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Viral Therapy in Treating Young Patients With Relapsed or Refractory Solid Tumors

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ClinicalTrials.gov Identifier: NCT01240538
Recruitment Status : Completed
First Posted : November 15, 2010
Last Update Posted : May 13, 2014
Information provided by (Responsible Party):

Study Description
Brief Summary:
This phase I trial studies the side effects and the best dose of viral therapy in treating young patients with solid tumors that have come back or that have not responded to standard therapy. Some tumors have cells with a genetic weakness that makes them unable to fight off a virus called wild-type reovirus. The virus causes cells with this weakness to die, and may therefore be able to kill tumor cells without damaging normal cells. Cyclophosphamide is a drug used in chemotherapy that stops tumor cells from dividing and causes them to die. Giving wild-type reovirus together with cyclophosphamide may kill more tumor cells.

Condition or disease Intervention/treatment Phase
Unspecified Childhood Solid Tumor, Protocol Specific Biological: wild-type reovirus Drug: cyclophosphamide Other: laboratory biomarker analysis Other: pharmacological study Phase 1

Detailed Description:


I. To estimate the maximum tolerated dose (MTD) and/or recommended Phase 2 dose (RP2D) of REOLYSIN (wild-type reovirus) administered as an intravenous infusion daily for 5 days, every 28 days to children with relapsed or refractory solid tumors.

II. To define and describe the toxicities of Reolysin in these patients. III. To define the toxicity and tolerability of combining Reolysin with oral cyclophosphamide in these patients.

IV. To characterize the pharmacokinetics (time course of viral clearance) of Reolysin in children with refractory cancer.


I. To define the antitumor activity of Reolysin within the confines of a phase I study.

II. To evaluate the development of neutralizing antibodies to Reolysin following intravenous administration of Reolysin alone and in combination with cyclophosphamide.

III. To assess the biologic activity of Reolysin.

OUTLINE: This is a dose-escalation study of wild-type reovirus.

Patients receive wild-type reovirus intravenously (IV) over 60 minutes once daily (QD) on days 1-5. Some patients also receive cyclophosphamide orally (PO) on days 1-21. Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity.

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

Study Design

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 26 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 1 Dose Escalation Study of Reolysin, a Replication Competent Reovirus, in Pediatric Patients With Relapsed or Refractory Solid Tumors
Study Start Date : December 2010
Primary Completion Date : April 2014
Arms and Interventions

Arm Intervention/treatment
Experimental: Treatment (virus and chemotherapy)
Patients receive wild-type reovirus IV over 60 minutes QD on days 1-5. Some patients also receive cyclophosphamide PO on days 1-21. Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity.
Biological: wild-type reovirus
Given IV
Other Name: REOLYSIN
Drug: cyclophosphamide
Given PO
Other Names:
  • CPM
  • CTX
  • Cytoxan
  • Endoxan
  • Endoxana
Other: laboratory biomarker analysis
Correlative studies
Other: pharmacological study
Correlative studies
Other Name: pharmacological studies

Outcome Measures

Primary Outcome Measures :
  1. Maximum-tolerated dose (MTD), defined as the maximum dose at which fewer than one-third of patients experience dose-limiting toxicity (DLT), graded using the NCI CTCAE v. 4.0 [ Time Frame: Up to 28 days ]

Secondary Outcome Measures :
  1. Time course of viral clearance of wild-type reovirus [ Time Frame: Up to 3 months ]
    Summarized with simple summary statistics, including means, medians, ranges, and standard deviations (if numbers and distribution permit).

  2. Development of neutralizing antibodies to wild-type reovirus [ Time Frame: Up to 3 months ]
    Summarized with simple summary statistics, including means, medians, ranges, and standard deviations (if numbers and distribution permit).

  3. Disease response, assessed according to Response Evaluation Criteria in Solid Tumors (RECIST) [ Time Frame: Up to 1 year ]
    Will be reported descriptively.

