Back to resultsEtoposide, Cyclophosphamide, Thalidomide, Celecoxib, and Fenofibrate in Relapsed or Progressive Cancer
Primary Purpose
Central Nervous System Tumor, Pediatric, Leukemia, Lymphoma
Status
Completed
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
celecoxib
cyclophosphamide
etoposide
fenofibrate
thalidomide
Sponsored by
About this trial
This is an interventional treatment trial for Central Nervous System Tumor, Pediatric focused on measuring Metronomic, antiangiogenic
Eligibility Criteria
DISEASE CHARACTERISTICS: Histologically confirmed cancer (at diagnosis or relapse), including any of the following: Leukemia and/or lymphoma (closed to accrual) Bone tumor (e.g., Ewing's sarcoma or osteosarcoma) (closed to accrual) Neuroblastoma (closed to accrual) High-grade glial tumor Low-grade glial tumor Ependymoma Medulloblastoma and/or primitive neuroectodermal tumor (PNET) Miscellaneous tumor (closed to accrual) Brain stem glioma, defined as intrinsic tumors of the pons causing diffuse enlargement Brain stem glioma that progressed after radiotherapy does not require histological confirmation Duration of symptoms at the time of diagnosis must be < 3 months Symptoms should consist of cranial nerve deficits, ataxia, and/or long tract signs Relapsed or progressive poor prognosis disease for which no available curative therapy exists PATIENT CHARACTERISTICS: Karnofsky performance status 50-100% OR Lansky play scale 50-100% (for infants) Life expectancy > 2 months Platelet count > 75,000/mm^3 (transfusion independent) Absolute neutrophil count > 1,000/mm^3 (in patients without bone marrow disease) Hemoglobin ≥ 9.0 g/dL Creatinine < 1.5 mg/dL OR creatinine clearance or glomerular filtration rate ≥ 70 mL/min Bilirubin ≤ 1.5 mg/dL SGPT ≤ 3 times normal SGOT ≤ 3 times normal (4 times normal for patients on ranitidine hydrochloride) Alkaline phosphatase ≤ 3 times normal Not pregnant or nursing Negative pregnancy test Fertile patients must use effective double-method contraception during and for 2 months after completion of study treatment Must be willing to participate in the Celgene STEPS® program Recent thromboembolic disease (e.g., deep vein thrombosis or pulmonary embolism) allowed if patient is clinically stable and the thromboembolic event occurred > 3 weeks prior to study entry No active infection No active uncontrolled cardiac, hepatic, renal, or psychiatric disease ≥ grade 3 No known allergies to sulfonamides No concurrent illness that would obscure toxicity or dangerously alter drug metabolism No other serious medical illness PRIOR CONCURRENT THERAPY: See Disease Characteristics Recovered from prior therapy Prior chemotherapy and/or radiotherapy allowed Prior celecoxib allowed Prior standard-dose IV etoposide and cyclophosphamide administered in 3-week courses allowed No prior oral therapy with etoposide, thalidomide, cyclophosphamide, or fenofibrate for > 2 months in duration No other concurrent investigational agents No other concurrent nonsteroidal anti-inflammatory drugs Concurrent steroids and/or antiseizure medications allowed
Sites / Locations
- Connecticut Children's Medical Center
- Miami Children's Hospital
- Children's Memorial Hospital - Chicago
- Maine Medical Center Research Institute
- Dana-Farber/Harvard Cancer Center at Dana Farber Cancer Institute
- Children's Hospitals and Clinics of Minnesota - Minneapolis
- St. Louis Children's Hospital
- Cancer Institute of New Jersey at UMDNJ - Robert Wood Johnson Medical School
- NYU Cancer Institute at New York University Medical Center
- Hasbro Children's Hospital
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
5-drug metronomic antiangiogenic regimen
Arm Description
Thalidomide: Start at 3 mg/kg (rounded to nearest 50 mg), increasing dose weekly by 50 mg as tolerated to 24 mg/kg (max 1,000 mg); Celecoxib: < 20 kg at 100 mg; 20-50 kg at 200 mg; > 50 kg at 400 mg; Fenofibrate: 90 mg/m2 (max 200 mg); Etoposide: 50 mg/m2; Cyclophosphamide: 2.5 mg/kg (max 100 mg); Patients receive oral etoposide once daily on days 1-21 and 43-63 (weeks 1-3 and 7-9) and oral cyclophosphamide once daily on days 22-42 (weeks 4-6). Patients also receive oral thalidomide once daily, oral celecoxib twice daily, and oral fenofibrate once daily in weeks 1-9. Treatment repeats approximately every 9 weeks for at least 3 courses in the absence of disease progression or unacceptable toxicity. Patients receive alternating etoposide and cyclophosphamide pulses (i.e., etoposide-cyclophosphamide-etoposide during courses 1 and 3 and cyclophosphamide-etoposide-cyclophosphamide during course 2).
