High-Dose Combination Chemotherapy and Radiation Therapy in Treating Patients With Newly Diagnosed Metastatic Rhabdomyosarcoma or Ectomesenchymoma

• Sponsor: Children's Oncology Group (Other)
• Overall Status: Completed
• CT.gov ID: NCT00354744
• Collaborator: National Cancer Institute (NCI) (NIH)
• Enrollment: 109
• Locations: 166
• Arm: 1
• Duration (Months): 156
• Patients Per Site: 0.7
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

RATIONALE: Drugs used in chemotherapy, such as vincristine, irinotecan, ifosfamide, etoposide, doxorubicin, cyclophosphamide, and dactinomycin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Radiation therapy uses high-energy x-rays to kill tumor cells. Giving high-dose combination chemotherapy together with radiation therapy may kill more tumor cells.

PURPOSE: This phase III trial is studying how well giving high-dose combination chemotherapy together with radiation therapy works in treating patients with newly diagnosed metastatic rhabdomyosarcoma or ectomesenchymoma.

Condition or Disease	Intervention/Treatment	Phase
Sarcoma	Biological: dactinomycin; Drug: cyclophosphamide; Drug: doxorubicin hydrochloride; Drug: etoposide; Drug: ifosfamide; Drug: irinotecan hydrochloride; Drug: vincristine sulfate; Procedure: conventional surgery; Radiation: radiation therapy; Biological: filgrastim	Phase 3

Detailed Description

OBJECTIVES:

Primary

• Improve the early disease control interval for patients with newly diagnosed, high-risk, metastatic rhabdomyosarcoma or ectomesenchymoma using intensive, interval-compression therapy (comprising vincristine, irinotecan hydrochloride, ifosfamide, etoposide, doxorubicin hydrochloride, cyclophosphamide, and dactinomycin) that permits maximal early exposure to known effective agents.

• Determine the feasibility and assess immediate- and short-term side effects of concurrent irinotecan hydrochloride and radiotherapy in these patients.

Secondary

• Expand the available data for response to irinotecan hydrochloride and vincristine in previously untreated patients with high-risk rhabdomyosarcoma.

• Evaluate, prospectively, and validate gene expression values with the intent to define the best diagnostic predictors and more powerful prognostic classifiers.

OUTLINE: This is a prospective, nonrandomized, multicenter study. Patients are stratified according to prognostic factors predictive of outcome (e.g. histology, bone/bone marrow involvement, and number of metastatic sites).

Patients receive high-dose chemotherapy comprising vincristine IV over 1 minute on day 1 of weeks 1-5, 7, 8, 11, 12, 15, 16, 20-24, 28, 29, 32, 33, 35, 38, 41-44, 47, 48, 50, and 51; irinotecan hydrochloride IV over 1 hour on days 1-5 of weeks 1, 4, 20, 23, 47, and 50; and ifosfamide IV over 1 hour and etoposide IV over 30-60 minutes on days 1-5 of weeks 9, 13, 17, 26, and 30. Patients also receive doxorubicin hydrochloride IV continuously over 24 hours on days 1 and 2 of weeks 7*, 11, 15, 28, and 32; cyclophosphamide IV over 30-60 minutes on day 1 of weeks 7, 11, 15, 28, 32, 35, 38, 41, and 44; and dactinomycin IV over 1-5 minutes on day 1 of weeks 35, 38, 41, and 44 in the absence of disease progression or unacceptable toxicity. Patients also receive filgrastim (G-CSF) subcutaneously in weeks 7-9, 11-13, 15-17, 22, 26, 28-30, 32, 33, 35, 38, and 41-44 beginning 24-36 hours after the last chemotherapy dose and continuing until blood counts recover.

NOTE: *Patients undergoing early radiotherapy for intracranial extension do not receive doxorubicin in week 7.

Beginning at week 20 (or week 1 for patients with parameningeal tumors with intracranial extension [or spinal cord compression] requiring emergency radiotherapy), patients also undergo radiotherapy once a day, 5 days a week, for approximately 5½ weeks. Some patients may also undergo second-look surgery.

After completion of study treatment, patients are followed periodically for ≥ 10 years.

PROJECTED ACCRUAL: A total of 75 patients will be accrued for this study.

Study Design

• Study Type: Interventional
• Actual Enrollment: 109 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Intensive Multi-Agent Therapy, Including Dose-Compressed Cycles of Ifosfamide/Etoposide (IE) and Vincristine/Doxorubicin/Cyclophosphamide (VDC) for Patients With High-Risk Rhabdomyosarcoma
• Study Start Date: Jul 1, 2006
• Actual Primary Completion Date: Jan 1, 2010
• Actual Study Completion Date: Jun 30, 2019

Arms and Interventions

Arm

Intervention/Treatment

Experimental: High Risk Rhabdomyosarcoma Parameningeal (without intracranial extension) and paraspinal tumors receive chemotherapy starting Week 1 and begin radiation therapy at Week 20. Weeks 1-6: vincristine sulfate and irinotecan hydrochloride. Weeks 7-34: vincristine sulfate and irinotecan hydrochloride, Cyclophosphamide with MESNA, Doxorubicin hydrochloride, Etoposide, Ifosfamide with MESNA. Weeks 35-54: vincristine sulfate, Dactinomycin, irinotecan hydrochloride and Cyclophosphamide with MESNA and Filgrastim. Radiation therapy beginning at Week 20. Second look conventional surgery: Surgical resection other than biopsy will be applicable for the majority of patients.

Biological: dactinomycin; Age based dosage: ≥ 1 year 0.045 mg/kg IV x 1(maximum dose 2.5 mg), < 1 year 0.025 mg/kg. Day 1 of Weeks 35, 38, 41 and 44. Given IV; Other Names: Actinomycin-D Cosmegen NSC #3053 ; Drug: cyclophosphamide; Age based dosage: ≥ 3 years 1200 mg/m2, <3 years 40 mg/kg. Day 1 of weeks 7, 11, 15, 28, 32, 35, 38, 41 and 44. Given IV; Other Names: Cytoxan NSC #26271 ; Drug: doxorubicin hydrochloride; Age based dosage: ≥ 1 year: 37.5mg/m²/day, < 1 year: treat with 50% doses calculated on a m2 basis. Total dose 75 mg/m². Days 1 and 2 of weeks 7, 11, 15, 28 and 32. Given IV; Other Names: Adriamycin NSC #123127 ; Drug: etoposide; Age based dosage: ≥ 1 year: 100 mg/m²/day, < 1 year: treat with 50% doses calculated on a m2 basis. Days 1-5 of weeks 9, 13, 17, 26 and 30. Given IV; Other Names: VePesid Etopophos VP-16 NSC #141540 ; Drug: ifosfamide; Age based dosage: ≥ 1 year: 1800 mg/m²/day, < 1 year: treat with 50% doses calculated on a m2 basis. Days 1-5 of weeks 9, 13, 17, 26 and 30. Given IV; Other Names: Isophosphamide Iphosphamide Z4942 Ifex NSC #109724 ; Drug: irinotecan hydrochloride; Dosage 50 mg/m2-max dose 100 mg/day. Days 1-5 of weeks 1, 4, 20, 23, 47 and 50. Given IV; Other Names: CPT-11 Camptothecin-11 7-ethyl-10-(4-[1-piperidino]-1-piperidino)-carbonyloxy-camptothecin Camptosar NSC #616348 ; Drug: vincristine sulfate; Age based dosage: ≥ 3 years 1.5 mg/m2 (max dose 2 mg), ≥ 1 year and < 3 years 0.05 mg/kg (max dose 2 mg), < 1 year 0.025 mg/kg. Days 1-5 of weeks 1, 2, 3, 4, 5, 7, 8, 11, 12, 15, 16, 20, 21, 22, 23, 24, 28, 29, 32, 33, 35, 38, 41, 42, 43, 44, 47, 48, 50, and 51. Given IV; Other Names: Oncovin VCR LCR NSC #67574 ; Procedure: conventional surgery; Resection of the primary tumor with a surrounding "envelope" of normal tissue; Radiation: radiation therapy; Radiotherapy beginning at Week 20 to the primary tumor and to the metastatic sites excepting those with parameningeal tumors with intracranial extension (direct extension into the brain) and those requiring emergency radiotherapy; Biological: filgrastim; 5 micrograms/kg/day (max 300 micrograms) beginning 24-36 hours after the last dose of chemotherapy. Continue at least 7 days, or until the ANC ≥750/μL whichever comes last. Given subcutaneously.; Other Names: Granulocyte Colony-Stimulating Factor r-metHuG-CSF G-CSF Neupogen NSC #614629

Outcome Measures

Primary Outcome Measures

1. Number of Patients With Complete or Partial Response Assessed by RECIST Criteria [Protocol week 6 evaluation]

   Volumetric measurements of the primary tumor using an elliptical model (0.5 x the product of the 3 largest perpendicular diameters) to assess response to neoadjuvant therapy. The RECIST (Response Evaluation Criteria in Solid Tumors) from the NCI will be used for assessment of the size of measurable metastases, including nodal metastases. Primary Tumor Measurement: Technical guidelines for cross-sectional imaging computed tomography (CT) slice thickness should be 5mm or less and the diameter of the "measurable" mass should be at least twice the reconstructed slice thickness. Smaller masses are considered detectable, but will be counted as "non-measurable." Complete Response (CR): Complete disappearance of the tumor confirmed at >4 weeks. Partial Response (PR): At least 64% decrease in volume compared to the measurement obtained at study enrollment. Progressive Disease (PD): At least 40% increase in tumor volume compared to the smallest volume obtained since the beginning.

2. Percentage of Patients Experiencing Adverse Events Due to Concurrent Therapy [From enrollment to up to 2 years]

   Adverse events are reported for patients receiving concurrent irinotecan hydrochloride and radiotherapy.

Secondary Outcome Measures

1. Percentage of Patients Event Free at 4 Years Following Study Entry [4 years]

   Event-free survival: Time to recurrence, second malignancy, or death as a first event, estimated from a Kaplan Meier curve

Eligibility Criteria

Criteria

• Ages Eligible for Study: N/A to 49 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

DISEASE CHARACTERISTICS:

• Histologically confirmed high-risk rhabdomyosarcoma or ectomesenchymoma

• Prior enrollment on COG-D9902 to confirm local histological diagnosis required

• Tissue must be submitted for pathologic review within 2 days of patient registration on COG-D9902

• Newly diagnosed disease

• Metastatic disease (stage IV, clinical group IV)

• Has undergone initial surgical procedure (including biopsy) that provided the definitive diagnosis within the past 42 days

• Parameningeal and paraspinal tumors allowed

• Patients with parameningeal (without intracranial extension [ICE]) and paraspinal tumors should begin study chemotherapy at week 1 and radiotherapy at week 20

• Patients with evidence of ICE, as defined by contrast MRI showing that primary tumor touches, displaces, invades, distorts, or otherwise causes a signal abnormality of the dura in contiguity to the primary site in brain or spinal cord, are eligible

• ICE is presumed to exist if the cerebrospinal fluid cytopathology is positive for tumor at diagnosis

• Patients requiring emergency radiotherapy are eligible

• Patients requiring emergency radiotherapy (for intracranial extension or spinal cord impingement) should begin study chemotherapy at week 1 (irinotecan hydrochloride and vincristine) concurrently with radiation therapy

PATIENT CHARACTERISTICS:

• ECOG or Zubrod performance status (PS) 0-2 (Lansky PS 50-100% for patients < 10 years of age and Karnofsky PS 50-100% for patients ≥ 10 years of age)

• Absolute neutrophil count ≥ 750/mm³*

• Platelet count ≥ 75,000/mm³*

• Creatinine clearance or radioisotope glomerular filtration rate ≥ 70 mL/min (≥ 40 mL/min for infants < 1 year of age)

• Patients with urinary tract obstruction by tumor must meet the renal function criteria listed above AND must have unimpeded urinary flow established via decompression of the obstructed portion of the urinary tract

• SGPT < 2.5 times normal

• Bilirubin < 1.5 mg/dL

• Shortening fraction ≥ 27% by echocardiogram OR ejection fraction ≥ 50% by MUGA

• Not pregnant or nursing

• Negative pregnancy test

• Fertile patients must use effective contraception during study and for ≥ 1 month after study completion

• No evidence of uncontrolled infection

• Able to undergo radiotherapy NOTE: *Abnormal blood counts allowed if there is bone marrow biopsy or aspirate proven bone marrow involvement by rhabdomyosarcoma

PRIOR CONCURRENT THERAPY:

• No prior chemotherapy except steroids

• No prior radiotherapy

• No concurrent aprepitant during ifosfamide or doxorubicin hydrochloride chemotherapy