Eligibility Criteria

Information from the National Library of Medicine

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Ages Eligible for Study:   3 Years to 21 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • Patients with relapsed or refractory solid tumors, with the exception of central nervous system (CNS) tumors and lymphomas, are eligible; patients must have had histologic verification of malignancy at original diagnosis or relapse
  • Patients must have either measurable or evaluable disease
  • Patient's current disease state must be one for which there is no known curative therapy or therapy proven to prolong survival with an acceptable quality of life
  • Karnofsky >= 50 for patients > 16 years of age and Lansky >= 50 for patients =< 16 years of age; patients who are unable to walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score
  • Patients must have fully recovered from the acute toxic effects of all prior anti-cancer chemotherapy and immunizations
  • Must not have received myelosuppressive chemotherapy within 3 weeks of enrollment onto this study (6 weeks if prior nitrosourea)
  • At least 14 days after the last dose of a long-acting growth factor (e.g. Neulasta) or 7 days for short-acting growth factor; for agents that have known adverse events occurring beyond 7 days after administration, this period must be extended beyond the time during which adverse events are known to occur; the duration of this interval must be discussed with the study chair
  • At least 7 days after the last dose of a biologic agent; for agents that have known adverse events occurring beyond 7 days after administration, this period must be extended beyond the time during which adverse events are known to occur; the duration of this interval must be discussed with the study chair
  • At least 6 weeks since the completion of any type of immunotherapy, e.g. tumor vaccines
  • At least 3 half-lives of the antibody after the last dose of a monoclonal antibody
  • >= 2 weeks for local palliative radiation therapy (XRT) (small port); >= 24 weeks must have elapsed if prior total-body irradiation (TBI), craniospinal XRT or if >= 50% radiation of pelvis; >= 6 weeks must have elapsed if other substantial bone marrow (BM) radiation
  • No evidence of active graft vs host disease and >= 12 weeks must have elapsed since stem cell transplant or infusion
  • Patients must not have received any previous viral-based anti-neoplastic therapies
  • Viral immunizations, including influenza, may not have been administered within 7 days prior to enrollment; Note: patients may not receive any viral immunizations after enrolling on study until 28 days post their last planned REOLYSIN infusion
  • Peripheral absolute neutrophil count (ANC) >= 1000/mm^3
  • Platelet count >= 100,000/mm^3 (transfusion independent (transfusion independent, defined as not receiving platelet transfusions within a 7 day period prior to enrollment)
  • Patients with known bone marrow metastatic disease will be eligible for study but not evaluable for hematologic toxicity (maximum of one per cohort); such patients must meet the blood counts above (may receive transfusions provided they are not be known to be refractory to red cell or platelet transfusion); if dose-limiting hematologic toxicity is observed, all subsequent patients enrolled must be evaluable for hematologic toxicity
  • Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70 mL/min OR serum creatinine based on age and/or gender as follows:

    • 0.8 mg/dL (3 to < 6 years of age)
    • 1.0 mg/dL (6 to < 10 years of age)
    • 1.2 mg/dL (10 to < 13 years of age)
    • 1.5 mg/dL (male) or 1.4 mg/dL (female) (13 to < 16 years of age)
    • 1.7 mg/dL (male) or 1.4 mg/dL (female) (>= 16 years of age)
  • Bilirubin (sum of conjugated plus unconjugated) =< 1.5 x upper limit of normal (ULN) for age
  • Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 110 U/L; for the purpose of this study, the ULN for SGPT is 45 U/L
  • Serum albumin >= 2 g/dL
  • Shortening fraction >= 27% by echocardiogram OR ejection fraction >= 50% by gated radionuclide study
  • Normal pulmonary function tests (PFTs) (including diffusion capacity of carbon monoxide [DLCO]) if there is clinical indication for determination (e.g. dyspnea at rest, known requirement for supplemental oxygen); for patients who do not have respiratory symptoms, full PFTs are NOT required
  • Patients with seizure disorder may be enrolled if on anticonvulsants and well controlled
  • Nervous system disorders National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events version 4 (CTCAE v. 4) resulting from prior therapy must be =< grade 2
  • All patients and/or their parents or legally authorized representatives must sign a written informed consent; assent, when appropriate, will be obtained according to institutional guidelines

Exclusion Criteria:

  • Pregnant or breast-feeding women will not be entered on this study due to risks of fetal and teratogenic adverse events as seen in animal/human studies; pregnancy tests must be obtained in girls who are post-menarchal; males or females of reproductive potential may not participate unless they have agreed to use an effective contraceptive method
  • Patients who have an uncontrolled infection are not eligible
  • Patients with chronic diarrhea, urinary incontinence during the day or at night, or patients who are not completely toilet trained will not be eligible
  • Patients will be excluded if they have household contacts who are pregnant, immunosuppressed or infants less than 3 months of age; household contacts are defined as anyone living with the patient during the isolation period of the treatment cycles
  • Patients who in the opinion of the investigator may not be able to comply with the safety monitoring requirements of the study are not eligible
  • Patients with known human immunodeficiency virus (HIV) or hepatitis B or C are excluded due to risk of viral infectivity of REOLYSIN; therefore, patients with a pre-existent infection are not eligible
  • Patients who are currently receiving other anti-cancer agents are not eligible
  • Patients who are currently receiving another investigational drug are not eligible
  • Patients who are receiving cyclosporine, tacrolimus or other agents to prevent either graft-versus-host disease post bone marrow transplant or organ rejection post transplant are not eligible for this trial
  • Patients must not have received corticosteroids, immune modulators or antiviral therapy for 7 days prior to enrollment and must not have an anticipated need for any of these therapies, intravenous immune globulin (IVIG) must not have been administered within 2 weeks prior to enrollment
  • Patients should avoid taking acetaminophen with REOLYSIN; whenever suitable, physicians should utilize alternative medications
  • Patients with known germline mutations affecting Ras activation (e.g. NF-1, Cardio-facial-cutaneous syndrome, Noonan syndrome, Costello syndrome) will be excluded from enrollment
  • Patients with known metastatic CNS disease involvement are excluded
  • Patients with primary CNS tumors are excluded
Contacts and Locations

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01240538

  Hide Study Locations
United States, Alabama
Children's Hospital of Alabama
Birmingham, Alabama, United States, 35233
United States, Arizona
Phoenix Childrens Hospital
Phoenix, Arizona, United States, 85016
United States, California
Children's Hospital Los Angeles
Los Angeles, California, United States, 90027
Childrens Hospital of Orange County
Orange, California, United States, 92868-3874
University of California San Francisco Medical Center-Parnassus
San Francisco, California, United States, 94143
United States, Delaware
Alfred I duPont Hospital for Children
Wilmington, Delaware, United States, 19803
United States, District of Columbia
Children's National Medical Center
Washington, District of Columbia, United States, 20010
United States, Florida
Nemours Children's Clinic - Jacksonville
Jacksonville, Florida, United States, 32207-8426
United States, Illinois
Lurie Children's Hospital-Chicago
Chicago, Illinois, United States, 60614
United States, Indiana
Indiana University Medical Center
Indianapolis, Indiana, United States, 46202
Riley Hospital for Children
Indianapolis, Indiana, United States, 46202
United States, Michigan
C S Mott Children's Hospital
Ann Arbor, Michigan, United States, 48109
United States, Minnesota
University of Minnesota Medical Center-Fairview
Minneapolis, Minnesota, United States, 55455
United States, New York
Montefiore Medical Center
Bronx, New York, United States, 10467-2490
Columbia University Medical Center
New York, New York, United States, 10032
United States, Ohio
Cincinnati Children's Hospital Medical Center
Cincinnati, Ohio, United States, 45229
United States, Oklahoma
University of Oklahoma Health Sciences Center
Oklahoma City, Oklahoma, United States, 73104
United States, Oregon
Oregon Health and Science University
Portland, Oregon, United States, 97239
United States, Pennsylvania
Children's Hospital of Pittsburgh of UPMC
Pittsburgh, Pennsylvania, United States, 15224
United States, Tennessee
St. Jude Children's Research Hospital
Memphis, Tennessee, United States, 38105
United States, Texas
University of Texas Southwestern Medical Center
Dallas, Texas, United States, 75390
Cook Children's Medical Center
Fort Worth, Texas, United States, 76104
Baylor College of Medicine
Houston, Texas, United States, 77030
United States, Washington
Seattle Children's Hospital
Seattle, Washington, United States, 98105
United States, Wisconsin
Midwest Children's Cancer Center
Milwaukee, Wisconsin, United States, 53226
Canada, Ontario
Hospital for Sick Children
Toronto, Ontario, Canada, M5G 1X8
Canada, Quebec
Centre Hospitalier Universitaire Sainte-Justine
Montreal, Quebec, Canada, H3T 1C5
Sponsors and Collaborators
National Cancer Institute (NCI)
Principal Investigator: E. Anders Kolb COG Phase I Consortium
More Information

Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT01240538     History of Changes
Other Study ID Numbers: NCI-2011-02617
NCI-2011-02617 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
ADVL1014 ( Other Identifier: COG Phase I Consortium )
ADVL1014 ( Other Identifier: CTEP )
U01CA097452 ( U.S. NIH Grant/Contract )
First Posted: November 15, 2010    Key Record Dates
Last Update Posted: May 13, 2014
Last Verified: January 2014

Additional relevant MeSH terms:
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists