Clinical trial NCT01240538: Viral Therapy in Treating Young Patients With Relapsed or Refractory Solid Tumors
Official title: A Phase 1 Dose Escalation Study of Reolysin, a Replication Competent Reovirus, in Pediatric Patients With Relapsed or Refractory Solid Tumors
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Unspecified Childhood Solid Tumor, Protocol Specific
Lead sponsor: National Cancer Institute (NCI)
Sponsor class: NIH
First posted: 2010-11-15
Enrollment: 26
Sex: ALL
Minimum age (years): 3
Maximum age (years): 21
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

Detailed description: PRIMARY OBJECTIVES:

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.

SECONDARY OBJECTIVES:

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.

Eligibility criteria: 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

Primary outcomes:
measure: 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
timeFrame: Up to 28 days
Secondary outcomes:
measure: Time course of viral clearance of wild-type reovirus
timeFrame: Up to 3 months
measure: Development of neutralizing antibodies to wild-type reovirus
timeFrame: Up to 3 months
measure: Disease response, assessed according to Response Evaluation Criteria in Solid Tumors (RECIST)
timeFrame: Up to 1 year
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: Children's Hospital of Alabama
state: Alabama
city: Phoenix
country: United States
facility: Phoenix Childrens Hospital
state: Arizona
city: Los Angeles
country: United States
facility: Children's Hospital Los Angeles
state: California
city: Orange
country: United States
facility: Childrens Hospital of Orange County
state: California
city: San Francisco
country: United States
facility: University of California San Francisco Medical Center-Parnassus
state: California
city: Wilmington
country: United States
facility: Alfred I duPont Hospital for Children
state: Delaware
city: Washington
country: United States
facility: Children's National Medical Center
state: District of Columbia
city: Jacksonville
country: United States
facility: Nemours Children's Clinic - Jacksonville
state: Florida
city: Chicago
country: United States
facility: Lurie Children's Hospital-Chicago
state: Illinois
city: Indianapolis
country: United States
facility: Indiana University Medical Center
state: Indiana
city: Indianapolis
country: United States
facility: Riley Hospital for Children
state: Indiana
city: Ann Arbor
country: United States
facility: C S Mott Children's Hospital
state: Michigan
city: Minneapolis
country: United States
facility: University of Minnesota Medical Center-Fairview
state: Minnesota
city: Bronx
country: United States
facility: Montefiore Medical Center
state: New York
city: New York
country: United States
facility: Columbia University Medical Center
state: New York
city: Cincinnati
country: United States
facility: Cincinnati Children's Hospital Medical Center
state: Ohio
city: Oklahoma City
country: United States
facility: University of Oklahoma Health Sciences Center
state: Oklahoma
city: Portland
country: United States
facility: Oregon Health and Science University
state: Oregon
city: Pittsburgh
country: United States
facility: Children's Hospital of Pittsburgh of UPMC
state: Pennsylvania
city: Memphis
country: United States
facility: St. Jude Children's Research Hospital
state: Tennessee
city: Dallas
country: United States
facility: University of Texas Southwestern Medical Center
state: Texas
city: Fort Worth
country: United States
facility: Cook Children's Medical Center
state: Texas
city: Houston
country: United States
facility: Baylor College of Medicine
state: Texas
city: Seattle
country: United States
facility: Seattle Children's Hospital
state: Washington
city: Milwaukee
country: United States
facility: Midwest Children's Cancer Center
state: Wisconsin
city: Toronto
country: Canada
facility: Hospital for Sick Children
state: Ontario
city: Montreal
country: Canada
facility: Centre Hospitalier Universitaire Sainte-Justine
state: Quebec
Study officials:
affiliation: COG Phase I Consortium
name: E. Anders Kolb
role: PRINCIPAL_INVESTIGATOR
References: