Combination Chemotherapy With or Without Radiation Therapy in Treating Young Patients With Newly Diagnosed Stage III or Stage IV Wilms' Tumor

• Sponsor: Children's Oncology Group (Other)
• Overall Status: Active, not recruiting
• CT.gov ID: NCT00379340
• Collaborator: National Cancer Institute (NCI) (NIH)
• Enrollment: 395
• Locations: 207
• Arms: 5
• Patients Per Site: 1.9

Study Details

Study Description

Brief Summary

This phase III trial is studying how well combination chemotherapy with or without radiation therapy works in treating young patients with newly diagnosed stage III or stage IV Favorable Histology Wilms' tumor. Drugs used in chemotherapy 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 more than one drug (combination chemotherapy) with or without radiation therapy may kill more tumor cells.

Condition or Disease	Intervention/Treatment	Phase
Stage III Wilms Tumor With Loss of Heterozygosity (LOH) for 1p and 16q; Stage IV Wilms Tumor	Drug: doxorubicin hydrochloride; Drug: liposomal vincristine sulfate; Procedure: conventional surgery; Radiation: 3-dimensional conformal radiation therapy; Biological: dactinomycin; Drug: cyclophosphamide; Drug: etoposide	Phase 3

Detailed Description

PRIMARY OBJECTIVES:

1. Determine the 4-year event-free survival (EFS) of patients with stage IV favorable histology (FH) Wilms' tumor with pulmonary metastases only who have complete resolution of pulmonary lesions without whole lung irradiation treated with DD4A chemotherapy comprising vincristine, dactinomycin, and doxorubicin hydrochloride.

2. Determine the 4-year EFS of these patients who do not have resolution of pulmonary metastases by week 6 treated with the addition of cyclophosphamide and etoposide to a modified-regimen DD4A (regimen M).

3. Determine the 4-year EFS of patients with stage III or IV FH Wilms' tumor with loss of heterozygosity for chromosomes 1p and 16q treated with regimen M.

SECONDARY OBJECTIVES:

1. Correlate the burden of pulmonary metastatic disease with outcome in patients with stage IV FH Wilms' tumor.

OUTLINE: This is a multicenter study.

REGIMEN DD4A (weeks 1-6): Patients receive dactinomycin IV over 1-5 minutes once in week 1; vincristine IV once in weeks 1-6; and doxorubicin hydrochloride IV over 15 minutes once in week 4 in the absence of disease progression or unacceptable toxicity. Patients with both pulmonary and extra-pulmonary metastases at diagnosis undergo radiotherapy once daily beginning in week 1 and continuing for 5-14 days. After completion of DD4A chemotherapy (week 6), patients undergo evaluation. Patients with stage IV disease and pulmonary metastases only with no loss of heterozygosity (LOH) who are rapid complete responders (RCR) (i.e., all pulmonary metastases disappear) proceed to regimen DD4A (weeks 7-25).

All other patients (i.e., patients with stage III or IV disease and LOH of both 1p and 16q; stage IV disease with pulmonary metastases only who are slow incomplete responders [SIR] [i.e., pulmonary metastases do not disappear]; or stage IV disease with nonpulmonary metastases or with nonpulmonary metastases in combination with pulmonary metastases proceed to regimen M (weeks 7-31).

Patients with initially unresectable or incompletely resected tumors are reevaluated at week 6, and if resectable, undergo surgery and then proceed to either regimen DD4A or regimen M as described above.

REGIMEN DD4A (weeks 7-25): Patients receive dactinomycin IV over 1-5 minutes once in weeks 7, 13, 19, and 25; vincristine IV once in weeks 7-10, 13, 16, 19, 22, and 25; and doxorubicin hydrochloride IV over 15 minutes once in weeks 10, 16, and 22 in the absence of disease progression or unacceptable toxicity.

REGIMEN M (weeks 7-31): Patients receive cyclophosphamide IV over 1 hour and etoposide IV over 1 hour on days 1-5 in weeks 7, 10, 19, and 25; vincristine IV once in weeks 8, 9, 11, 12, 13, 16, 22, 28, and 31; and dactinomycin IV or doxorubicin hydrochloride IV over 15 minutes once in weeks 13, 16, 22, 28, and 31 in the absence of disease progression or unacceptable toxicity. Patients with pulmonary metastases only who are SIR also undergo whole lung radiotherapy once daily beginning in week 7 and continuing for 5-14 days.

NOTE: Patients who begin study treatment after undergoing resection of all pulmonary metastases are not eligible for this study. It is recommended that these patients be treated as per the current gold standard of therapy which is chemotherapy according to regimen DD4A (weeks 1-25) and whole lung radiotherapy for 5-14 days beginning in week 1.