• No concurrent dexrazoxane

• No concurrent sargramostim (GM-CSF) or pegfilgrastim

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Lurleen Wallace Comprehensive Cancer at University of Alabama - Birmingham	Birmingham	Alabama	United States	35294
2	Phoenix Children's Hospital	Phoenix	Arizona	United States	85016-7710
3	Arizona Cancer Center at University of Arizona Health Sciences Center	Tucson	Arizona	United States	85724-5024
4	Arkansas Cancer Research Center at University of Arkansas for Medical Sciences	Little Rock	Arkansas	United States	72205
5	Southern California Permanente Medical Group	Downey	California	United States	90242-2814
6	Loma Linda University Cancer Institute at Loma Linda University Medical Center	Loma Linda	California	United States	92354
7	Jonathan Jaques Children's Cancer Center at Miller Children's Hospital	Long Beach	California	United States	90801
8	Childrens Hospital Los Angeles	Los Angeles	California	United States	90027
9	Children's Hospital Central California	Madera	California	United States	93638-8762
10	Children's Hospital and Research Center Oakland	Oakland	California	United States	94609
11	Children's Hospital of Orange County	Orange	California	United States	92868
12	Sutter Cancer Center	Sacramento	California	United States	95816
13	University of California Davis Cancer Center	Sacramento	California	United States	95817
14	Kaiser Permanente Medical Center - Oakland	Sacramento	California	United States	95825
15	Rady Children's Hospital - San Diego	San Diego	California	United States	92123-4282
16	UCSF Helen Diller Family Comprehensive Cancer Center	San Francisco	California	United States	94115
17	Stanford Cancer Center	Stanford	California	United States	94305-5824
18	Children's Hospital Center for Cancer and Blood Disorders	Aurora	Colorado	United States	80045
19	Carole and Ray Neag Comprehensive Cancer Center at the University of Connecticut Health Center	Farmington	Connecticut	United States	06360-2875
20	Alfred I. duPont Hospital for Children	Wilmington	Delaware	United States	19803
21	Lombardi Comprehensive Cancer Center at Georgetown University Medical Center	Washington	District of Columbia	United States	20007
22	Children's National Medical Center	Washington	District of Columbia	United States	20010-2970
23	Walter Reed Army Medical Center	Washington	District of Columbia	United States	20307-5001
24	Broward General Medical Center Cancer Center	Fort Lauderdale	Florida	United States	33316
25	Lee Cancer Care of Lee Memorial Health System	Fort Myers	Florida	United States	33901
26	University of Florida Shands Cancer Center	Gainesville	Florida	United States	32610-0232
27	Memorial Cancer Institute at Memorial Regional Hospital	Hollywood	Florida	United States	33021
28	Nemours Children's Clinic	Jacksonville	Florida	United States	32207
29	Miami Children's Hospital	Miami	Florida	United States	33155
30	Baptist-South Miami Regional Cancer Program	Miami	Florida	United States	33176
31	Florida Hospital Cancer Institute at Florida Hospital Orlando	Orlando	Florida	United States	32803-1273
32	M.D. Anderson Cancer Center at Orlando	Orlando	Florida	United States	32806
33	Nemours Children's Clinic - Orlando	Orlando	Florida	United States	32806
34	Sacred Heart Cancer Center at Sacred Heart Hospital	Pensacola	Florida	United States	32504
35	All Children's Hospital	Saint Petersburg	Florida	United States	33701
36	St. Joseph's Cancer Institute at St. Joseph's Hospital	Tampa	Florida	United States	33607
37	Kaplan Cancer Center at St. Mary's Medical Center	West Palm Beach	Florida	United States	33407
38	Winship Cancer Institute of Emory University	Atlanta	Georgia	United States	30322
39	MBCCOP - Medical College of Georgia Cancer Center	Augusta	Georgia	United States	30912-3730
40	Curtis and Elizabeth Anderson Cancer Institute at Memorial Health University Medical Center	Savannah	Georgia	United States	31403-3089
41	Cancer Research Center of Hawaii	Honolulu	Hawaii	United States	96813
42	University of Illinois Cancer Center	Chicago	Illinois	United States	60612-7243
43	Children's Memorial Hospital - Chicago	Chicago	Illinois	United States	60614
44	University of Chicago Cancer Research Center	Chicago	Illinois	United States	60637-1470
45	Advocate Christ Medical Center	Oak Lawn	Illinois	United States	60453
46	Advocate Lutheran General Cancer Care Center	Park Ridge	Illinois	United States	60068-1174
47	Saint Jude Midwest Affiliate	Peoria	Illinois	United States	61637
48	Simmons Cooper Cancer Institute	Springfield	Illinois	United States	62794-9677
49	Indiana University Melvin and Bren Simon Cancer Center	Indianapolis	Indiana	United States	46202-5289
50	St. Vincent Indianapolis Hospital	Indianapolis	Indiana	United States	46260
51	Kansas Masonic Cancer Research Institute at the University of Kansas Medical Center	Kansas City	Kansas	United States	66160-7357
52	Lucille P. Markey Cancer Center at University of Kentucky	Lexington	Kentucky	United States	40536-0093
53	Kosair Children's Hospital	Louisville	Kentucky	United States	40232
54	Tulane Cancer Center Office of Clinical Research	Alexandria	Louisiana	United States	71315-3198
55	Children's Hospital of New Orleans	New Orleans	Louisiana	United States	70118
56	Alvin and Lois Lapidus Cancer Institute at Sinai Hospital	Baltimore	Maryland	United States	21215
57	Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins	Baltimore	Maryland	United States	21231-2410
58	Floating Hospital for Children at Tufts - New England Medical Center	Boston	Massachusetts	United States	02111
59	Massachusetts General Hospital	Boston	Massachusetts	United States	02114
60	Dana-Farber/Harvard Cancer Center at Dana Farber Cancer Institute	Boston	Massachusetts	United States	02115
61	C.S. Mott Children's Hospital at University of Michigan Medical Center	Ann Arbor	Michigan	United States	48109-0286
62	Barbara Ann Karmanos Cancer Institute	Detroit	Michigan	United States	48201-1379
63	Hurley Medical Center	Flint	Michigan	United States	48503
64	Butterworth Hospital at Spectrum Health	Grand Rapids	Michigan	United States	49503-2560
65	CCOP - Kalamazoo	Kalamazoo	Michigan	United States	49007-5341
66	Breslin Cancer Center at Ingham Regional Medical Center	Lansing	Michigan	United States	48910
67	Children's Hospitals and Clinics of Minnesota - Minneapolis	Minneapolis	Minnesota	United States	55404
68	University of Minnesota Cancer Center	Minneapolis	Minnesota	United States	55455
69	Mayo Clinic Cancer Center	Rochester	Minnesota	United States	55905
70	University of Mississippi Cancer Clinic	Jackson	Mississippi	United States	39216-4505
71	Children's Mercy Hospital	Kansas City	Missouri	United States	64108
72	Siteman Cancer Center at Barnes-Jewish St. Peters Hospital - Saint Louis	Saint Louis	Missouri	United States	63110
73	Children's Hospital	Omaha	Nebraska	United States	68114-4113
74	UNMC Eppley Cancer Center at the University of Nebraska Medical Center	Omaha	Nebraska	United States	68198-6805
75	Sunrise Hospital and Medical Center	Las Vegas	Nevada	United States	89109-2306
76	Norris Cotton Cancer Center at Dartmouth-Hitchcock Medical Center	Lebanon	New Hampshire	United States	03756-0002
77	Hackensack University Medical Center Cancer Center	Hackensack	New Jersey	United States	07601
78	Overlook Hospital	Morristown	New Jersey	United States	07962
79	Cancer Institute of New Jersey at UMDNJ - Robert Wood Johnson Medical School	New Brunswick	New Jersey	United States	08903
80	Newark Beth Israel Medical Center	Newark	New Jersey	United States	07112
