Vinblastine, Celecoxib, and Combination Chemotherapy in Treating Patients With Newly-Diagnosed Metastatic Ewing's Sarcoma Family of Tumors

• Sponsor: Children's Oncology Group (Other)
• Overall Status: Completed
• CT.gov ID: NCT00061893
• Collaborator: National Cancer Institute (NCI) (NIH)
• Enrollment: 38
• Locations: 101
• Arm: 1
• Duration (Months): 116
• Patients Per Site: 0.4
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

RATIONALE: Drugs used in chemotherapy, such as vinblastine, work in different ways to stop tumor cells from dividing so they stop growing or die. Celecoxib may stop the growth of Ewing's sarcoma by stopping blood flow to the tumor. Combining more than one chemotherapy drug with celecoxib may kill more tumor cells.

PURPOSE: Phase II trial to study the effectiveness of combining low-dose vinblastine and celecoxib with standard regimens of combination chemotherapy in treating patients who have newly-diagnosed metastatic Ewing's sarcoma family of tumors.

Condition or Disease	Intervention/Treatment	Phase
Sarcoma	Drug: celecoxib; Drug: cyclophosphamide; Drug: doxorubicin hydrochloride; Drug: etoposide; Drug: ifosfamide; Drug: vinblastine sulfate; Drug: vincristine sulfate; Procedure: conventional surgery; Radiation: radiation therapy; Drug: MESNA; Drug: Filgrastim	Phase 2

Detailed Description

OBJECTIVES:

• Determine the feasibility and safety of low-dose vinblastine and celecoxib in combination with standard multiagent chemotherapy in patients with newly diagnosed metastatic Ewing's sarcoma family of tumors.

• Determine the event-free survival of patients treated with this regimen.

• Determine the pharmacokinetics of this regimen in these patients.

OUTLINE: This is a pilot, multicenter study.

• Induction therapy: Patients receive the following alternating regimens:

• VAC (courses 1 and 3): Patients receive vincristine IV and cyclophosphamide IV over 1 hour on day 1 and doxorubicin IV continuously on days 1 and 2 of weeks 1 and 7.

• IE (courses 2 and 4): Patients receive ifosfamide IV over 1 hour and etoposide IV over 1-2 hours on days 1-5 of weeks 4 and 10.

Patients also receive filgrastim (G-CSF) subcutaneously (SC) beginning 24-48 hours after the last dose of chemotherapy and continuing until blood counts recover.

Treatment repeats every 21 days for a total of 4 courses in the absence of disease progression or unacceptable toxicity.

• Local control and consolidation therapy: Beginning on week 13, patients are assigned to 1 of 4 regimens based on disease status.

• Regimen A (surgery only): Patients who respond to induction chemotherapy undergo surgery on week 13. Patients then begin consolidation therapy on week 15 with the following alternating regimens:

• VAC (courses 5, 7, and 9): Patients receive VAC on weeks 15, 21, and 27.

• IE (courses 6, 8, 10, 12, and 14): Patients receive IE on weeks 18, 24, 30, 36, and 42.

• VC (courses 11 and 13): Patients receive vincristine IV and cyclophosphamide IV over 1 hour on weeks 33 and 39.

• Regimen B (radiotherapy only): Patients with unresectable lesions undergo radiotherapy once daily 5 days a week for up to approximately 6 weeks beginning on week 13. Patients also receive consolidation therapy beginning on week 13, with the following alternating regimens:

• VAC (courses 5, 9, and 11): Patients receive VAC on weeks 13, 25, and 31.

• IE (courses 6, 8, 10, 12, and 14): Patients receive IE on weeks 16, 22, 28, 34, and 40.

• VC (courses 7 and 13): Patients receive VC on weeks 19 and 37.

• Regimen C (surgery and radiotherapy): Patients who respond to induction chemotherapy undergo surgery on week 13. Patients who have inadequate margins after surgery undergo radiotherapy (as in regimen B) beginning on week 15. Patients also receive consolidation therapy, beginning on week 15, with the following alternating regimens:

• VAC (courses 5, 9, and 11): Patients receive VAC on weeks 15, 27, and 33.

• IE (courses 6, 8, 10, 12, and 14): Patients receive IE on weeks 18, 24, 30, 36, and 42.

• VC (courses 7 and 13): Patients receive VC on weeks 21 and 39.

• Regimen D (preoperative radiotherapy): Patients with bulky lesions who do not have a good clinical and radiographic response to induction therapy begin consolidation therapy on week 13 with VAC (course 5) and undergo concurrent radiotherapy as in regimen B. Patients then receive IE on weeks 16 and 19 for courses 6 and 7. Patients undergo surgery on week 22. Patients continue consolidation therapy with the following alternating regimens:

• VAC (courses 8 and 9): Patients receive VAC on weeks 24 and 27.

• IE (courses 10, 12, and 14): Patients receive IE on weeks 30, 36, and 42.

