title: Phase I trial of Seneca Valley Virus (NTX-010) in children with relapsed/refractory solid tumors: a report of the Children's Oncology Group.
abstract: BACKGROUND
  To determine the MTD of Seneca Valley Virus (NTX-010) in children with relapsed/refractory solid tumors. Patients (≥ 3-≤ 21 years) with neuroblastoma, rhabdomyosarcoma, or rare tumors with neuroendocrine features were eligible.
  
  
  METHODS
  Part A (single dose of NTX-010) enrolled 13 patients at three dose levels (1 × 10(9) viral particles (vp)/kg [n = 6], 1 × 10(10) vp/kg [n = 3], 1 × 10(11) vp/kg [n = 4]). Diagnoses included neuroblastoma (n = 9), rhabdomyosarcoma (n = 2), carcinoid tumor (n = 1), and adrenocorticocarcinoma (n = 1). Part B added cyclophosphamide (CTX) (oral CTX (25 mg/m(2) /day) days 1-14 and IV CTX (750 mg/m(2) ) days 8 and 29) to two doses of NTX-010 (1 × 10(11) vp/kg, days 8 and 29). Nine patients enrolled to Part B. Diagnoses included neuroblastoma (n = 3), rhabdomyosarcoma (n = 1), Wilms tumor (n = 3), and adrenocorticocarcinoma (n = 2).
  
  
  RESULTS
  Twelve patients on Part A were evaluable for toxicity. There was a single DLT (grade 3 pain) at dose level 1. Additional grade ≥ 3 related adverse events (AEs) included leukopenia (n = 1), neutropenia (n = 3), lymphopenia (n = 3), and tumor pain (n = 1). No DLTs occurred on part B. Other grade ≥ 3 related AEs on Part B included: Leukopenia (n = 3), nausea (n = 1), emesis (n = 1), anemia (n = 1), neutropenia (n = 4), platelets (n = 1), alanine aminotransferase (n = 1), and lymphopenia (n = 2). All patients cleared NTX-010 from blood and stool by 3 weeks with 17/18 patients developing neutralizing antibodies.
  
  
  CONCLUSIONS
  NTX-010 is feasible and tolerable at the dose levels tested in pediatric patients with relapsed/refractory solid tumors either alone or in combination with cyclophosphamide. However, despite the addition of cyclophosphamide, neutralizing antibodies appeared to limit applicability.
authors.affiliation: Department of Pediatrics, Division of Hematology/Oncology/BMT, Medical College of Wisconsin, Milwaukee, Wisconsin.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Burke
authors.forename: Charlotte
authors.initials: C
authors.lastname: Ahern
authors.forename: Brenda J
authors.initials: BJ
authors.lastname: Weigel
authors.forename: John T
authors.initials: JT
authors.lastname: Poirier
authors.forename: Charles M
authors.initials: CM
authors.lastname: Rudin
authors.forename: Yingbei
authors.initials: Y
authors.lastname: Chen
authors.forename: Timothy P
authors.initials: TP
authors.lastname: Cripe
authors.forename: M Brooke
authors.initials: MB
authors.lastname: Bernhardt
authors.forename: Susan M
authors.initials: SM
authors.lastname: Blaney
mesh_terms: D000293:Adolescent; D000328:Adult; D057134:Antibodies, Neutralizing / Q000097:blood; D018906:Antineoplastic Agents, Alkylating / Q000627:therapeutic use; D002648:Child; D002675:Child, Preschool; D003131:Combined Modality Therapy; D003520:Cyclophosphamide / Q000627:therapeutic use*; D019008:Drug Resistance, Neoplasm; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D009364:Neoplasm Recurrence, Local / Q000473:pathology / Q000628:therapy* / Q000821:virology; D009367:Neoplasm Staging; D009369:Neoplasms / Q000473:pathology / Q000628:therapy* / Q000821:virology; D050130:Oncolytic Virotherapy; D010849:Picornaviridae; D011379:Prognosis; D016879:Salvage Therapy; D055815:Young Adult
chemical_list: D057134:Antibodies, Neutralizing; D018906:Antineoplastic Agents, Alkylating; D003520:Cyclophosphamide
keywords: oncolytic; pediatric; relapsed; seneca valley virus; solid tumors