81	St. Joseph's Hospital and Medical Center	Paterson	New Jersey	United States	07503
82	University of New Mexico Cancer Center	Albuquerque	New Mexico	United States	87131-5636
83	Albany Medical Center Hospital	Albany	New York	United States	12208-3419
84	Roswell Park Cancer Institute	Buffalo	New York	United States	14263-0001
85	Schneider Children's Hospital	New Hyde Park	New York	United States	11040
86	NYU Cancer Institute at New York University Medical Center	New York	New York	United States	10016
87	Herbert Irving Comprehensive Cancer Center at Columbia University Medical Center	New York	New York	United States	10032
88	James P. Wilmot Cancer Center at University of Rochester Medical Center	Rochester	New York	United States	14642
89	Stony Brook University Cancer Center	Stony Brook	New York	United States	11794-9446
90	SUNY Upstate Medical University Hospital	Syracuse	New York	United States	13210
91	New York Medical College	Valhalla	New York	United States	10595
92	Mission Hospitals - Memorial Campus	Asheville	North Carolina	United States	28801
93	Lineberger Comprehensive Cancer Center at University of North Carolina - Chapel Hill	Chapel Hill	North Carolina	United States	27599-7295
94	Blumenthal Cancer Center at Carolinas Medical Center	Charlotte	North Carolina	United States	28232-2861
95	Presbyterian Cancer Center at Presbyterian Hospital	Charlotte	North Carolina	United States	28233-3549
96	Duke Comprehensive Cancer Center	Durham	North Carolina	United States	27710
97	Wake Forest University Comprehensive Cancer Center	Winston-Salem	North Carolina	United States	27157-1096
98	Akron Children's Hospital	Akron	Ohio	United States	44308-1062
99	Cincinnati Children's Hospital Medical Center	Cincinnati	Ohio	United States	45229-3039
100	Rainbow Babies and Children's Hospital	Cleveland	Ohio	United States	44106-5000
101	Cleveland Clinic Taussig Cancer Center	Cleveland	Ohio	United States	44195
102	Nationwide Children's Hospital	Columbus	Ohio	United States	43205-2696
103	Children's Medical Center - Dayton	Dayton	Ohio	United States	45404-1815
104	Toledo Hospital	Toledo	Ohio	United States	43606
105	Medical University of Ohio Cancer Center	Toledo	Ohio	United States	43614
106	Oklahoma University Cancer Institute	Oklahoma City	Oklahoma	United States	73104
107	Oregon Health and Science University Cancer Institute	Portland	Oregon	United States	97239-3098
108	Lehigh Valley Hospital - Muhlenberg	Bethlehem	Pennsylvania	United States	18107
109	Geisinger Cancer Institute at Geisinger Health	Danville	Pennsylvania	United States	17822-0001
110	Penn State Cancer Institute at Milton S. Hershey Medical Center	Hershey	Pennsylvania	United States	17033-0850
111	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania	United States	19104-9786
112	Children's Hospital of Pittsburgh	Pittsburgh	Pennsylvania	United States	15213
113	Hollings Cancer Center at Medical University of South Carolina	Charleston	South Carolina	United States	29425
114	Palmetto Health South Carolina Cancer Center	Columbia	South Carolina	United States	29203
115	Greenville Hospital Cancer Center	Greenville	South Carolina	United States	29605
116	Sanford Cancer Center at Sanford USD Medical Center	Sioux Falls	South Dakota	United States	57117-5039
117	T.C. Thompson Children's Hospital	Chattanooga	Tennessee	United States	37403
118	East Tennessee Children's Hospital	Knoxville	Tennessee	United States	37901
119	St. Jude Children's Research Hospital	Memphis	Tennessee	United States	38105
120	Vanderbilt-Ingram Cancer Center	Nashville	Tennessee	United States	37232-6838
121	Texas Tech University Health Sciences Center School of Medicine - Amarillo	Amarillo	Texas	United States	79106
122	Dell Children's Medical Center of Central Texas	Austin	Texas	United States	78723
123	Driscoll Children's Hospital	Corpus Christi	Texas	United States	78411
124	Medical City Dallas Hospital	Dallas	Texas	United States	75230
125	Simmons Comprehensive Cancer Center at University of Texas Southwestern Medical Center - Dallas	Dallas	Texas	United States	75390
126	Cook Children's Medical Center - Fort Worth	Fort Worth	Texas	United States	76104
127	Baylor University Medical Center - Houston	Houston	Texas	United States	77030-2399
128	M. D. Anderson Cancer Center at University of Texas	Houston	Texas	United States	77030-4009
129	Covenant Children's Hospital	Lubbock	Texas	United States	79410
130	University of Texas Health Science Center at San Antonio	San Antonio	Texas	United States	78207
131	Methodist Children's Hospital of South Texas	San Antonio	Texas	United States	78229-3993
132	CCOP - Scott and White Hospital	Temple	Texas	United States	76508
133	Primary Children's Medical Center	Salt Lake City	Utah	United States	84113-1100
134	Fletcher Allen Health Care - University Health Center Campus	Burlington	Vermont	United States	05401
135	Inova Fairfax Hospital	Falls Church	Virginia	United States	22042-3300
136	Children's Hospital of The King's Daughters	Norfolk	Virginia	United States	23507-1971
137	Carilion Medical Center for Children at Roanoke Community Hospital	Roanoke	Virginia	United States	24029
138	Children's Hospital and Regional Medical Center - Seattle	Seattle	Washington	United States	98105
139	Providence Cancer Center at Sacred Heart Medical Center	Spokane	Washington	United States	99220-2555
140	Mary Bridge Children's Hospital and Health Center - Tacoma	Tacoma	Washington	United States	98405
141	West Virginia University Health Sciences Center - Charleston	Charleston	West Virginia	United States	25302
142	Marshfield Clinic - Marshfield Center	Marshfield	Wisconsin	United States	54449
143	Midwest Children's Cancer Center	Milwaukee	Wisconsin	United States	53226
144	John Hunter Hospital	Newcastle	New South Wales	Australia	2310
145	Westmead Institute for Cancer Research at Westmead Hospital	Westmead	New South Wales	Australia	2145
146	Royal Children's Hospital	Herston, Brisbane	Queensland	Australia	4029
147	Women's and Children's Hospital	North Adelaide	South Australia	Australia	5006
148	Royal Children's Hospital	Parkville	Victoria	Australia	3052
149	Princess Margaret Hospital for Children	Perth	Western Australia	Australia	6001
150	Alberta Children's Hospital	Calgary	Alberta	Canada	T3B 6A8
151	University of Alberta Hospital	Edmonton	Alberta	Canada	T6G 1Z2
152	Children's & Women's Hospital of British Columbia	Vancouver	British Columbia	Canada	V6H 3V4
153	CancerCare Manitoba	Winnipeg	Manitoba	Canada	R3E 0V9
154	Janeway Children's Health and Rehabilitation Centre	St. John's	Newfoundland and Labrador	Canada	A1B 3V6
155	IWK Health Centre	Halifax	Nova Scotia	Canada	B3K 6R8
156	McMaster Children's Hospital at Hamilton Health Sciences	Hamilton	Ontario	Canada	L8N 3Z5
157	Cancer Centre of Southeastern Ontario at Kingston General Hospital	Kingston	Ontario	Canada	K7L 3N6
158	Children's Hospital of Western Ontario	London	Ontario	Canada	N6A 4G5
159	Children's Hospital of Eastern Ontario	Ottawa	Ontario	Canada	K1H 8L1
160	Hospital for Sick Children	Toronto	Ontario	Canada	M5G 1X8
161	Montreal Children's Hospital at McGill University Health Center	Montreal	Quebec	Canada	H3H 1P3
162	Hopital Sainte Justine	Montreal	Quebec	Canada	H3T 1C5
163	Saskatoon Cancer Centre at the University of Saskatchewan	Saskatoon	Saskatchewan	Canada	S7N 4H4
164	Centre Hospitalier Universitaire de Quebec	Quebec		Canada	G1V 4G2
165	San Jorge Children's Hospital	Santurce		Puerto Rico	00912
166	Swiss Pediatric Oncology Group Bern	Bern		Switzerland	3010

