Seneca Valley Virus-001 and Cyclophosphamide in Treating Young Patients With Relapsed or Refractory Neuroblastoma, Rhabdomyosarcoma, or Rare Tumors With Neuroendocrine Features

A Phase 1 Dose Escalation Study of Seneca Valley Virus (NTX-010), A Replication-Competent Picornavirus, in Relapsed/Refractory Pediatric Patients With Neuroblastoma, Rhabdomyosarcoma, or Rare Tumors With Neuroendocrine Features

RATIONALE: Seneca Valley virus-001 may be able to kill certain kinds of tumor cells without damaging normal cells. Adding low dose cyclophosphamide (in part B of study) may help to kill even more tumor cells.

PURPOSE: This phase I trial is studying the side effects and best dose of Seneca Valley virus-001 in treating young patients with relapsed or refractory neuroblastoma, rhabdomyosarcoma, or rare tumors with neuroendocrine features.

Study Overview

• Status: Completed
• Conditions: Sarcoma; Kidney Cancer; Neuroblastoma; Retinoblastoma; Adrenocortical Carcinoma; Gastrointestinal Carcinoid Tumor
• Intervention / Treatment: Drug: cyclophosphamide; Other: pharmacological study; Other: laboratory biomarker analysis; Biological: Seneca Valley virus-001

Detailed Description

OBJECTIVES:

Primary

• To estimate the maximum-tolerated dose and/or recommended phase II dose of Seneca Valley virus-001 (NTX-010) when administered as a single infusion to pediatric patients with relapsed or refractory neuroblastoma, rhabdomyosarcoma, or rare tumors with neuroendocrine features (Wilms tumor, retinoblastoma, adrenocortical carcinoma, or carcinoid tumors). (Part A [completed])
• To confirm that there is viral replication in these patients following NTX-010 administration. (Part A [completed])
• To define and describe the toxicities of NTX-010 when administered on this schedule. (Part A [completed])
• To determine whether the number of regulatory T cells (as measured by flow cytometry) can effectively be reduced following administration of NTX-010 plus low-dose metronomic and intravenous cyclophosphamide. (Part B)
• To characterize the pharmacokinetics (time course of viral clearance) following NTX-010 administration in these patients.

Secondary

• To preliminarily define the antitumor activity of NTX-010 within the confines of a phase I study. (Part A [completed])
• To evaluate the development of neutralizing antibodies to NTX-010 following IV administration of NTX-010. (Part A [completed])
• To evaluate development of neutralizing antibodies to NTX-010 following the combination of NTX-010 and cyclophosphamide. (Part B)
• To investigate the presence and permissivity of occult circulating tumor cells prior to and after the initial intravenous administration of NTX-010.

OUTLINE: This is a multicenter study.

Part A (completed): Patients receive Seneca Valley virus-001 (NTX-010) IV over 1 hour on day 1.

Part B: Patients receive cyclophosphamide IV orally (PO) on days 1-14 and NTX-010 IV over 1 hour on day 8. In the absence of disease progression or unacceptable toxicity, patients then receive cyclophosphamide orally (PO) on days 22-35, plus cyclophosphamide IV over 1 hour and NTX-010 IV over 1 hour on day 29.

Tumor tissue samples are collected at baseline for biomarker studies. Blood and stool samples are collected periodically for neutralizing antibody and viral clearance studies. Additional blood samples may also be collected for the presence and permissivity of occult tumor cells.

After completion of study treatment, patients are followed up periodically for up to 1 year.

• Study Type: Interventional
• Enrollment (Actual): 22
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294
      • Uab Comprehensive Cancer Center
  • California
    • Orange, California, United States, 92868
      • Children's Hospital of Orange County
    • San Francisco, California, United States, 94115
      • UCSF Helen Diller Family Comprehensive Cancer Center
  • District of Columbia
    • Washington, District of Columbia, United States, 20010-2970
      • Children's National Medical Center
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Children's Memorial Hospital - Chicago
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Riley's Children Cancer Center at Riley Hospital for Children
  • Massachusetts
    • Boston, Massachusetts, United States, 2115
      • Dana-Farber/Harvard Cancer Center at Dana-Farber Cancer Institute
  • Michigan
    • Ann Arbor, Michigan, United States, 48109-0286
      • C.S. Mott Children's Hospital at University of Michigan Medical Center
  • Minnesota
    • Minneapolis, Minnesota, United States, 55455
      • Masonic Cancer Center at University of Minnesota
  • Missouri
    • St. Louis, Missouri, United States, 63110
      • Siteman Cancer Center at Barnes-Jewish Hospital - Saint Louis
  • New York
    • New York, New York, United States, 10032
      • Herbert Irving Comprehensive Cancer Center at Columbia University Medical Center
  • Ohio
    • Cincinnati, Ohio, United States, 45229-3039
      • Cincinnati Children's Hospital Medical Center
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15213
      • Children's Hospital of Pittsburgh of UPMC
  • Tennessee
    • Memphis, Tennessee, United States, 38105
      • St. Jude Children's Research Hospital
  • Texas
    • Dallas, Texas, United States, 75390
      • Simmons Comprehensive Cancer Center at University of Texas Southwestern Medical Center - Dallas
    • Houston, Texas, United States, 77030-2399
      • Baylor University Medical Center - Houston
  • Washington
    • Seattle, Washington, United States, 98105
      • Children's Hospital and Regional Medical Center - Seattle
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • Midwest Children's Cancer Center at Children's Hospital of Wisconsin

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 3 years to 21 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

DISEASE CHARACTERISTICS:

• Histologically confirmed diagnosis of 1 of the following:

  • Neuroblastoma
  • Rhabdomyosarcoma
  • Wilms tumor
  • Retinoblastoma
  • Adrenocortical carcinoma
  • Carcinoid tumor
• Relapsed or refractory disease
• Measurable or evaluable disease
• No known curative therapy or therapy proven to prolong survival with an acceptable quality of life
• No known pulmonary tumors or metastases > 5 cm, as evaluated by chest CT scan
• No clinically significant pulmonary and/or pericardial effusions (≥ grade 3), as evaluated by ECHO
• No primary CNS tumors or known metastatic CNS disease involvement

PATIENT CHARACTERISTICS:

• Karnofsky performance status (PS) 50-100% (for patients > 16 years of age)
• Lansky PS 50-100% (for patients ≤ 16 years of age)
• Peripheral ANC ≥ 1,000/mm^3
• Platelet count ≥ 100,000/mm^3 (transfusion independent, defined as no platelet transfusions within a 7-day period before study enrollment)
• Hemoglobin ≥ 8.0 g/dL (RBC transfusions allowed)

• Creatine clearance or radioisotope GFR ≥ 70 mL/min OR serum creatinine based on age/gender as follows:

  • ≤ 0.8 mg/dL (for patients 3 to 5 years of age)
  • ≤ 1.0 mg/dL (for patients 6 to 9 years of age)
  • ≤ 1.2 mg/dL (for patients 10 to 12 years of age)
  • ≤ 1.4 mg/dL (for female patients ≥ 13 years of age)
  • ≤ 1.5 mg/dL (for male patients 13 to 15 years of age)
  • ≤ 1.7 mg/dL (for male patients ≥ 16 years of age)
• Bilirubin (sum of conjugated and unconjugated) ≤ 1.5 times upper limit of normal (ULN)
• SGPT ≤ 110 U/L (for the purpose of this study, the ULN for SGPT is 45 U/L)
• Serum albumin ≥ 2 g/dL
• Oxygen saturation > 92% on room air
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• Able to comply with the safety monitoring requirements of the study, in the opinion of the investigator
• Completely toilet trained
• No chronic diarrhea or urinary incontinence during the day or night, , and no in-dwellling urinary catheters
• No uncontrolled infection
• No known pregnant member of the household