• VC (courses 11 and 13): Patients receive VC on weeks 33 and 39. Patients receive G-CSF SC (as in induction therapy) during all consolidation courses.

Consolidation therapy continues for 10 courses in the absence of disease progression or unacceptable toxicity.

• Vinblastine and celecoxib therapy: Throughout induction, local control, and consolidation therapies, patients also receive vinblastine IV 3 times a week (twice a week during the weeks that vincristine is given) and oral celecoxib twice daily, beginning on day 1 of course 1 and continuing until the completion of course 14.* NOTE: *To assess for safety, the first 6 patients enrolled receive vinblastine only during courses 1 and 2 and celecoxib is then added for all subsequent courses.

Patients are followed every 3 months for 3 years and then every 6 months for 2 years.

PROJECTED ACCRUAL: A total of 6-36 patients will be accrued for this study within 1.17 years.

Study Design

• Study Type: Interventional
• Actual Enrollment: 38 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Pilot Study of Low-Dose Antiangiogenic Chemotherapy in Combination With Standard Multiagent Chemotherapy for Patients With Newly Diagnosed Metastatic Ewing Sarcoma Family of Tumors
• Study Start Date: Apr 1, 2004
• Actual Primary Completion Date: Apr 1, 2008
• Actual Study Completion Date: Dec 1, 2013

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Combination chemotherapy Metastatic Ewing Sarcoma - 14-cycle study building on conventional tx (cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, ifosfamide, etoposide) and adding two antiangiogenic agents: the vinca alkaloid vinblastine and the cyclooxygenase-2 inhibitor celecoxib. Refer to the Interventions section for dosages, method of delivery and frequency of administration.

Drug: celecoxib; Given orally, Celecoxib 250 mg/m2 PO BID (500mg/m2/day) from Day 1 of Cycle 1 through Day 21 of Cycle 14. The dose should be rounded off to the nearest 100 mg. If PK studies are being done, Celecoxib should be given 24 hours prior to the other drugs for Cycle 1 only. [Celecoxib may be interrupted for up to 7 days around the time of surgical procedures.] .; Drug: cyclophosphamide; Given IV, 1200 mg/m2 IV infusion over 1 hour with MESNA uroprotection, on Day 1. For children < 1 year treat with 50% doses calculated on a m2 basis. If tolerated (no delay in administration of the next cycle due to delayed count recovery or delayed resolution of other toxicities and no serious toxicities), consider increasing to 75% and then to 100% of the calculated full dose.; Drug: doxorubicin hydrochloride; Given IV, Doxorubicin 75 mg/ m2 /course continuous IV infusion over 48 hours, beginning Day 1. Note: The total doxorubicin dose per cycle is 75 mg/ m2, which will be given as 37.5 mg/m2/day x 2 days. Doxorubicin may be given as a continuous infusion or brief infusion.; Drug: etoposide; Given IV, Vincristine 2 mg/m2 IV push, on Day 1. Maximum dose 2 mg. For children < 1 year treat with 50% doses calculated on a m2 basis. If tolerated (no delay in administration of the next cycle due to delayed count recovery or delayed resolution of other toxicities and no serious toxicities), consider increasing to 75% and then to 100% of the calculated full dose.; Drug: ifosfamide; Given IV,Ifosfamide 1800 mg/m2 /day IV infusion over 1 hour, Days 1-5 of each cycle. (9,000 mg/m2 max total dose per cycle). Prehydrate for 6 hours, 1,000 ml/m2 total volume (165 ml/m2/hour for 6 hours). For children < 1 year treat with 50% doses calculated on a m2 basis. If tolerated (no delay in administration of the next cycle due to delayed count recovery or delayed resolution of other toxicities and no serious toxicities), consider increasing to 75% and then to 100% of the calculated full dose.; Drug: vinblastine sulfate; Given IV, Vinblastine 1 mg/m2/d IV push three times per week beginning Day 1 of Cycle 1 and continuing through Day 21 of Cycle 14. In weeks during which vincristine is given, hold one dose of vinblastine and administer only 2 doses of vinblastine during that week. If vinblastine is due the same day as vincristine, hold that dose of vinblastine. [Vinblastine may be interrupted for up to 7 days around the time of surgical procedures.]; Drug: vincristine sulfate; Given IV, Vincristine 2 mg/m2 IV push, on Day 1. Maximum dose 2 mg. For children < 1 year treat with 50% doses calculated on a m2 basis. If tolerated (no delay in administration of the next cycle due to delayed count recovery or delayed resolution of other toxicities and no serious toxicities), consider increasing to 75% and then to 100% of the calculated full dose.; Procedure: conventional surgery; Patients who respond to induction chemotherapy undergo surgery on week 13. Patients who have inadequate margins after surgery undergo radiotherapy beginning on week 15. (see Detailed Description for frequency of administration and groups evaluated); Radiation: radiation therapy; Patients with unresectable lesions undergo radiotherapy 5 days a week for approximately 6 weeks beginning on week 13. (see Detailed Description for frequency of administration and groups evaluated); Drug: MESNA; The total daily MESNA dose is equal to at least 60% of the daily cyclophosphamide or ifosfamide dose, or by continuous infusion of the 60% dose. MESNA continuous infusion should be started at the same time as the cyclophosphamide/ifosfamide and be completed no sooner than 8 hours after the end of the cyclophosphamide or ifosfamide infusion. The oral dose of MESNA is 2x the IV dose. Patients able to tolerate oral MESNA may receive the final dose by mouth at 40% of the oxazaphosphorine (cyclophosphamide or ifosfamide) dose. The dose should be given two hours earlier than the IV dose would be given. Additionally, if the patient vomits within two hours after the oral dose, the dose should be repeated or IV MESNA given.; Drug: Filgrastim; G-CSF (Filgrastim) 5 micrograms/kg/day subcutaneously beginning 24 to 48 hours after the last dose of chemotherapy, and continuing until the absolute neutrophil count is 2,000/µL or greater after nadir.; Other Names: G-CSF

