Supplementary Table S1. Dose administered based on post-injection titers.

Purpose: Early-phase clinical trials (EPTs) have led to new, more effective treatment options for children with cancer. Despite the extensive use of EPTs in pediatric oncology, little is known about parent and child experiences during EPT participation. The purposes of this pilot study were to assess the feasibility and preliminary results of having children with cancer and their parents complete measures of treatment burden and quality of life (QOL) concurrent with EPT participation. Methods: In this descriptive, longitudinal, pilot study, parents and children were followed for the first 60 days of an EPT. Feasibility was assessed by participant enrollment and retention and completion of measures. Measures completed included the following: demographic form (completed at baseline); Diary of Trial Experiences to capture treatment burden (completed ongoing); and PedsQL™ Quality of Life Inventories, Cancer Modules, and Family Impact Module (completed at baseline, post–first disease evaluation, and off-study). Data were analyzed using descriptive statistics. Results: Feasibility goals of enrollment, retention, and measure completion were partially met. Preliminary treatment burden and QOL results are provided. Conclusions: While QOL assessments may provide insight into EPT experiences, future studies need to be conducted at multiple sites and enrollment goals must account for participant attrition.

Abstract 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.

10047 Background: HSV1716 is a mutant herpes simplex virus type 1 deleted in the RL1 gene which encodes the protein ICP34.5, a specific determinant of virulence. Mutants lacking the RL1 gene are capable of replication in actively dividing cells but not in terminally differentiated cells – a phenotype exploited to selectively kill tumor cells. Studies in adult patients with high grade glioma, melanoma and squamous cell carcinoma report that HSV1716 is safe when administered by intra-tumoral injection. This is the first study of HSV1716 in pediatric/young adult patients. Methods: The primary endpoint of the study is to assess safety of intratumoral HSV1716 in pediatric/young adult patients, and to determine any dose-limiting toxicities (DLT) at the doses given. Patients undergo long-term follow up in accordance with FDA guidelines for viral vectors. The secondary endpoints of the study are to measure: (i) antiviral immune response; (ii) systemic viremia and viral shedding and (iii) the antitumor activity of HSV1716 by radiological response within the confines of a Phase I study. Patients aged 7 to 30 with solid non-CNS tumors refractory to standard therapy (or for which no therapy exists) are eligible for the study provided the target lesion is accessible to image-guided injection. Eligible patients receive a single dose of HSV1716 (Virttu Biologics Limited) at either 105 or 2x106 plaque forming units (pfu) HSV1716 administered directly into the tumor via ultrasound or CT-guided injection by an interventional radiologist. Tumor response between baseline and day 28 is assessed by modified RECIST criteria. Patients showing at least stable disease may receive up to a 3 additional doses of HSV1716. Results: Recruitment of the first cohort of 3 patients has been completed without DLT or procedure related severe adverse events. In the second cohort, 2 patients have been treated without DLT or procedure related SAE. Conclusions: The trial is in progress and the study is open to recruitment. Clinical trial information: NCT00931931.