Sponsors and Collaborators

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

Investigators

• Study Chair: Brenda Weigel, MD, Masonic Cancer Center, University of Minnesota
• Study Chair: Carola A Arndt, MD, Mayo Clinic

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Data Available: Select individual patient-level data from this trial can be requested from the NCTN/NCORP Data Archive

Publications

None provided.

• Responsible Party: Children's Oncology Group
• ClinicalTrials.gov Identifier: NCT00354744
• Other Study ID Numbers: ARST0431; CDR0000489215; COG-ARST0431
• First Posted: Jul 20, 2006
• Last Update Posted: Jan 29, 2020
• Last Verified: Feb 1, 2019

• Keywords provided by Children's Oncology Group: adult rhabdomyosarcoma; previously untreated childhood rhabdomyosarcoma; adult malignant mesenchymoma; childhood malignant mesenchymoma; metastatic childhood soft tissue sarcoma; stage IV adult soft tissue sarcoma
• Additional relevant MeSH terms: Sarcoma; Rhabdomyosarcoma; Dactinomycin; Cyclophosphamide; Ifosfamide; Isophosphamide mustard; Doxorubicin; Liposomal doxorubicin; Irinotecan; Etoposide; Vincristine; Camptothecin; Lenograstim

Study Results

Participant Flow

Arm/Group Title	High_Risk_Rhabdomyosarcoma
Arm/Group Description	Parameningeal (without intracranial extension) and paraspinal tumors receive chemotherapy starting Week 1 and begin radiation therapy at Week 20. Weeks 1-6: vincristine sulfate and irinotecan hydrochloride. Weeks 7-34: vincristine sulfate and irinotecan hydrochloride, Cyclophosphamide with MESNA, Doxorubicin hydrochloride, Etoposide, Ifosfamide with MESNA. Weeks 35-54: vincristine sulfate, Dactinomycin, irinotecan hydrochloride and Cyclophosphamide with MESNA and Filgrastim. Radiation therapy beginning at Week 20. Second look conventional surgery: Surgical resection other than biopsy will be applicable for the majority of patients.
Period Title: Overall Study
STARTED	109
COMPLETED	67
NOT COMPLETED	42

Baseline Characteristics

Arm/Group Title	High_Risk_Rhabdomyosarcoma
Arm/Group Description	Parameningeal (without intracranial extension) and paraspinal tumors receive chemotherapy starting Week 1 and begin radiation therapy at Week 20. Weeks 1-6: vincristine sulfate and irinotecan hydrochloride. Weeks 7-34: vincristine sulfate and irinotecan hydrochloride, Cyclophosphamide with MESNA, Doxorubicin hydrochloride, Etoposide, Ifosfamide with MESNA. Weeks 35-54: vincristine sulfate, Dactinomycin, irinotecan hydrochloride and Cyclophosphamide with MESNA and Filgrastim. Radiation therapy beginning at Week 20. Second look conventional surgery: Surgical resection other than biopsy will be applicable for the majority of patients.
Overall Participants	109
Age (Count of Participants)
<=18 years	96 88.1%
Between 18 and 65 years	13 11.9%
>=65 years	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	11.85 (6.55)
Sex: Female, Male (Count of Participants)
Female	49 45%
Male	60 55%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	18 16.5%
Not Hispanic or Latino	86 78.9%
Unknown or Not Reported	5 4.6%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	1 0.9%
Asian	5 4.6%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	16 14.7%
White	76 69.7%
More than one race	0 0%
Unknown or Not Reported	11 10.1%
Region of Enrollment (participants) [Number]
United States	92 84.4%
Canada	11 10.1%
Australia	6 5.5%

Outcome Measures

1. Primary Outcome

Title	Number of Patients With Complete or Partial Response Assessed by RECIST Criteria
Description	Volumetric measurements of the primary tumor using an elliptical model (0.5 x the product of the 3 largest perpendicular diameters) to assess response to neoadjuvant therapy. The RECIST (Response Evaluation Criteria in Solid Tumors) from the NCI will be used for assessment of the size of measurable metastases, including nodal metastases. Primary Tumor Measurement: Technical guidelines for cross-sectional imaging computed tomography (CT) slice thickness should be 5mm or less and the diameter of the "measurable" mass should be at least twice the reconstructed slice thickness. Smaller masses are considered detectable, but will be counted as "non-measurable." Complete Response (CR): Complete disappearance of the tumor confirmed at >4 weeks. Partial Response (PR): At least 64% decrease in volume compared to the measurement obtained at study enrollment. Progressive Disease (PD): At least 40% increase in tumor volume compared to the smallest volume obtained since the beginning.
Time Frame	Protocol week 6 evaluation

Outcome Measure Data

Analysis Population Description

All eligible patients with protocol week tumor assessment (N=102)

Arm/Group Title	High_Risk_Rhabdomyosarcoma
Arm/Group Description	Parameningeal (without intracranial extension) and paraspinal tumors receive chemotherapy starting Week 1 and begin radiation therapy at Week 20. Weeks 1-6: vincristine sulfate and irinotecan hydrochloride. Weeks 7-34: vincristine sulfate and irinotecan hydrochloride, Cyclophosphamide with MESNA, Doxorubicin hydrochloride, Etoposide, Ifosfamide with MESNA. Weeks 35-54: vincristine sulfate, Dactinomycin, irinotecan hydrochloride and Cyclophosphamide with MESNA and Filgrastim. Radiation therapy beginning at Week 20. Second look conventional surgery: Surgical resection other than biopsy will be applicable for the majority of patients
Measure Participants	102
Number [percentage of participants]	63 57.8%

2. Primary Outcome

Title	Percentage of Patients Experiencing Adverse Events Due to Concurrent Therapy
Description	Adverse events are reported for patients receiving concurrent irinotecan hydrochloride and radiotherapy.
Time Frame	From enrollment to up to 2 years

Outcome Measure Data

Analysis Population Description

Percentage of patients experiencing a grade 3/4/5 toxicity in a course.

