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

This study has been completed.
Sponsor:
Collaborators:
Children's Hospital Boston
Information provided by (Responsible Party):
Mark W. Kieran, MD, PhD, Dana-Farber Cancer Institute
ClinicalTrials.gov Identifier:
NCT00357500
First received: July 26, 2006
Last updated: September 19, 2014
Last verified: September 2014
  Purpose

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.


Condition Intervention Phase
Central Nervous System Tumor, Pediatric
Leukemia
Lymphoma
Neuroblastoma
Sarcoma
Unspecified Childhood Solid Tumor, Protocol Specific
Drug: celecoxib
Drug: cyclophosphamide
Drug: etoposide
Drug: fenofibrate
Drug: thalidomide
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
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

Resource links provided by NLM:


Further study details as provided by Dana-Farber Cancer Institute:

Primary Outcome Measures:
  • Therapy Completion Rate [ Time Frame: 27 weeks ] [ Designated as safety issue: No ]
    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 [ Time Frame: Assessed every 9 weeks on treatment and annually until death or initiation of new therapy, up to 27 weeks. ] [ Designated as safety issue: No ]
    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 [ Time Frame: Assessed every 9 weeks on treatment and annually until death or initiation of new therapy, up to 27 weeks. ] [ Designated as safety issue: No ]
    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 [ Time Frame: Assessed at study entry, every 9 weeks on treatment and at treatment discontinuation, up to 27 weeks. ] [ Designated as safety issue: No ]
    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.


Enrollment: 101
Study Start Date: January 2005
Study Completion Date: December 2013
Primary Completion Date: February 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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: celecoxib Drug: cyclophosphamide Drug: etoposide Drug: fenofibrate Drug: thalidomide

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.

  Eligibility

Ages Eligible for Study:   up to 21 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00357500

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

Additional Information:
Publications:
Responsible Party: Mark W. Kieran, MD, PhD, Principal Investigator, Dana-Farber Cancer Institute
ClinicalTrials.gov Identifier: NCT00357500     History of Changes
Obsolete Identifiers: NCT00165321
Other Study ID Numbers: 04-343, P30CA006516, CDR0000487628
Study First Received: July 26, 2006
Results First Received: December 13, 2012
Last Updated: September 19, 2014
Health Authority: United States: Federal Government

Keywords provided by Dana-Farber Cancer Institute:
Metronomic
antiangiogenic

Additional relevant MeSH terms:
Central Nervous System Neoplasms
Neoplasms
Nervous System Neoplasms
Neuroblastoma
Neoplasms by Histologic Type
Neoplasms by Site
Neoplasms, Germ Cell and Embryonal
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Neoplasms, Neuroepithelial
Nervous System Diseases
Neuroectodermal Tumors
Neuroectodermal Tumors, Primitive
Neuroectodermal Tumors, Primitive, Peripheral
Celecoxib
Cyclophosphamide
Etoposide
Etoposide phosphate
Fenofibrate
Thalidomide
Alkylating Agents
Analgesics
Analgesics, Non-Narcotic
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Anti-Bacterial Agents
Anti-Infective Agents
Anti-Inflammatory Agents
Anti-Inflammatory Agents, Non-Steroidal
Antimetabolites

ClinicalTrials.gov processed this record on October 22, 2014