequential cohort, phase II study investigating the effects of prophylaxis with loperamide ± the long-acting corticosteroid budesonide or bile acid sequestrant colestipol on neratinib-associated diarrhea. We present updated data from this study. Methods: Pts with stage 1–3c HER2+ breast cancer who completed trastuzumab-based adjuvant therapy within 1 year were eligible. All pts received oral neratinib 240 mg once daily for 1 year + oral loperamide prophylaxis for 1 or 2 cycles (1 cycle = 28 days) ± budesonide or colestipol for the first cycle (see table). Adverse events were graded according to NCI-CTCAE (v4.0). Primary endpoint: incidence of grade ≥3 diarrhea. Results: StudyCONTROLExteNET5Cohort or study armLoperamideBudesonideColestipolNeratinibAntidiarrheal prophylaxisLoperamide1,2Budesonide + loperamide2,3Colestipol + loperamide2,4Loperamide prnN (at data cut-off)137664391408Diarrhea, % Any grade78.179.753.895.4Grade 124.125.025.622.9Grade 223.429.720.532.5Grade 330.725.07.739.8Grade 40000.1Median cumulative duration of diarrhea, days Any grade12.013.011.059.0Grade ≥24.03.02.010.0Grade ≥373.02.04.05.0Median episodes of diarrhea per patient, n Any grade2.04.03.08.0Grade ≥22.02.01.03.0Grade ≥371.01.02.02.0Neratinib discontinuation (due to diarrhea), %20.49.4016.8Hospitalization, %1.5001.4Median duration of neratinib treatment, mo811.06.32.111.61. Oral loperamide 4 mg, then 2 mg q4h d1-3, then 2 mg q6-8h d4-56 (original); 2. Oral loperamide 4 mg, then 4 mg tid d1-14, then 4 mg bid d15-56 (modified); 3. Oral budesonide 9 mg qd d1-28; 4. Oral colestipol 2 g qd d1-28; 5. Chan et al. Lancet Oncol 2016; 6. Original,1 n=28; modified,2 n=109; 7. Grade 4 events: CONTROL, n=0; ExteNET, n=1; 8. Treatment ongoing in all CONTROL cohorts. CONTROL data cut-off: Apr 2017. Conclusions: A structured loperamide prophylactic regimen for 1 or 2 cycles reduces the incidence, severity and duration of neratinib-associated diarrhea compared with events observed in the ExteNET trial. Adding budesonide or colestipol appears to further diminish the duration and number of episodes of diarrhea and improves neratinib tolerability. Final analysis of the CONTROL study will be performed when all pts have completed 12 months of neratinib therapy. Updated data will be available at the meeting. Clinicaltrials.gov: NCT02400476. Citation Format: Hurvitz S, Chan A, Iannotti N, Ibrahim E, Chien J, Chan N, Kellum A, Hansen V, Marx G, Kendall SD, Wilkinson M, Castrellon A, Ruiz R, Fang P, Hunt D, Moran S, Olek E, Barcenas CH, Rugo HS. Effects of adding budesonide or colestipol to loperamide prophylaxis on neratinib-associated diarrhea in patients with HER2+ early-stage breast cancer: The CONTROL trial [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P3-14-01.
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