PRIOR CONCURRENT THERAPY:

• Fully recovered from the acute toxic effects of all prior anti-cancer chemotherapy
• At least 6 months since prior total-body irradiation (TBI), craniospinal radiotherapy, or radiotherapy to ≥ 50% of the pelvis

• At least 3 months since prior stem cell transplantation or rescue (without TBI)

  • No evidence of active graft-vs-host disease
• At least 6 weeks since other prior substantial bone marrow radiotherapy or treatment with therapeutic doses of MIBG
• More than 3 weeks since prior myelosuppressive chemotherapy
• At least 2 weeks since prior local palliative radiotherapy (small port)
• More than 7 days since prior growth factor(s) that support platelet or white blood cell number or function
• At least 7 days since prior biologic agents
• At least 3 half-lives since prior monoclonal antibodies
• More than 7 days since prior viral immunizations, including influenza
• At least 42 days since the completion of any type of immunotherapy, e.g., tumor vaccines
• No other viral immunizations after enrolling on study until 28 days after their last planned Seneca Valley virus-001 infusion or until documented viral clearance, whichever is longest
• Concurrent corticosteroids allowed provided the patient has been on a stable or decreasing dose for the past 7 days
• No other concurrent investigational drugs
• No other concurrent anticancer agents (e.g., chemotherapy, radiotherapy, immunotherapy, or biologic therapy)
• Prior treatment with Seneca Valley virus-001 is not allowed

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Treatment (NTX-010)	Drug: cyclophosphamide; Other: pharmacological study; Other: laboratory biomarker analysis; Biological: Seneca Valley virus-001

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Safety and tolerability	12 months post-documented viral clearance
Recommended phase II dose of Seneca Valley virus-001 (NTX-010)	56 days

Secondary Outcome Measures

Outcome Measure	Time Frame
Tumor response	Up to 12 months post documented viral clearance
Viral titers in blood and stool	Up to 56 days post treatment
Development of antibodies to NTX-010	Up to 4 weeks post treatment

Collaborators and Investigators

• Sponsor: Children's Oncology Group
• Collaborators: National Cancer Institute (NCI)
• Investigators: Study Chair: Michael J. Burke, MD, Masonic Cancer Center, University of Minnesota

Study record dates

Study Major Dates

• Study Start: September 1, 2009
• Primary Completion (Actual): June 1, 2013

Study Registration Dates

• First Submitted: January 13, 2010
• First Submitted That Met QC Criteria: January 13, 2010
• First Posted (Estimate): January 14, 2010

Study Record Updates

• Last Update Posted (Estimate): January 30, 2014
• Last Update Submitted That Met QC Criteria: January 29, 2014
• Last Verified: January 1, 2014

More Information

Terms related to this study

• Keywords: recurrent gastrointestinal carcinoid tumor; previously treated childhood rhabdomyosarcoma; recurrent childhood rhabdomyosarcoma; recurrent neuroblastoma; recurrent adrenocortical carcinoma; recurrent Wilms tumor and other childhood kidney tumors; recurrent retinoblastoma
• Additional Relevant MeSH Terms: Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Eye Diseases; Endocrine System Diseases; Retinal Diseases; Endocrine Gland Neoplasms; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Eye Diseases, Hereditary; Neuroendocrine Tumors; Sarcoma; Neuroectodermal Tumors, Primitive; Neoplasms, Muscle Tissue; Neuroectodermal Tumors, Primitive, Peripheral; Eye Neoplasms; Retinal Neoplasms; Adrenal Gland Diseases; Myosarcoma; Adrenal Cortex Neoplasms; Adrenal Gland Neoplasms; Adrenal Cortex Diseases; Neuroblastoma; Retinoblastoma; Rhabdomyosarcoma; Carcinoid Tumor; Adrenocortical Carcinoma; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Cyclophosphamide
• Other Study ID Numbers: ADVL0911; COG-ADVL0911; CDR0000663520 (Other Identifier: Clinical Trials.gov)