Arm/Group Title	High_Risk_Rhabdomyosarcoma
Arm/Group Description	Parameningeal (without intracranial extension) and paraspinal tumors receive chemotherapy starting Week 1 and begin radiation therapy at Week 20. Weeks 1-6: vincristine sulfate and irinotecan hydrochloride. Weeks 7-34: vincristine sulfate and irinotecan hydrochloride, Cyclophosphamide with MESNA, Doxorubicin hydrochloride, Etoposide, Ifosfamide with MESNA. Weeks 35-54: vincristine sulfate, Dactinomycin, irinotecan hydrochloride and Cyclophosphamide with MESNA and Filgrastim. Radiation therapy beginning at Week 20. Second look conventional surgery: Surgical resection other than biopsy will be applicable for the majority of patients.
Measure Participants	109
Course 1	53.3
Course 2	68.4
Course 3	79.3
Course 4	55.7

3. Secondary Outcome

Title	Percentage of Patients Event Free at 4 Years Following Study Entry
Description	Event-free survival: Time to recurrence, second malignancy, or death as a first event, estimated from a Kaplan Meier curve
Time Frame	4 years

Outcome Measure Data

Analysis Population Description

All eligible patients

Arm/Group Title	High_Risk_Rhabdomyosarcoma
Arm/Group Description	Patients with parameningeal (without intracranial extension) and paraspinal tumors should receive chemotherapy beginning Week 1 and begin radiation therapy at Week 20. Weeks 1-6 vincristine sulfate (VCR) & irinotecan hydrochloride (IRIN), Weeks 7-34 vincristine sulfate (VCR), Cyclophosphamide (CPM) with MESNA, Doxorubicin hydrochloride (DOX), Etoposide (ETOP), Ifosfamide (IFOS) with MESNA. Weeks 35-54 vincristine sulfate (VCR), Dactinomycin (DACT) and Cyclophosphamide (CPM) with MESNA and Filgrastim. Radiation therapy beginning at Week 20. Second look conventional surgery: Surgical resection other than biopsy will be applicable for the majority of patients.
Measure Participants	109
Number (95% Confidence Interval) [Percentage of patients]	36