Outcomes
Primary Outcome Measures
Therapy Completion Rate
Proportion of patients alive at 27 weeks without progressive disease (PD) and having tolerated therapy. As appropriate for tumor type and location, gadolinium-enhanced MRI and other imaging modalites were used to assess response. Progressive disease was defined as >/=25% increase in product of diameters, development of new areas of disease, or disease-attributable clinical deterioration or death, progressive disease. For patients with leukemia PD was defined as >/=25% or >/=5,000 cells/mm3 increase in number of circulating cells, development of extramedullary disease, or other clinical evidence of progression.
Secondary Outcome Measures
27-Week Progression-Free Survival
27-week progression-free survival is the probability of patients remaining alive and progression-free at 27-weeks from study entry estimated using Kaplan-Meier methods. As appropriate for tumor type and location, gadolinium-enhanced MRI and other imaging modalites were used to assess response. Progressive disease was defined as >/=25% increase in product of diameters, development of new areas of disease, or disease-attributable clinical deterioration or death, progressive disease. For patients with leukemia PD was defined as >/=25% or >/=5,000 cells/mm3 increase in number of circulating cells, development of extramedullary disease, or other clinical evidence of progression.
27-Week Overall Survival
27-week overall survival is the probability of patients remaining alive at 27-weeks from study entry estimated using with Kaplan-Meier methods.
Best Response
As appropriate for tumor type and location, gadolinium-enhanced MRI and other imaging modalites were used to assess response. Best response was regarded as best response at any single assessment. Response was defined as follows: complete resolution of all demonstrable tumor, complete response (CR); >/=50% decrease in the product of the 2 maximum perpendicular diameters relative to the baseline evaluation, partial response (PR); <50% decrease and <25% increase in product of diameters, stable disease (SD); and >/=25% increase in product of diameters, development of new areas of disease, or disease-attributable clinical deterioration or death, progressive disease (PD). For patients with leukemia PD was defined as >/=25% or >/=5,000 cells/mm3 increase in number of circulating cells, development of extramedullary disease, or other clinical evidence of progression.
Full Information
NCT ID
NCT00357500
First Posted
July 26, 2006
Last Updated
September 19, 2014
Sponsor
Dana-Farber Cancer Institute
Collaborators
National Cancer Institute (NCI), Boston Children's Hospital
1. Study Identification
Unique Protocol Identification Number
NCT00357500
Brief Title
Etoposide, Cyclophosphamide, Thalidomide, Celecoxib, and Fenofibrate in Relapsed or Progressive Cancer
Official Title
Anti-Angiogenic Chemotherapy: A Phase II Trial of the Oral 5-Drug Regimen (Thalidomide, Celecoxib, Fenofibrate, Etoposide and Cyclophosphamide) in Patients With Relapsed or Progressive Cancer
Study Type
Interventional
2. Study Status
Record Verification Date
September 2014
Overall Recruitment Status
Completed
Study Start Date
January 2005 (undefined)
Primary Completion Date
February 2013 (Actual)
Study Completion Date
December 2013 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Dana-Farber Cancer Institute
Collaborators
National Cancer Institute (NCI), Boston Children's Hospital
4. Oversight
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
RATIONALE: Drugs used in chemotherapy, such as etoposide and cyclophosphamide, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Thalidomide, celecoxib, and fenofibrate may stop the growth of cancer cells by blocking blood flow to the cancer. Celecoxib also may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving combination chemotherapy together with thalidomide, celecoxib, and fenofibrate may kill more cancer cells.
