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

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

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.

Study Overview

• Status: Completed
• Conditions: Sarcoma; Lymphoma; Unspecified Childhood Solid Tumor, Protocol Specific; Leukemia; Neuroblastoma; Central Nervous System Tumor, Pediatric
• Intervention / Treatment: Drug: cyclophosphamide; Drug: etoposide; Drug: thalidomide; Drug: celecoxib; Drug: fenofibrate

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.

• Study Type: Interventional
• Enrollment (Actual): 101
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Connecticut
    • Hartford, Connecticut, United States, 06106
      • Connecticut Children's Medical Center
  • Florida
    • Miami, Florida, United States, 33155-4069
      • Miami Children's Hospital
  • Illinois
    • Chicago, Illinois, United States, 60614
      • Children's Memorial Hospital - Chicago
  • Maine
    • Scarborough, Maine, United States, 04074-7205
      • Maine Medical Center Research Institute
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Dana-Farber/Harvard Cancer Center at Dana Farber Cancer Institute
  • Minnesota
    • Minneapolis, Minnesota, United States, 55404
      • Children's Hospitals and Clinics of Minnesota - Minneapolis
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • St. Louis Children's Hospital
  • New Jersey
    • New Brunswick, New Jersey, United States, 08903
      • Cancer Institute of New Jersey at UMDNJ - Robert Wood Johnson Medical School
  • New York
    • New York, New York, United States, 10016
      • NYU Cancer Institute at New York University Medical Center
  • Rhode Island
    • Providence, Rhode Island, United States, 02903
      • Hasbro Children's Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 19 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: 5-drug metronomic 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).

Drug: cyclophosphamide; Drug: etoposide; Drug: thalidomide; Drug: celecoxib; Drug: fenofibrate

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	27 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Assessed every 9 weeks on treatment and annually until death or initiation of new therapy, up to 27 weeks.
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.	Assessed every 9 weeks on treatment and annually until death or initiation of new therapy, up to 27 weeks.
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.	Assessed at study entry, every 9 weeks on treatment and at treatment discontinuation, up to 27 weeks.

Collaborators and Investigators

• Sponsor: Dana-Farber Cancer Institute
• Collaborators: National Cancer Institute (NCI); Boston Children's Hospital
• Investigators: Study Chair: Mark W. Kieran, MD, PhD, Dana-Farber Cancer Institute

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start: January 1, 2005
• Primary Completion (Actual): February 1, 2013
• Study Completion (Actual): December 1, 2013

Study Registration Dates

• First Submitted: July 26, 2006
• First Submitted That Met QC Criteria: July 26, 2006
• First Posted (Estimate): July 27, 2006

Study Record Updates

• Last Update Posted (Estimate): October 1, 2014
• Last Update Submitted That Met QC Criteria: September 19, 2014
• Last Verified: September 1, 2014

More Information

Terms related to this study

• Keywords: antiangiogenic; Metronomic
• Additional Relevant MeSH Terms: Nervous System Diseases; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Neoplasms, Glandular and Epithelial; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Neuroectodermal Tumors, Primitive; Neuroectodermal Tumors, Primitive, Peripheral; Nervous System Neoplasms; Central Nervous System Neoplasms; Neuroblastoma; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Peripheral Nervous System Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Cyclooxygenase Inhibitors; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Antineoplastic Agents, Phytogenic; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Hypolipidemic Agents; Lipid Regulating Agents; Anti-Bacterial Agents; Leprostatic Agents; Cyclooxygenase 2 Inhibitors; Cyclophosphamide; Etoposide; Thalidomide; Celecoxib; Fenofibrate
• Other Study ID Numbers: 04-343; P30CA006516 (U.S. NIH Grant/Contract); CDR0000487628 (Other Identifier: NCI)