Pexa-Vec (pexastimogene devacirepvec, JX-594) is an oncolytic and immunotherapeutic vaccinia virus designed to destroy cancer cells through viral lysis and induction of GM-CSF-driven tumor-specific immunity. Pexa-Vec has undergone phase I and II testing alone and in combination with other therapies in adult patients, via both intratumoral and intravenous administration routes. We sought to determine the safety of intratumoral administration in pediatric patients. In a dose-escalation study using either 10⁶ or 10⁷ plaque forming units per kilogram, we performed one-time injections in up to three tumor sites in five pediatric patients and two injections in one patient. Ages at study entry ranged from 4 to 21 years, and their cancer diagnoses included neuroblastoma, hepatocellular carcinoma, and Ewing sarcoma. All toxicities were < grade 3. The most common side effects were sinus fever and sinus tachycardia. All three patients at the higher dose developed asymptomatic Grade 1 treatment-related skin pustules that resolved within 3-4 weeks. One patient showed imaging evidence suggestive of anti-tumor biological activity. The two patients tested for cellular immunoreactivity to vaccinia antigens showed strong responses. Overall, our study suggests Pexa-Vec is safe to administer to pediatric patients by intratumoral administration, and could be studied further in this patient population.

Purpose: HSV1716 is an oncolytic herpes simplex virus-1 (HSV-1) studied in adults via injection into the brain and superficial tumors. To determine the safety of administering HSV1716 to pediatric patients with cancer, we conducted a phase I trial of image-guided injection in young patients with relapsed or refractory extracranial cancers. Experimental Design: We delivered a single dose of 105 to 107 infectious units of HSV1716 via computed tomography–guided intratumoral injection and measured tumor responses by imaging. Patients were eligible for up to three more doses if they achieved stable disease. We monitored HSV-1 serum titers and shedding by PCR and culture. Results: We administered a single dose of HSV1716 to eight patients and two doses to one patient. We did not observe any dose-limiting toxicities. Adverse events attributed to virus included low-grade fever, chills, and mild cytopenias. Six of eight HSV-1 seronegative patients at baseline showed seroconversion on day 28. Six of nine patients had detectable HSV-1 genomes by PCR in peripheral blood appearing on day +4 consistent with de novo virus replication. Two patients had transient focal increases in metabolic activity on 18fluorine-deoxyglucose PET, consistent with inflammatory reactions. In one case, the same geographic region that flared later appeared necrotic on imaging. No patient had an objective response to HSV1716. Conclusions: Intratumoral HSV1716 is safe and well-tolerated without shedding in children and young adults with late-stage, aggressive cancer. Viremia consistent with virus replication and transient inflammatory reactions hold promise for future HSV1716 studies. Clin Cancer Res; 23(14); 3566–74. ©2017 AACR.

Background & Aims No treatment for nonalcoholic fatty liver disease (NAFLD) has been approved by regulatory agencies. We performed a randomized controlled trial to determine whether 52 weeks of cysteamine bitartrate delayed release (CBDR) reduces the severity of liver disease in children with NAFLD. Methods We performed a double-masked trial of 169 children with NAFLD activity scores of 4 or higher at 10 centers. From June 2012 to January 2014, the patients were assigned randomly to receive CBDR or placebo twice daily (300 mg for patients weighing ≤65 kg, 375 mg for patients weighing >65 to 80 kg, and 450 mg for patients weighing >80 kg) for 52 weeks. The primary outcome from the intention-to-treat analysis was improvement in liver histology over 52 weeks, defined as a decrease in the NAFLD activity score of 2 points or more without worsening fibrosis; patients without biopsy specimens from week 52 (17 in the CBDR group and 6 in the placebo group) were considered nonresponders. We calculated the relative risks (RR) of improvement using a stratified Cochran–Mantel–Haenszel analysis. Results There was no significant difference between groups in the primary outcome (28% of children in the CBDR group vs 22% in the placebo group; RR, 1.3; 95% confidence interval [CI], 0.8–2.1; P = .34). However, children receiving CBDR had significant changes in prespecified secondary outcomes: reduced mean levels of alanine aminotransferase (reduction, 53 ± 88 U/L vs 8 ± 77 U/L in the placebo group; P = .02) and aspartate aminotransferase (reduction, 31 ± 52 vs 4 ± 36 U/L in the placebo group; P = .008), and a larger proportion had reduced lobular inflammation (36% in the CBDR group vs 21% in the placebo group; RR, 1.8; 95% CI, 1.1–2.9; P = .03). In a post hoc analysis of children weighing 65 kg or less, those taking CBDR had a 4-fold better chance of histologic improvement (observed in 50% of children in the CBDR group vs 13% in the placebo group; RR, 4.0; 95% CI, 1.3–12.3; P = .005). Conclusions In a randomized trial, we found that 1 year of CBDR did not reduce overall histologic markers of NAFLD compared with placebo in children. Children receiving CBDR, however, had significant reductions in serum aminotransferase levels and lobular inflammation. ClinicalTrials.gov no: NCT01529268.

To develop diagnostic reference ranges (DRRs) and a method for an individual practice to calculate site-specific reference doses for computed tomographic (CT) scans of the abdomen or abdomen and pelvis in children on the basis of body width (BW). This HIPAA-compliant multicenter retrospective study was approved by institutional review boards of participating institutions; informed consent was waived. In 939 pediatric patients, CT doses were reviewed in 499 (53%) male and 440 (47%) female patients (mean age, 10 years). Doses were from 954 scans obtained from September 1 to December 1, 2009, through Quality Improvement Registry for CT Scans in Children within the National Radiology Data Registry, American College of Radiology. Size-specific dose estimate (SSDE), a dose estimate based on BW, CT dose index, dose-length product, and effective dose were analyzed. BW measurement was obtained with electronic calipers from the axial image at the splenic vein level after completion of the CT scan. An adult-sized patient was defined as a patient with BW of 34 cm. An appropriate dose range for each DRR was developed by reviewing image quality on a subset of CT scans through comparison with a five-point visual reference scale with increments of added simulated quantum mottle and by determining DRR to establish lower and upper bounds for each range. For 954 scans, DRRs (SSDEs) were 5.8-12.0, 7.3-12.2, 7.6-13.4, 9.8-16.4, and 13.1-19.0 mGy for BWs less than 15, 15-19, 20-24, 25-29, and 30 cm or greater, respectively. The fractions of adult doses, adult SSDEs, used within the consortium for patients with BWs of 10, 14, 18, 22, 26, and 30 cm were 0.4, 0.5, 0.6, 0.7, 0.8, and 0.9, respectively. The concept of DRRs addresses the balance between the patient's risk (radiation dose) and benefit (diagnostic image quality). Calculation of reference doses as a function of BW for an individual practice provides a tool to help develop site-specific CT protocols that help manage pediatric patient radiation doses.