Outcome Measures

Primary Outcome Measures

1. Occurrence of Severe Toxicity [The first two cycles (6 weeks) of protocol chemotherapy]

   An incidence of severe toxicity is defined to be the occurrence of grade 3 or higher infection or grade 3 or higher sensory neuropathy during cycles 1-2 of protocol therapy. If 12 or more patients experience grade 3 or higher infection or five or more patients experience grade 3 or higher sensory neuropathy during cycles 1-2 of protocol therapy, the regimen will be flagged as being associated with an excessive rate of severe toxicity.

Secondary Outcome Measures

1. Event Free Survival [24 months after start of protocol therapy]

Eligibility Criteria

Criteria

• Ages Eligible for Study: N/A to 50 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

DISEASE CHARACTERISTICS:

• Newly diagnosed Ewing's sarcoma family of tumors of the bone or soft tissues

• Paraspinal tumors of extra-dural origin and Askin's tumor of the chest wall are eligible

• Metastatic disease, defined by the following criteria:

• Lesions are discontinuous from the primary tumor, are not regional lymph nodes, and do not share a body cavity with the primary tumor

• A single pulmonary or pleural nodule greater than 1 cm OR multiple nodules greater than 0.5 cm are considered evidence of pulmonary or pleural metastases (unless there is another clear medical explanation for these lesions)

• Contralateral pleural effusions are considered metastatic disease

• No CNS involvement

PATIENT CHARACTERISTICS:

Age

• 50 and under (at diagnosis)

Performance status

• Lansky 50-100% (under 17 years of age)

• Karnofsky 50-100% (age 17 and over)

• Patients whose performance status is affected by a pathological fracture are allowed provided they are able to undergo treatment

Life expectancy

• Not specified

Hematopoietic

• Not specified

Hepatic

• Bilirubin no greater than 1.5 times upper limit of normal (ULN)

• AST or ALT less than 5 times ULN

Renal

• Creatinine adjusted according to age as follows*:

• No greater than 0.4 mg/dL (≤ 5 months)

• No greater than 0.5 mg/dL (6 months -11 months)

• No greater than 0.6 mg/dL (1 year-23 months)

• No greater than 0.8 mg/dL (2 years-5 years)

• No greater than 1.0 mg/dL (6 years-9 years)

• No greater than 1.2 mg/dL (10 years-12 years)

• No greater than 1.4 mg/dL (13 years and over [female])

• No greater than 1.5 mg/dL (13 years to 15 years [male])

• No greater than 1.7 mg/dL (16 years and over [male]) OR

• Creatinine clearance or radioisotope glomerular filtration rate at least 70 mL/min* NOTE: *Unless these values are related to renal insufficiency secondary to tumor involvement that is expected to improve once the tumor mass is smaller (e.g., pelvic mass causing obstructive hydronephrosis)

Cardiovascular

• Shortening fraction at least 27% by echocardiogram OR

• Ejection fraction at least 50% by MUGA

Other

• Not pregnant or nursing

• Fertile patients must use effective contraception

• Body surface area at least 0.4 m^2

• No allergy to sulfa

• No aspirin hypersensitivity

• No asthma triad (asthma with nasal polyps, and urticaria)

• No other prior cancer, including nonmelanoma skin cancer

PRIOR CONCURRENT THERAPY:

Biologic therapy

• No prior bone marrow or stem cell transplantation

Chemotherapy

• No prior chemotherapy

Endocrine therapy

• Not specified

Radiotherapy

• No prior radiotherapy

Surgery

• Not specified

Other

• No other concurrent nonsteroidal anti-inflammatory medications, including salicylates

• No concurrent dexrazoxane unless approved by the study investigator

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Alabama at Birmingham Comprehensive Cancer Center	Birmingham	Alabama	United States	35294
2	Phoenix Children's Hospital	Phoenix	Arizona	United States	85016-7710
3	Arkansas Cancer Research Center at University of Arkansas for Medical Sciences	Little Rock	Arkansas	United States	72205
4	Southern California Permanente Medical Group	Downey	California	United States	90242-2814
5	Loma Linda University Cancer Institute at Loma Linda University Medical Center	Loma Linda	California	United States	92354
6	Jonathan Jaques Children's Cancer Center at Miller Children's Hospital	Long Beach	California	United States	90801
7	Childrens Hospital Los Angeles	Los Angeles	California	United States	90027
8	Children's Hospital Central California	Madera	California	United States	93638-8762
9	University of California Davis Cancer Center	Sacramento	California	United States	95817
10	Carole and Ray Neag Comprehensive Cancer Center at the University of Connecticut Health Center	Farmington	Connecticut	United States	06360-2875
11	Alfred I. duPont Hospital for Children	Wilmington	Delaware	United States	19899
12	Lee Cancer Care of Lee Memorial Health System	Fort Myers	Florida	United States	33901
13	Nemours Children's Clinic	Jacksonville	Florida	United States	32207
14	University of Miami Sylvester Comprehensive Cancer Center	Miami	Florida	United States	33136
15	Florida Hospital Cancer Institute at Florida Hospital Orlando	Orlando	Florida	United States	32803-1273
16	Nemours Children's Clinic - Orlando	Orlando	Florida	United States	32806
17	Sacred Heart Cancer Center at Sacred Heart Hospital	Pensacola	Florida	United States	32504
18	All Children's Hospital	Saint Petersburg	Florida	United States	33701
19	St. Joseph's Cancer Institute at St. Joseph's Hospital	Tampa	Florida	United States	33607
20	Kaplan Cancer Center at St. Mary's Medical Center	West Palm Beach	Florida	United States	33407
21	Winship Cancer Institute of Emory University	Atlanta	Georgia	United States	30322
22	MBCCOP - Medical College of Georgia Cancer Center	Augusta	Georgia	United States	30912-3730
23	Curtis & Elizabeth Anderson Cancer Institute at Memorial Health University Medical Center	Savannah	Georgia	United States	31403-3089
24	Southern Illinois University School of Medicine	Springfield	Illinois	United States	62794-9620
25	Indiana University Cancer Center	Indianapolis	Indiana	United States	46202-5289
26	St. Vincent Indianapolis Hospital	Indianapolis	Indiana	United States	46260
27	Kansas Masonic Cancer Research Institute at the University of Kansas Medical Center	Kansas City	Kansas	United States	66160-7357
28	Markey Cancer Center at University of Kentucky Chandler Medical Center	Lexington	Kentucky	United States	40536-0293
29	Kosair Children's Hospital	Louisville	Kentucky	United States	40232
30	CancerCare of Maine at Eastern Maine Medial Center	Bangor	Maine	United States	04401
31	Dana-Farber/Harvard Cancer Center at Dana Farber Cancer Institute	Boston	Massachusetts	United States	02115
32	C.S. Mott Children's Hospital at University of Michigan	Ann Arbor	Michigan	United States	48109-0238
33	Barbara Ann Karmanos Cancer Institute	Detroit	Michigan	United States	48201-1379
34	Hurley Medical Center	Flint	Michigan	United States	48503
35	Spectrum Health Hospital - Butterworth Campus	Grand Rapids	Michigan	United States	49503-2560
36	Van Elslander Cancer Center at St. John Hospital and Medical Center	Grosse Pointe Woods	Michigan	United States	48236
37	Children's Hospitals and Clinics of Minneapolis	Minneapolis	Minnesota	United States	55404
38	University of Minnesota Medical Center & Children's Hospital - Fairview	Minneapolis	Minnesota	United States	55455
39	Mayo Clinic Cancer Center	Rochester	Minnesota	United States	55905
40	University of Mississippi Medical Center	Jackson	Mississippi	United States	39216-4505
41	Children's Mercy Hospital	Kansas City	Missouri	United States	64108
42	Siteman Cancer Center at Barnes-Jewish Hospital	Saint Louis	Missouri	United States	63110
43	Sunrise Hospital and Medical Center	Las Vegas	Nevada	United States	89109-2306
44	Hackensack University Medical Center Cancer Center	Hackensack	New Jersey	United States	07601
45	Cancer Institute of New Jersey at UMDNJ - Robert Wood Johnson Medical School	New Brunswick	New Jersey	United States	08903
46	Albert Einstein Cancer Center at Albert Einstein College of Medicine	Bronx	New York	United States	10461
47	Roswell Park Cancer Institute	Buffalo	New York	United States	14263-0001
48	Herbert Irving Comprehensive Cancer Center at Columbia University	New York	New York	United States	10032
49	James P. Wilmot Cancer Center at University of Rochester Medical Center	Rochester	New York	United States	14642
50	SUNY Upstate Medical University Hospital	Syracuse	New York	United States	13210
51	New York Medical College	Valhalla	New York	United States	10595
52	Blumenthal Cancer Center at Carolinas Medical Center	Charlotte	North Carolina	United States	28232-2861
53	Presbyterian Cancer Center at Presbyterian Hospital	Charlotte	North Carolina	United States	28233-3549
54	Children's Hospital Medical Center of Akron	Akron	Ohio	United States	44308-1062
55	Rainbow Babies and Children's Hospital	Cleveland	Ohio	United States	44106-5000
56	Cleveland Clinic Taussig Cancer Center	Cleveland	Ohio	United States	44195-5217
57	Columbus Children's Hospital	Columbus	Ohio	United States	43205-2696
58	Children's Medical Center - Dayton	Dayton	Ohio	United States	45404-1815
59	Medical University of Ohio Cancer Center	Toledo	Ohio	United States	43614
60	Tod Children's Hospital - Forum Health	Youngstown	Ohio	United States	44501
61	OU Cancer Institute	Oklahoma City	Oklahoma	United States	73104
62	Legacy Emanuel Hospital and Health Center & Children's Hospital	Portland	Oregon	United States	97227
63	Penn State Cancer Institute at Milton S. Hershey Medical Center	Hershey	Pennsylvania	United States	17033-0850
64	St. Christopher's Hospital for Children	Philadelphia	Pennsylvania	United States	19134-1095
65	Hollings Cancer Center at Medical University of South Carolina	Charleston	South Carolina	United States	29425
66	Palmetto Health South Carolina Cancer Center	Columbia	South Carolina	United States	29203
67	Greenville Hospital System Cancer Center	Greenville	South Carolina	United States	29605
68	East Tennessee Children's Hospital	Knoxville	Tennessee	United States	37916
69	Vanderbilt-Ingram Cancer Center	Nashville	Tennessee	United States	37232-6310
70	Texas Tech University Health Sciences Center School of Medicine - Amarillo	Amarillo	Texas	United States	79106
71	Medical City Dallas Hospital	Dallas	Texas	United States	75230
72	Simmons Comprehensive Cancer Center at University of Texas Southwestern Medical Center - Dallas	Dallas	Texas	United States	75390
73	Cook Children's Medical Center - Fort Worth	Fort Worth	Texas	United States	76104-9958
74	Baylor University Medical Center - Houston	Houston	Texas	United States	77030-2399
75	Methodist Children's Hospital of South Texas	San Antonio	Texas	United States	78229-3993
76	CCOP - Scott and White Hospital	Temple	Texas	United States	76508
77	Primary Children's Medical Center	Salt Lake City	Utah	United States	84113-1100
78	INOVA Fairfax Hospital	Fairfax	Virginia	United States	22031
79	Children's Hospital of The King's Daughters	Norfolk	Virginia	United States	23507-1971
80	Virginia Commonwealth University Massey Cancer Center	Richmond	Virginia	United States	23298-0037
81	Carilion Cancer Center of Western Virginia	Roanoke	Virginia	United States	24029
82	Providence Cancer Center at Sacred Heart Medical Center	Spokane	Washington	United States	99220-2555
83	West Virginia University - Robert C. Byrd Health Sciences Center - Charleston Division	Charleston	West Virginia	United States	25302
84	Edwards Comprehensive Cancer Center at Cabell Huntington Hospital	Huntington	West Virginia	United States	25701
85	St. Vincent Hospital Regional Cancer Center	Green Bay	Wisconsin	United States	54307-3508
86	Marshfield Clinic - Marshfield Center	Marshfield	Wisconsin	United States	54449
87	Midwest Children's Cancer Center	Milwaukee	Wisconsin	United States	53226
88	Westmead Institute for Cancer Research at Westmead Hospital	Westmead	New South Wales	Australia	2145
89	University of Alberta Hospital	Edmonton	Alberta	Canada	T6G 1Z2
90	Children's & Women's Hospital of British Columbia	Vancouver	British Columbia	Canada	V6H 3V4
91	CancerCare Manitoba	Winnipeg	Manitoba	Canada	R3E 0V9
92	IWK Health Centre	Halifax	Nova Scotia	Canada	B3K 6R8
93	McMaster Children's Hospital at Hamilton Health Sciences	Hamilton	Ontario	Canada	L8N 3Z5
94	Cancer Centre of Southeastern Ontario at Kingston General Hospital	Kingston	Ontario	Canada	K7L 3N6
95	Children's Hospital of Eastern Ontario	Ottawa	Ontario	Canada	K1H 8L1
96	Hospital for Sick Children	Toronto	Ontario	Canada	M5G 1X8
97	Montreal Children's Hospital at McGill University Health Center	Montreal	Quebec	Canada	H3H 1P3
98	Hopital Sainte Justine	Montreal	Quebec	Canada	H3T 1C5
99	Saskatoon Cancer Centre at the University of Saskatchewan	Saskatoon	Saskatchewan	Canada	S7N 4H4
100	Centre Hospitalier Universitaire de Quebec	Quebec		Canada	G1V 4G2
101	San Jorge Children's Hospital	Santurce		Puerto Rico	00912

Sponsors and Collaborators

• Children's Oncology Group
• National Cancer Institute (NCI)

Investigators

• Study Chair: Judy L. Felgenhauer, MD, PS, Sacred Heart Children's Hospital

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Children's Oncology Group
• ClinicalTrials.gov Identifier: NCT00061893
• Other Study ID Numbers: AEWS02P1; CDR0000302409
• First Posted: Jun 6, 2003
• Last Update Posted: Feb 15, 2019
• Last Verified: Jan 1, 2019

• Keywords provided by Children's Oncology Group: metastatic Ewing sarcoma/peripheral primitive neuroectodermal tumor
• Additional relevant MeSH terms: Sarcoma; Sarcoma, Ewing; Celecoxib; Cyclophosphamide; Ifosfamide; Doxorubicin; Liposomal doxorubicin; Etoposide; Vincristine; Vinblastine

Study Results

Participant Flow

Arm/Group Title	Combination Chemotherapy
Arm/Group Description	Metastatic Ewing Sarcoma - 14-cycle study building on conventional tx (cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, ifosfamide, etoposide) and adding two antiangiogenic agents: the vinca alkaloid vinblastine and the cyclooxygenase-2 inhibitor celecoxib. Angiogenesis may be a suitable target for cancer therapy because tumor growth is partially dependent upon neovascularization. Vinblastine sulfate has been shown to have antiangiogenic activity and in preclinical studies, celecoxib has demonstrated antiangiogenic activity as well as inducing apoptosis in tumor vessel endothelial cells. The feasibility and safety of adding antiangiogenic agents to conventional chemotherapy will be assessed by imaging studies (DeMRI, PET, Thallium scintigraphy). Local control with conventional surgery, radiation therapy or both will be tailored for each patient to optimally treat all sites of disease.
Period Title: Overall Study
STARTED	38
COMPLETED	20
NOT COMPLETED	18

Baseline Characteristics

Arm/Group Title	Combination Chemotherapy
Arm/Group Description	Metastatic Ewing Sarcoma - 14-cycle study building on conventional tx (cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, ifosfamide, etoposide) and adding two antiangiogenic agents: the vinca alkaloid vinblastine and the cyclooxygenase-2 inhibitor celecoxib. Angiogenesis may be a suitable target for cancer therapy because tumor growth is partially dependent upon neovascularization. Vinblastine sulfate has been shown to have antiangiogenic activity and in preclinical studies, celecoxib has demonstrated antiangiogenic activity as well as inducing apoptosis in tumor vessel endothelial cells. The feasibility and safety of adding antiangiogenic agents to conventional chemotherapy will be assessed by imaging studies (DeMRI, PET, Thallium scintigraphy). Local control with conventional surgery, radiation therapy or both will be tailored for each patient to optimally treat all sites of disease.
Overall Participants	38
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	12.97 (5.81)
Sex: Female, Male (Count of Participants)
Female	15 39.5%
Male	23 60.5%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	5 13.2%
Not Hispanic or Latino	31 81.6%
Unknown or Not Reported	2 5.3%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	1 2.6%
Asian	1 2.6%
Native Hawaiian or Other Pacific Islander	1 2.6%
Black or African American	0 0%
White	30 78.9%
More than one race	0 0%
Unknown or Not Reported	5 13.2%
Region of Enrollment (participants) [Number]
United States	34 89.5%
Canada	4 10.5%

Outcome Measures

1. Primary Outcome

Title	Occurrence of Severe Toxicity
Description	An incidence of severe toxicity is defined to be the occurrence of grade 3 or higher infection or grade 3 or higher sensory neuropathy during cycles 1-2 of protocol therapy. If 12 or more patients experience grade 3 or higher infection or five or more patients experience grade 3 or higher sensory neuropathy during cycles 1-2 of protocol therapy, the regimen will be flagged as being associated with an excessive rate of severe toxicity.
Time Frame	The first two cycles (6 weeks) of protocol chemotherapy

Outcome Measure Data

Analysis Population Description

By protocol design, all eligible patients who received protocol therapy were considered in the evaluation of severe toxicity. Three (3) patients were considered ineligible. All other patients (35) started protocol therapy and are thus included in the evaluation for this measure.

