Julia Glade Bender

PURPOSE: We conducted a pediatric phase I trial of the vascular endothelial growth factor (VEGF)-neutralizing antibody bevacizumab (BV). Primary aims included estimating the maximum-tolerated dose (MTD) and determining the dose-limiting toxicities (DLTs), pharmacokinetics, and biologic effects of BV in children with cancer. PATIENTS AND METHODS: BV (5, 10, 15 mg/kg) was administered intravenously every 2 weeks in 28-day courses to children with refractory solid tumors. RESULTS: Twenty-one patients enrolled, 20 (median age, 13 years) were eligible, and 18 completed one course and were fully assessable for toxicity. A total of 67 courses were administered (median, three courses per patient; range, one to 16 courses). Treatment was well tolerated with no DLTs observed. Non-DLTs included infusional reaction, rash, mucositis, proteinuria, and lymphopenia. Increases in systolic and diastolic blood pressure not meeting Common Terminology Criteria for Adverse Events (CTCAEv3) pediatric-specific criteria for hypertension were observed. There was no hemorrhage or thrombosis. Growth perturbation was not detected in a limited sample over the first course. The serum exposure to BV as measured by area under the concentration-time curve (AUC) seemed to increase in proportion to dose. The median clearance of BV was 4.1 mL/d/kg (range, 3.1 to 15.5 mL/d/kg), and the median half-life was 11.8 days (range, 4.4 to 14.6 days). No objective responses were observed. Exploratory analyses on circulating endothelial mobilization and viability are consistent with the available adult data. CONCLUSION: BV is well tolerated in children. Phase II pediatric studies of BV in combination with chemotherapy in dosing schedules similar to adults are planned.

IMPORTANCE: Pediatric cancers represent a unique case with respect to cancer genomics and precision medicine, as the mutation frequency is low, and targeted therapies are less available. Consequently, it is unknown whether clinical sequencing can be of benefit. OBJECTIVE: To assess the feasibility of identifying actionable alterations and making individualized cancer therapy (iCat) recommendations in pediatric patients with extracranial solid tumors. DESIGN, SETTING, AND PARTICIPANTS: Clinical sequencing study at 4 academic medical centers enrolling patients between September 5, 2012, and November 19, 2013, with 1 year of clinical follow-up. Participants were 30 years or younger with high-risk, recurrent, or refractory extracranial solid tumors. The data analysis was performed October 28, 2014. INTERVENTIONS: Tumor profiling performed on archived clinically acquired specimens consisted of mutation detection by a Sequenom assay or targeted next-generation sequencing and copy number assessment by array comparative genomic hybridization. Results were reviewed by a multidisciplinary expert panel, and iCat recommendations were made if an actionable alteration was present, and an appropriate drug was available. MAIN OUTCOMES AND MEASURES: Feasibility was assessed using a 2-stage design based on the proportion of patients with recommendations. RESULTS: Of 100 participants (60 male; median [range] age, 13.4 [0.8-29.8] years), profiling was technically successful in 89 (89% [95% CI, 83%-95%]). Median (range) follow-up was 6.8 (2.0-23.6) months. Overall, 31 (31% [95% CI, 23%-41%]) patients received an iCat recommendation and 3 received matched therapy. The most common actionable alterations leading to an iCat recommendation were cancer-associated signaling pathway gene mutations (n = 10) and copy number alterations in MYC/MYCN (n = 6) and cell cycle genes (n = 11). Additional alterations with implications for clinical care but not resulting in iCat recommendations were identified, including mutations indicating the possible presence of a cancer predisposition syndrome and translocations suggesting a change in diagnosis. In total, 43 (43% [95% CI, 33%-53%]) participants had results with potential clinical significance. CONCLUSIONS AND RELEVANCE: A multi-institution clinical genomics study in pediatric oncology is feasible and a substantial proportion of relapsed or refractory pediatric solid tumors have actionable alterations. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01853345.

Mitochondrial dysfunction plays a major role in the pathogenesis of Parkinson disease (PD). Creatine (Cr) is an ergogenic compound that exerts neuroprotective effects in animal models of PD. We conducted a 2-year placebo-controlled randomized clinical trial on the effect of Cr in 60 patients with PD. Cr improved patient mood and led to a smaller dose increase of dopaminergic therapy but had no effect on overall Unified Parkinson9s Disease Rating Scale scores or dopamine transporter SPECT.