Adverse Events

Adverse Event Reporting Description	The denominator for adverse events is 108 rather than 109 is because 1 patient did not receive treatment, therefore was excluded from the denominator.
Arm/Group Title	High_Risk_Rhabdomyosarcoma
Arm/Group Description	Parameningeal (without intracranial extension) and paraspinal tumors receive chemotherapy starting Week 1 and begin radiation therapy at Week 20. Weeks 1-6: vincristine sulfate and irinotecan hydrochloride. Weeks 7-34: vincristine sulfate and irinotecan hydrochloride, Cyclophosphamide with MESNA, Doxorubicin hydrochloride, Etoposide, Ifosfamide with MESNA. Weeks 35-54: vincristine sulfate, Dactinomycin, irinotecan hydrochloride and Cyclophosphamide with MESNA and Filgrastim. Radiation therapy beginning at Week 20. Second look conventional surgery: Surgical resection other than biopsy will be applicable for the majority of patients.
All Cause Mortality
	High_Risk_Rhabdomyosarcoma
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	High_Risk_Rhabdomyosarcoma
	Affected / at Risk (%)	# Events
Total	4/108 (3.7%)
Infections and infestations
Anorectal infection	1/108 (0.9%)
Infections and infestations - Other	1/108 (0.9%)
Sepsis	1/108 (0.9%)
Injury, poisoning and procedural complications
Radiation recall reaction (dermatologic)	1/108 (0.9%)
Other (Not Including Serious) Adverse Events
	High_Risk_Rhabdomyosarcoma
	Affected / at Risk (%)	# Events
Total	95/108 (88%)
Blood and lymphatic system disorders
Anemia	8/108 (7.4%)
Blood and lymphatic system disorders - Other	1/108 (0.9%)
Febrile neutropenia	44/108 (40.7%)
Cardiac disorders
Cardiac disorders - other	1/108 (0.9%)
Pericardial effusion	1/108 (0.9%)
Supraventricular tachycardia	1/108 (0.9%)
Gastrointestinal disorders
Abdominal distension	1/108 (0.9%)
Abdominal pain	15/108 (13.9%)
Anal pain	3/108 (2.8%)
Ascites	1/108 (0.9%)
Colitis	9/108 (8.3%)
Constipation	4/108 (3.7%)
Diarrhea	34/108 (31.5%)
Dysphagia	3/108 (2.8%)
Enterocolitis	1/108 (0.9%)
Esophageal pain	2/108 (1.9%)
Esophageal stenosis	1/108 (0.9%)
Esophagitis	4/108 (3.7%)
Gastritis	1/108 (0.9%)
Gastrointestinal disorders - Other	2/108 (1.9%)
Ileus	3/108 (2.8%)
Lower gastrointestinal hemorrhage	1/108 (0.9%)
Malabsorption	1/108 (0.9%)
Mucositis oral	20/108 (18.5%)
Nausea	21/108 (19.4%)
Oral pain	4/108 (3.7%)
Proctitis	1/108 (0.9%)
Rectal mucositis	2/108 (1.9%)
Rectal pain	2/108 (1.9%)
Small intestinal obstruction	2/108 (1.9%)
Stomach pain	1/108 (0.9%)
Typhlitis	1/108 (0.9%)
Vomiting	16/108 (14.8%)
General disorders
Edema limbs	1/108 (0.9%)
Fatigue	7/108 (6.5%)
Fever	4/108 (3.7%)
Gait disturbance	2/108 (1.9%)
General disorders and administration site conditions - Other	1/108 (0.9%)
Non-cardiac chest pain	2/108 (1.9%)
Pain	4/108 (3.7%)
Hepatobiliary disorders
Hepatic failure	1/108 (0.9%)
Immune system disorders
Anaphylaxis	3/108 (2.8%)
Infections and infestations
Abdominal infection	2/108 (1.9%)
Anorectal infection	1/108 (0.9%)
Bladder infection	3/108 (2.8%)
Catheter related infection	8/108 (7.4%)
Enterocolitis infectious	11/108 (10.2%)
Infections and infestations - Other	51/108 (47.2%)
Lung infection	1/108 (0.9%)
Nail infection	1/108 (0.9%)
Otitis externa	1/108 (0.9%)
Otitis media	1/108 (0.9%)
Peripheral nerve infection	1/108 (0.9%)
Pleural infection	1/108 (0.9%)
Skin infection	2/108 (1.9%)
Tooth infection	1/108 (0.9%)
Upper respiratory infection	4/108 (3.7%)
Urinary tract infection	4/108 (3.7%)
Wound infection	1/108 (0.9%)
Injury, poisoning and procedural complications
Dermatitis radiation	6/108 (5.6%)
Radiation recall reaction (dermatologic)	1/108 (0.9%)
Vascular access complication	1/108 (0.9%)
Venous injury	1/108 (0.9%)
Investigations
Activated partial thromboplastin time prolonged	1/108 (0.9%)
Alanine aminotransferase increased	12/108 (11.1%)
Aspartate aminotransferase increased	8/108 (7.4%)
Blood antidiuretic hormone abnormal	1/108 (0.9%)
Blood bilirubin increased	4/108 (3.7%)
Creatinine increased	2/108 (1.9%)
GGT increased	3/108 (2.8%)
INR increased	1/108 (0.9%)
Lipase increased	4/108 (3.7%)
Lymphocyte count decreased	1/108 (0.9%)
Neutrophil count decreased	9/108 (8.3%)
Platelet count decreased	4/108 (3.7%)
Serum amylase increased	1/108 (0.9%)
Weight loss	14/108 (13%)
White blood cell decreased	4/108 (3.7%)
Metabolism and nutrition disorders
Acidosis	1/108 (0.9%)
Alkalosis	1/108 (0.9%)
Anorexia	24/108 (22.2%)
Dehydration	17/108 (15.7%)
Hypercalcemia	3/108 (2.8%)
Hyperglycemia	8/108 (7.4%)
Hyperkalemia	3/108 (2.8%)
Hypernatremia	2/108 (1.9%)
Hyperuricemia	1/108 (0.9%)
Hypoalbuminemia	5/108 (4.6%)
Hypocalcemia	5/108 (4.6%)
Hypoglycemia	1/108 (0.9%)
Hypokalemia	20/108 (18.5%)
Hyponatremia	7/108 (6.5%)
Hypophosphatemia	5/108 (4.6%)
Musculoskeletal and connective tissue disorders
Back pain	4/108 (3.7%)
Bone pain	1/108 (0.9%)
Buttock pain	1/108 (0.9%)
Generalized muscle weakness	1/108 (0.9%)
Muscle weakness lower limb	2/108 (1.9%)
Muscle weakness upper limb	1/108 (0.9%)
Musculoskeletal and connective tissue disorder - Other	1/108 (0.9%)
Myalgia	1/108 (0.9%)
Neck pain	1/108 (0.9%)
Pain in extremity	2/108 (1.9%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Tumor Pain	4/108 (3.7%)
Nervous system disorders
Cognitive disturbance	2/108 (1.9%)
Encephalopathy	1/108 (0.9%)
Headache	5/108 (4.6%)
Nervous system disorders - Other	1/108 (0.9%)
Neuralgia	1/108 (0.9%)
Peripheral motor neuropathy	8/108 (7.4%)
Peripheral sensory neuropathy	8/108 (7.4%)
Seizure	1/108 (0.9%)
Sinus pain	1/108 (0.9%)
Syncope	1/108 (0.9%)
Psychiatric disorders
Depression	4/108 (3.7%)
Personality change	1/108 (0.9%)
Renal and urinary disorders
Acute kidney injury	1/108 (0.9%)
Chronic kidney disease	1/108 (0.9%)
Cystitis noninfective	3/108 (2.8%)
Hematuria	2/108 (1.9%)
Proteinuria	1/108 (0.9%)
Renal and urinary disorders - Other	2/108 (1.9%)
Urinary tract obstruction	1/108 (0.9%)
Urinary tract pain	1/108 (0.9%)
Reproductive system and breast disorders
Perineal pain	1/108 (0.9%)
Uterine hemorrhage	1/108 (0.9%)
Respiratory, thoracic and mediastinal disorders
Adult respiratory distress syndrome	1/108 (0.9%)
Cough	2/108 (1.9%)
Dyspnea	1/108 (0.9%)
Epistaxis	2/108 (1.9%)
Hypoxia	5/108 (4.6%)
Laryngeal edema	1/108 (0.9%)
Pharyngolaryngeal pain	3/108 (2.8%)
Pleural effusion	2/108 (1.9%)
Pneumonitis	4/108 (3.7%)
Respiratory, thoracic and mediastinal disorders - Other	1/108 (0.9%)
Skin and subcutaneous tissue disorders
Purpura	1/108 (0.9%)
Rash maculo-papular	1/108 (0.9%)
Vascular disorders
Hypotension	3/108 (2.8%)
Thromboembolic event	1/108 (0.9%)
Vascular disorders - Other	1/108 (0.9%)

Limitations/Caveats

[Not Specified]

More Information

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.