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

• ClinicalTrials.gov Identifier: NCT00357500
• Recruitment Status: Completed
• First Posted: July 27, 2006
• Results First Posted: September 9, 2014
• Last Update Posted: October 1, 2014
• Sponsor: Dana-Farber Cancer Institute
• Collaborators: National Cancer Institute (NCI); Boston Children's Hospital
• Information provided by (Responsible Party): Mark W. Kieran, MD, PhD, Dana-Farber Cancer Institute

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.

Condition or disease	Intervention/treatment	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

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 101 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (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
• Study Start Date: January 2005
• Actual Primary Completion Date: February 2013
• Actual Study Completion Date: December 2013

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures :

1. Therapy Completion Rate [ Time Frame: 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 Outcome Measures :

1. 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. ]
   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.
2. 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. ]
   27-week overall survival is the probability of patients remaining alive at 27-weeks from study entry estimated using with Kaplan-Meier methods.
3. Best Response [ Time Frame: 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.

Eligibility Criteria

• Ages Eligible for Study: up to 21 Years (Child, Adult)
• Sexes Eligible for Study: All
• 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

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

National Cancer Institute (NCI)

Boston Children's Hospital

Investigators

• Study Chair: Mark W. Kieran, MD, PhD; Dana-Farber Cancer Institute

More Information

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.

• Responsible Party: Mark W. Kieran, MD, PhD, Principal Investigator, Dana-Farber Cancer Institute
• ClinicalTrials.gov Identifier: NCT00357500
• Obsolete Identifiers: NCT00165321
• Other Study ID Numbers: 04-343; P30CA006516 ( U.S. NIH Grant/Contract ); CDR0000487628 ( Other Identifier: NCI )
• First Posted: July 27, 2006
• Results First Posted: September 9, 2014
• Last Update Posted: October 1, 2014
• Last Verified: September 2014

Keywords provided by Mark W. Kieran, MD, PhD, Dana-Farber Cancer Institute:

Metronomic; antiangiogenic

Additional relevant MeSH terms:

Neuroblastoma; Nervous System Neoplasms; Central Nervous System Neoplasms; Neoplasms; Neoplasms by Histologic Type; Neuroectodermal Tumors, Primitive, Peripheral; Neuroectodermal Tumors, Primitive; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue; Neoplasms by Site; Nervous System Diseases; Thalidomide; Celecoxib; Cyclophosphamide; Etoposide; Fenofibrate; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs; Antirheumatic Agents; Antineoplastic Agents, Alkylating; Alkylating Agents; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Myeloablative Agonists; Antineoplastic Agents, Phytogenic; Topoisomerase II Inhibitors