PURPOSE: This phase II trial is studying how well giving etoposide and cyclophosphamide together with thalidomide, celecoxib, and fenofibrate works in treating young patients with relapsed or progressive cancer.
Detailed Description
OBJECTIVES:
Primary
Evaluate the activity of etoposide, cyclophosphamide, thalidomide, celecoxib, and fenofibrate, in terms of prolonging the time to disease progression, in young patients with relapsed or progressive cancer.
Secondary
Determine, preliminarily, the biologic activity of this regimen, in terms of tumor response and overall survival, in these patients.
Determine the toxicity of this regimen in these patients.
Evaluate different radiographic techniques as markers of tumor response in these patients.
Evaluate the predictive ability of in vitro correlative studies as markers of tumor response.
STATISTICAL DESIGN: Patients were classified into one of 8 strata according to diagnosis: leukemia/lymphoma, bone tumors, neuroblastoma, high grade glial tumors, low grade glial tumors, ependymoma, medulloblastoma/PNET, and miscellaneous. A two-stage design for each disease stratum was planned. The accrual goal at the end of the two-stage design was 20 subjects for each stratum. A stopping rule was applied after the accrual of the first 10 eligible subjects enrolled in each disease stratum. If 1 or more patients in the first 10 evaluable patients were alive and progression-free at 27 weeks and have tolerated therapy then accrual to stage two would proceed. Among 20 patients within a stratum, if 3 or more patients met primary endpoint then regimen would be considered successful. The probability of concluding the treatment is feasible is 0.95 if true success rate is 30% and 0.07 if true succes rate is 5%. Overall accrual target was 80-160 patients. Please see published manuscript (Robison et al Pediatr Blood Cancer 2014) for results within disease strata.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Central Nervous System Tumor, Pediatric, Leukemia, Lymphoma, Neuroblastoma, Sarcoma, Unspecified Childhood Solid Tumor, Protocol Specific
Keywords
Metronomic, antiangiogenic
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
101 (Actual)
8. Arms, Groups, and Interventions
Arm Title
5-drug metronomic antiangiogenic regimen
Arm Type
Experimental
Arm Description
Thalidomide: Start at 3 mg/kg (rounded to nearest 50 mg), increasing dose weekly by 50 mg as tolerated to 24 mg/kg (max 1,000 mg); Celecoxib: < 20 kg at 100 mg; 20-50 kg at 200 mg; > 50 kg at 400 mg; Fenofibrate: 90 mg/m2 (max 200 mg); Etoposide: 50 mg/m2; Cyclophosphamide: 2.5 mg/kg (max 100 mg); Patients receive oral etoposide once daily on days 1-21 and 43-63 (weeks 1-3 and 7-9) and oral cyclophosphamide once daily on days 22-42 (weeks 4-6). Patients also receive oral thalidomide once daily, oral celecoxib twice daily, and oral fenofibrate once daily in weeks 1-9. Treatment repeats approximately every 9 weeks for at least 3 courses in the absence of disease progression or unacceptable toxicity. Patients receive alternating etoposide and cyclophosphamide pulses (i.e., etoposide-cyclophosphamide-etoposide during courses 1 and 3 and cyclophosphamide-etoposide-cyclophosphamide during course 2).
Intervention Type
Drug
Intervention Name(s)
celecoxib
Intervention Type
Drug
Intervention Name(s)
cyclophosphamide
Intervention Type
Drug
Intervention Name(s)
etoposide
Intervention Type
Drug
Intervention Name(s)
fenofibrate
Intervention Type
Drug
Intervention Name(s)
thalidomide
Primary Outcome Measure Information:
Title
Therapy Completion Rate
Description
Proportion of patients alive at 27 weeks without progressive disease (PD) and having tolerated therapy. As appropriate for tumor type and location, gadolinium-enhanced MRI and other imaging modalites were used to assess response. Progressive disease was defined as >/=25% increase in product of diameters, development of new areas of disease, or disease-attributable clinical deterioration or death, progressive disease. For patients with leukemia PD was defined as >/=25% or >/=5,000 cells/mm3 increase in number of circulating cells, development of extramedullary disease, or other clinical evidence of progression.
Time Frame
27 weeks
Secondary Outcome Measure Information:
Title
27-Week Progression-Free Survival
Description
27-week progression-free survival is the probability of patients remaining alive and progression-free at 27-weeks from study entry estimated using Kaplan-Meier methods. As appropriate for tumor type and location, gadolinium-enhanced MRI and other imaging modalites were used to assess response. Progressive disease was defined as >/=25% increase in product of diameters, development of new areas of disease, or disease-attributable clinical deterioration or death, progressive disease. For patients with leukemia PD was defined as >/=25% or >/=5,000 cells/mm3 increase in number of circulating cells, development of extramedullary disease, or other clinical evidence of progression.
Time Frame
Assessed every 9 weeks on treatment and annually until death or initiation of new therapy, up to 27 weeks.
Title
27-Week Overall Survival
Description
27-week overall survival is the probability of patients remaining alive at 27-weeks from study entry estimated using with Kaplan-Meier methods.
Time Frame
Assessed every 9 weeks on treatment and annually until death or initiation of new therapy, up to 27 weeks.
Title
Best Response
Description
As appropriate for tumor type and location, gadolinium-enhanced MRI and other imaging modalites were used to assess response. Best response was regarded as best response at any single assessment. Response was defined as follows: complete resolution of all demonstrable tumor, complete response (CR); >/=50% decrease in the product of the 2 maximum perpendicular diameters relative to the baseline evaluation, partial response (PR); <50% decrease and <25% increase in product of diameters, stable disease (SD); and >/=25% increase in product of diameters, development of new areas of disease, or disease-attributable clinical deterioration or death, progressive disease (PD). For patients with leukemia PD was defined as >/=25% or >/=5,000 cells/mm3 increase in number of circulating cells, development of extramedullary disease, or other clinical evidence of progression.
Time Frame
Assessed at study entry, every 9 weeks on treatment and at treatment discontinuation, up to 27 weeks.
10. Eligibility
Sex
All
Maximum Age & Unit of Time
21 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
DISEASE CHARACTERISTICS:
Histologically confirmed cancer (at diagnosis or relapse), including any of the following:
Leukemia and/or lymphoma (closed to accrual)
Bone tumor (e.g., Ewing's sarcoma or osteosarcoma) (closed to accrual)
Neuroblastoma (closed to accrual)
High-grade glial tumor
Low-grade glial tumor
Ependymoma
Medulloblastoma and/or primitive neuroectodermal tumor (PNET)
Miscellaneous tumor (closed to accrual)
Brain stem glioma, defined as intrinsic tumors of the pons causing diffuse enlargement
Brain stem glioma that progressed after radiotherapy does not require histological confirmation
Duration of symptoms at the time of diagnosis must be < 3 months
Symptoms should consist of cranial nerve deficits, ataxia, and/or long tract signs
Relapsed or progressive poor prognosis disease for which no available curative therapy exists
