Central Nervous System Tumor, Pediatric, Leukemia, Lymphoma, Neuroblastoma, Sarcoma, Unspecified Childhood Solid Tumor, Protocol Specific
Conditions
Keywords
Metronomic, antiangiogenic
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.
Interventions
DRUGcelecoxib
DRUGcyclophosphamide
DRUGetoposide
DRUGfenofibrate
DRUGthalidomide
Sponsors
National Cancer Institute (NCI)
Boston Children's Hospital
Dana-Farber Cancer Institute
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
No minimum to 21 Years
Healthy volunteers
No
Inclusion 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Therapy Completion Rate | 27 weeks | 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
| Measure | Time frame | Description |
|---|---|---|
| 27-Week Progression-Free Survival | Assessed every 9 weeks on treatment and annually until death or initiation of new therapy, up to 27 weeks. | 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 | Assessed every 9 weeks on treatment and annually until death or initiation of new therapy, up to 27 weeks. | 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 | Assessed at study entry, every 9 weeks on treatment and at treatment discontinuation, up to 27 weeks. | 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. |
Countries
United States
Participant flow
Recruitment details
The study was open for patient accrual at 11 different pediatric oncology centers from January 7, 2005 through March 6, 2009.
Pre-assignment details
Patients must have recovered or stabalized the toxicity from prior therapy.
Participants by arm
| Arm | Count |
|---|---|
| 5-drug Metronmic Antiangiogenic Regimen 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). | 97 |
| Total | 97 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 3 |
| Overall Study | Not Started Protocol Therapy | 4 |
| Overall Study | Progressive Disease | 65 |
| Overall Study | Withdrawal by Subject | 5 |
Baseline characteristics
| Characteristic | 5-drug Metronmic Antiangiogenic Regimen |
|---|---|
| Age, Categorical <=18 years | 91 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 6 Participants |
| Age, Continuous | 10 years |
| Disease Group Bone Tumors | 12 participants |
| Disease Group Ependymoma | 19 participants |
| Disease Group High Grade Glioma | 21 participants |
| Disease Group Leukemia/Lymphoma | 4 participants |
| Disease Group Low Grade Glioma | 12 participants |
| Disease Group Medulloblastoma/PNET | 8 participants |
| Disease Group Miscellaneous CNS Tumors | 9 participants |
| Disease Group Miscellaneous non-CNS Tumors | 9 participants |
| Disease Group Neuroblastoma | 3 participants |
| Region of Enrollment United States | 97 participants |
| Sex: Female, Male Female | 47 Participants |
| Sex: Female, Male Male | 50 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 81 / 97 |
| serious Total, serious adverse events | 74 / 97 |
Outcome results
Primary
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.
Time frame: 27 weeks
Population: The analysis dataset is comprised of all treated patients.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 5-drug Metronomic Antiangiogenic Regimen | Therapy Completion Rate | .25 proportion of patients |
Secondary
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.
Time frame: Assessed every 9 weeks on treatment and annually until death or initiation of new therapy, up to 27 weeks.
Population: The analysis dataset is comprised of all treated patients.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 5-drug Metronomic Antiangiogenic Regimen | 27-Week Overall Survival | 0.61 Probability |
Secondary
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.
Time frame: Assessed every 9 weeks on treatment and annually until death or initiation of new therapy, up to 27 weeks.
Population: The analysis dataset is comprised of all treated patients.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 5-drug Metronomic Antiangiogenic Regimen | 27-Week Progression-Free Survival | 0.31 Probability |
Secondary
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.
Time frame: Assessed at study entry, every 9 weeks on treatment and at treatment discontinuation, up to 27 weeks.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| 5-drug Metronomic Antiangiogenic Regimen | Best Response | Stable Disease | 36 participants |
| 5-drug Metronomic Antiangiogenic Regimen | Best Response | Complete Response | 1 participants |
| 5-drug Metronomic Antiangiogenic Regimen | Best Response | Partial Response | 12 participants |
| 5-drug Metronomic Antiangiogenic Regimen | Best Response | Progressive Disease | 47 participants |
| 5-drug Metronomic Antiangiogenic Regimen | Best Response | Not Evaluable | 1 participants |