This study aimed to evaluate the use of tolvaptan in a consecutive series of pediatric patients with heart failure. Patients 18 years of age or younger with heart failure prescribed tolvaptan between January 2009 and October 2011 were retrospectively identified at Children's Medical Center Dallas. Laboratory parameters, urine output, fluid balance, and concurrent medications were recorded at baseline and at specified intervals after a single dose of tolvaptan. The 28 patients in the study had a median age of 2 years (range 1 month-18 years). The median tolvaptan dose administered was 0.3 mg/kg (range 0.1-1.3 mg/kg). The study patients had a median baseline serum sodium concentration of 127 mmol/L, and the increases in sodium were 2.5 mmol/L at 12 h, 5 mmol/L at 24 h, 4 mmol/L at 48 h, and 5 mmol/L at 72 h (all p < 0.001). Urine output was increased at 24 h (p < 0.001) and 48 h (p = 0.03), and fluid balance changes were significantly different at 24 h (p = 0.004). The changes in potassium, blood urea nitrogen, and serum creatinine were not significant at any interval. When controlling for traditional diuretic therapy, increases in serum sodium concentration and urine output remained statistically significant. A single dose of tolvaptan increased serum sodium concentrations for the majority in this small series of pediatric patients with heart failure. These results suggest that tolvaptan can be safely and effectively administered to pediatric patients. Prospective, randomized controlled trials are needed to evaluate the safety and efficacy of its use further.
TPS2087 Background: Diffuse gliomas are primary brain tumors characterized by substantial morbidity and mortality. Standard treatment includes maximal safe surgical resection followed by combination radiation and chemotherapy. Despite aggressive treatment, diffuse gliomas inevitably recur. Alkylating agents, and in particular temozolomide, play an important role in the treatment of gliomas, resulting in single-strand DNA breakages which require PARP activity for detection and repair. Gliomas with mutations in isocitrate dehydrogenase ( IDH) 1 or 2 have an accumulation of 2-hydroxyglutarate (2HG) which results in a BRCA-like state of homologous recombination deficiency (HRD). When PARP is inhibited in the setting of HRD, single-strand DNA damage progresses to double-strand breaks resulting in synthetic lethality. PARP inhibition has also been shown to increase mutational burden and neoantigen expression (“immune-priming”) and increases tumor-infiltrating lymphocytes and expression of PD-L1. Here, we present an ongoing clinical trial combining the checkpoint inhibitor pembrolizumab, the PARP inhibitor olaparib, and temozolomide for treatment of recurrent gliomas with HRD. Methods: This is an open-label, non-randomized phase II trial of combination pembrolizumab, olaparib, and temozolomide for patients with recurrent glioma. The main study cohort (A) will consist of 52 patients with recurrent enhancing grade 2 or 3 IDH-mutant gliomas. An exploratory cohort (B) will consist of 5 patients with recurrent IDH-wildtype gliomas and mutations associated HRD. Study intervention is administered in 21-day cycles and includes pembrolizumab (200mg IV q3 weeks day 1), olaparib (200mg bid orally days 8-14) and temozolomide (50mg/m2 orally days 8-14). The primary outcome is overall response rate (ORR) in cohort A. Secondary objectives include safety and toxicity of triplet therapy, overall and progression-free survival, and best radiographic response. Exploratory objectives will describe outcomes in the IDH-wildtype cohort and associate response to tumor markers obtained through archival tissue and cell free DNA of cerebrospinal fluid. The trial includes a 6-patient safety lead-in to assess tolerability of triplet therapy. Cohort A patients must have grade 2 or 3 IDH-mutant glioma without known CDKN2A/B loss. Patients in Cohort B must have IDH-wildtype glioma with an alternate deleterious mutation involved in homologous recombination. Additional inclusion criteria include age ≥ 18, ECOG 0-1, and glioma recurrent after prior therapy with measurable disease by RANO. Patients must be on a stable dose of corticosteroids not to exceed 2mg/day. There are no restrictions regarding number of recurrences or prior therapies if an appropriate washout has been completed. To date, seven of 57 patients have enrolled. The safety-lead in was completed without dose-limiting toxicities. Clinical trial information: NCT05188508 .
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