PATIENT CHARACTERISTICS:
Karnofsky performance status 50-100% OR Lansky play scale 50-100% (for infants)
Life expectancy > 2 months
Platelet count > 75,000/mm^3 (transfusion independent)
Absolute neutrophil count > 1,000/mm^3 (in patients without bone marrow disease)
Hemoglobin ≥ 9.0 g/dL
Creatinine < 1.5 mg/dL OR creatinine clearance or glomerular filtration rate ≥ 70 mL/min
Bilirubin ≤ 1.5 mg/dL
SGPT ≤ 3 times normal
SGOT ≤ 3 times normal (4 times normal for patients on ranitidine hydrochloride)
Alkaline phosphatase ≤ 3 times normal
Not pregnant or nursing
Negative pregnancy test
Fertile patients must use effective double-method contraception during and for 2 months after completion of study treatment
Must be willing to participate in the Celgene STEPS® program
Recent thromboembolic disease (e.g., deep vein thrombosis or pulmonary embolism) allowed if patient is clinically stable and the thromboembolic event occurred > 3 weeks prior to study entry
No active infection
No active uncontrolled cardiac, hepatic, renal, or psychiatric disease ≥ grade 3
No known allergies to sulfonamides
No concurrent illness that would obscure toxicity or dangerously alter drug metabolism
No other serious medical illness
PRIOR CONCURRENT THERAPY:
See Disease Characteristics
Recovered from prior therapy
Prior chemotherapy and/or radiotherapy allowed
Prior celecoxib allowed
Prior standard-dose IV etoposide and cyclophosphamide administered in 3-week courses allowed
No prior oral therapy with etoposide, thalidomide, cyclophosphamide, or fenofibrate for > 2 months in duration
No other concurrent investigational agents
No other concurrent nonsteroidal anti-inflammatory drugs
Concurrent steroids and/or antiseizure medications allowed
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Mark W. Kieran, MD, PhD
Organizational Affiliation
Dana-Farber Cancer Institute
Official's Role
Study Chair
Facility Information:
Facility Name
Connecticut Children's Medical Center
City
Hartford
State/Province
Connecticut
ZIP/Postal Code
06106
Country
United States
Facility Name
Miami Children's Hospital
City
Miami
State/Province
Florida
ZIP/Postal Code
33155-4069
Country
United States
Facility Name
Children's Memorial Hospital - Chicago
City
Chicago
State/Province
Illinois
ZIP/Postal Code
60614
Country
United States
Facility Name
Maine Medical Center Research Institute
City
Scarborough
State/Province
Maine
ZIP/Postal Code
04074-7205
Country
United States
Facility Name
Dana-Farber/Harvard Cancer Center at Dana Farber Cancer Institute
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02115
Country
United States
Facility Name
Children's Hospitals and Clinics of Minnesota - Minneapolis
City
Minneapolis
State/Province
Minnesota
ZIP/Postal Code
55404
Country
United States
Facility Name
St. Louis Children's Hospital
City
Saint Louis
State/Province
Missouri
ZIP/Postal Code
63110
Country
United States
Facility Name
Cancer Institute of New Jersey at UMDNJ - Robert Wood Johnson Medical School
City
New Brunswick
State/Province
New Jersey
ZIP/Postal Code
08903
Country
United States
Facility Name
NYU Cancer Institute at New York University Medical Center
City
New York
State/Province
New York
ZIP/Postal Code
10016
Country
United States
Facility Name
Hasbro Children's Hospital
City
Providence
State/Province
Rhode Island
ZIP/Postal Code
02903
Country
United States
12. IPD Sharing Statement
Citations:
PubMed Identifier
24123865
Citation
Robison NJ, Campigotto F, Chi SN, Manley PE, Turner CD, Zimmerman MA, Chordas CA, Werger AM, Allen JC, Goldman S, Rubin JB, Isakoff MS, Pan WJ, Khatib ZA, Comito MA, Bendel AE, Pietrantonio JB, Kondrat L, Hubbs SM, Neuberg DS, Kieran MW. A phase II trial of a multi-agent oral antiangiogenic (metronomic) regimen in children with recurrent or progressive cancer. Pediatr Blood Cancer. 2014 Apr;61(4):636-42. doi: 10.1002/pbc.24794. Epub 2013 Oct 4.
Results Reference
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Etoposide, Cyclophosphamide, Thalidomide, Celecoxib, and Fenofibrate in Relapsed or Progressive Cancer
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