Arm/Group Title	Combination Chemotherapy
Arm/Group Description	Metastatic Ewing Sarcoma - 14-cycle study building on conventional tx (cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, ifosfamide, etoposide) and adding two antiangiogenic agents: the vinca alkaloid vinblastine and the cyclooxygenase-2 inhibitor celecoxib. Angiogenesis may be a suitable target for cancer therapy because tumor growth is partially dependent upon neovascularization. Vinblastine sulfate has been shown to have antiangiogenic activity and in preclinical studies, celecoxib has demonstrated antiangiogenic activity as well as inducing apoptosis in tumor vessel endothelial cells. The feasibility and safety of adding antiangiogenic agents to conventional chemotherapy will be assessed by imaging studies (DeMRI, PET, Thallium scintigraphy). Local control with conventional surgery, radiation therapy or both will be tailored for each patient to optimally treat all sites of disease.
Measure Participants	35
Grade 3 or Higher Infection	1 2.6%
Grade 3 or Higher Sensory Neuropathy	1 2.6%

2. Secondary Outcome

Title	Event Free Survival
Time Frame	24 months after start of protocol therapy

Outcome Measure Data

Analysis Population Description

By protocol design, all eligible patients who received protocol therapy were considered in the evaluation of Event Free Survival. Three (3) patients were considered ineligible. All other patients (35) started protocol therapy and are thus included in the evaluation for this measure.

Arm/Group Title	Combination Chemotherapy
Arm/Group Description	Metastatic Ewing Sarcoma - 14-cycle study building on conventional tx (cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, ifosfamide, etoposide) and adding two antiangiogenic agents: the vinca alkaloid vinblastine and the cyclooxygenase-2 inhibitor celecoxib. Angiogenesis may be a suitable target for cancer therapy because tumor growth is partially dependent upon neovascularization. Vinblastine sulfate has been shown to have antiangiogenic activity and in preclinical studies, celecoxib has demonstrated antiangiogenic activity as well as inducing apoptosis in tumor vessel endothelial cells. The feasibility and safety of adding antiangiogenic agents to conventional chemotherapy will be assessed by imaging studies (DeMRI, PET, Thallium scintigraphy). Local control with conventional surgery, radiation therapy or both will be tailored for each patient to optimally treat all sites of disease.
Measure Participants	35
Number (95% Confidence Interval) [percentage of participants]	35 92.1%

