Etoposide, Cyclophosphamide, Thalidomide, Celecoxib, and Fenofibrate in Relapsed or Progressive Cancer

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.

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