Adverse Events

Adverse Event Reporting Description	By protocol design, all eligible patients who received any protocol therapy were considered in the evaluation of study outcome measures, including the occurence of Adverse Events. Three (3) patients were considered ineligible. The remaining eligible 35 patients started protocol therapy and are included in the valuation of Adverse Event experience.
Arm/Group Title	Combination Chemotherapy
Arm/Group Description	Metastatic Ewing Sarcoma - 14-cycle study building on conventional tx (cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, ifosfamide, etoposide) and adding two antiangiogenic agents: the vinca alkaloid vinblastine and the cyclooxygenase-2 inhibitor celecoxib. Angiogenesis may be a suitable target for cancer therapy because tumor growth is partially dependent upon neovascularization. Vinblastine sulfate has been shown to have antiangiogenic activity and in preclinical studies, celecoxib has demonstrated antiangiogenic activity as well as inducing apoptosis in tumor vessel endothelial cells. The feasibility and safety of adding antiangiogenic agents to conventional chemotherapy will be assessed by imaging studies (DeMRI, PET, Thallium scintigraphy). Local control with conventional surgery, radiation therapy or both will be tailored for each patient to optimally treat all sites of disease.
All Cause Mortality
	Combination Chemotherapy
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Combination Chemotherapy
	Affected / at Risk (%)	# Events
Total	33/35 (94.3%)
Blood and lymphatic system disorders
Anemia	12/35 (34.3%)
Febrile neutropenia	15/35 (42.9%)
Cardiac disorders
Myocardial infarction	1/35 (2.9%)
Pericardial effusion	1/35 (2.9%)
Gastrointestinal disorders
Abdominal pain	2/35 (5.7%)
Colitis	1/35 (2.9%)
Constipation	2/35 (5.7%)
Diarrhea	4/35 (11.4%)
Dysphagia	3/35 (8.6%)
Esophagitis	2/35 (5.7%)
Gastritis	3/35 (8.6%)
Gastrointestinal disorders - Other, specify	1/35 (2.9%)
Ileus	1/35 (2.9%)
Intra-abdominal hemorrhage	1/35 (2.9%)
Mucositis oral	3/35 (8.6%)
Nausea	3/35 (8.6%)
Upper gastrointestinal hemorrhage	1/35 (2.9%)
Vomiting	4/35 (11.4%)
General disorders
Fatigue	1/35 (2.9%)
Fever	1/35 (2.9%)
Infections and infestations
Bladder infection	1/35 (2.9%)
Bronchial infection	1/35 (2.9%)
Catheter related infection	2/35 (5.7%)
Infections and infestations - Other, specify	18/35 (51.4%)
Lung infection	1/35 (2.9%)
Sepsis	1/35 (2.9%)
Upper respiratory infection	1/35 (2.9%)
Urinary tract infection	2/35 (5.7%)
Wound infection	1/35 (2.9%)
Injury, poisoning and procedural complications
Vascular access complication	1/35 (2.9%)
Investigations
Activated partial thromboplastin time prolonged	1/35 (2.9%)
Alanine aminotransferase increased	2/35 (5.7%)
Aspartate aminotransferase increased	2/35 (5.7%)
Blood bilirubin increased	3/35 (8.6%)
Electrocardiogram QT corrected interval prolonged	1/35 (2.9%)
Fibrinogen decreased	1/35 (2.9%)
Forced expiratory volume decreased	1/35 (2.9%)
GGT increased	2/35 (5.7%)
Lymphocyte count decreased	2/35 (5.7%)
Neutrophil count decreased	19/35 (54.3%)
Platelet count decreased	16/35 (45.7%)
Weight loss	4/35 (11.4%)
White blood cell decreased	16/35 (45.7%)
Metabolism and nutrition disorders
Anorexia	6/35 (17.1%)
Dehydration	4/35 (11.4%)
Hyperglycemia	1/35 (2.9%)
Hyperkalemia	1/35 (2.9%)
Hypermagnesemia	1/35 (2.9%)
Hypernatremia	1/35 (2.9%)
Hypoalbuminemia	1/35 (2.9%)
Hypocalcemia	2/35 (5.7%)
Hypokalemia	14/35 (40%)
Hypomagnesemia	1/35 (2.9%)
Hyponatremia	6/35 (17.1%)
Hypophosphatemia	3/35 (8.6%)
Musculoskeletal and connective tissue disorders
Back pain	1/35 (2.9%)
Nervous system disorders
Peripheral motor neuropathy	1/35 (2.9%)
Peripheral sensory neuropathy	2/35 (5.7%)
Vasovagal reaction	1/35 (2.9%)
Renal and urinary disorders
Bladder spasm	1/35 (2.9%)
Cystitis noninfective	1/35 (2.9%)
Hematuria	3/35 (8.6%)
Urinary retention	1/35 (2.9%)
Reproductive system and breast disorders
Perineal pain	1/35 (2.9%)
Respiratory, thoracic and mediastinal disorders
Adult respiratory distress syndrome	1/35 (2.9%)
Dyspnea	2/35 (5.7%)
Hypoxia	6/35 (17.1%)
Pharyngeal mucositis	1/35 (2.9%)
Pleural hemorrhage	1/35 (2.9%)
Pneumonitis	2/35 (5.7%)
Pulmonary hypertension	1/35 (2.9%)
Skin and subcutaneous tissue disorders
Pain of skin	1/35 (2.9%)
Vascular disorders
Hypotension	3/35 (8.6%)
Other (Not Including Serious) Adverse Events
	Combination Chemotherapy
	Affected / at Risk (%)	# Events
Total	34/35 (97.1%)
Blood and lymphatic system disorders
Anemia	2/35 (5.7%)
Gastrointestinal disorders
Constipation	1/35 (2.9%)
Gastritis	8/35 (22.9%)
Gastrointestinal disorders - Other, specify	2/35 (5.7%)
Intra-abdominal hemorrhage	2/35 (5.7%)
Mucositis oral	1/35 (2.9%)
Proctitis	1/35 (2.9%)
Vomiting	2/35 (5.7%)
Infections and infestations
Catheter related infection	1/35 (2.9%)
Infections and infestations - Other, specify	1/35 (2.9%)
Urinary tract infection	1/35 (2.9%)
Injury, poisoning and procedural complications
Burn	1/35 (2.9%)
Radiation recall reaction (dermatologic)	1/35 (2.9%)
Investigations
Activated partial thromboplastin time prolonged	1/35 (2.9%)
Alanine aminotransferase increased	3/35 (8.6%)
Aspartate aminotransferase increased	1/35 (2.9%)
Blood bilirubin increased	2/35 (5.7%)
INR increased	1/35 (2.9%)
Metabolism and nutrition disorders
Acidosis	9/35 (25.7%)
Hyperglycemia	2/35 (5.7%)
Hypermagnesemia	1/35 (2.9%)
Hypoalbuminemia	1/35 (2.9%)
Hypocalcemia	3/35 (8.6%)
Hypokalemia	9/35 (25.7%)
Hypophosphatemia	17/35 (48.6%)
Nervous system disorders
Peripheral motor neuropathy	2/35 (5.7%)
Peripheral sensory neuropathy	4/35 (11.4%)
Psychiatric disorders
Depression	1/35 (2.9%)
Psychosis	1/35 (2.9%)
Renal and urinary disorders
Bladder spasm	1/35 (2.9%)
Hematuria	12/35 (34.3%)
Proteinuria	15/35 (42.9%)
Urinary frequency	1/35 (2.9%)
Urinary tract pain	1/35 (2.9%)
Skin and subcutaneous tissue disorders
Rash maculo-papular	10/35 (28.6%)
Vascular disorders
Hypertension	1/35 (2.9%)
Thromboembolic event	1/35 (2.9%)

Limitations/Caveats

[Not Specified]

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Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.