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

Study Design

• Study Type: Interventional
• Actual Enrollment: 395 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Treatment of Newly Diagnosed Higher Risk Favorable Histology Wilms Tumors
• Actual Study Start Date: Feb 26, 2007
• Actual Primary Completion Date: Jun 30, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Stage IV and rapid complete response (RCR) of lung metastases Stage IV and rapid complete response (RCR) of lung metastases continuously treated with DD4A after 6 weeks of DD4A	Drug: doxorubicin hydrochloride; Given IV; Other Names: ADM ADR Adria Adriamycin PFS Adriamycin RDF ; Drug: liposomal vincristine sulfate; Given IV; Other Names: liposomal vincristine Marqibo vincristine liposomal vincristine sulfate liposome injection ; Procedure: conventional surgery; Other Names: surgery, conventional ; Biological: dactinomycin; Given IV; Other Names: ACT-D actinomycin C1 AD Cosmegen DACT
Experimental: Stage IV and slow incomplete response (SIR) of lung metastases Stage IV and slow incomplete response (SIR) of lung metastases treated with Regimen M after 6 weeks of DD4A	Drug: doxorubicin hydrochloride; Given IV; Other Names: ADM ADR Adria Adriamycin PFS Adriamycin RDF ; Drug: liposomal vincristine sulfate; Given IV; Other Names: liposomal vincristine Marqibo vincristine liposomal vincristine sulfate liposome injection ; Procedure: conventional surgery; Other Names: surgery, conventional ; Radiation: 3-dimensional conformal radiation therapy; Other Names: 3D conformal radiation therapy 3D-CRT ; Biological: dactinomycin; Given IV; Other Names: ACT-D actinomycin C1 AD Cosmegen DACT ; Drug: cyclophosphamide; Given IV; Other Names: CPM CTX Cytoxan Endoxan Endoxana ; Drug: etoposide; Given IV; Other Names: EPEG VP-16 VP-16-213
Other: Stage III/IV with LOH 1p and 16q treated with Regimen M Stage III/IV with LOH 1p and 16q treated with Regimen M	Drug: doxorubicin hydrochloride; Given IV; Other Names: ADM ADR Adria Adriamycin PFS Adriamycin RDF ; Drug: liposomal vincristine sulfate; Given IV; Other Names: liposomal vincristine Marqibo vincristine liposomal vincristine sulfate liposome injection ; Procedure: conventional surgery; Other Names: surgery, conventional ; Radiation: 3-dimensional conformal radiation therapy; Other Names: 3D conformal radiation therapy 3D-CRT ; Biological: dactinomycin; Given IV; Other Names: ACT-D actinomycin C1 AD Cosmegen DACT ; Drug: cyclophosphamide; Given IV; Other Names: CPM CTX Cytoxan Endoxan Endoxana ; Drug: etoposide; Given IV; Other Names: EPEG VP-16 VP-16-213
Other: Stage IV with non-lung disease treated with Regimen M Stage IV with non-lung disease treated with Regimen M	Drug: doxorubicin hydrochloride; Given IV; Other Names: ADM ADR Adria Adriamycin PFS Adriamycin RDF ; Drug: liposomal vincristine sulfate; Given IV; Other Names: liposomal vincristine Marqibo vincristine liposomal vincristine sulfate liposome injection ; Procedure: conventional surgery; Other Names: surgery, conventional ; Biological: dactinomycin; Given IV; Other Names: ACT-D actinomycin C1 AD Cosmegen DACT ; Drug: cyclophosphamide; Given IV; Other Names: CPM CTX Cytoxan Endoxan Endoxana ; Drug: etoposide; Given IV; Other Names: EPEG VP-16 VP-16-213
Other: Stage IV with lung metastases Stage IV with lung metastases treated with DD4A for less than 6 weeks and/or response inevaluable at week 6	Drug: doxorubicin hydrochloride; Given IV; Other Names: ADM ADR Adria Adriamycin PFS Adriamycin RDF ; Drug: liposomal vincristine sulfate; Given IV; Other Names: liposomal vincristine Marqibo vincristine liposomal vincristine sulfate liposome injection ; Procedure: conventional surgery; Other Names: surgery, conventional ; Biological: dactinomycin; Given IV; Other Names: ACT-D actinomycin C1 AD Cosmegen DACT

Outcome Measures

Primary Outcome Measures

1. Event Free Survival Probability [4 years]

   Probability of no relapse, secondary malignancy, or death after 4 year in the study.

2. Event Free Survival (EFS) Probability [At 4 years]

   Probability of no relapse, secondary malignancy, or death after 4 year in the study.

3. Event Free Survival Probability [At 4 years]

   Probability of no relapse, secondary malignancy, or death after 4 year in the study

Secondary Outcome Measures

1. Event Free Survival Associated With the Burden of Pulmonary Metastatic Disease [At 4 years]

   Probability of no relapse, secondary malignancy, or death after 4 year in the study.

Eligibility Criteria

Criteria

• Ages Eligible for Study: N/A to 29 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Newly diagnosed Wilms' tumor meeting 1 of the following criteria:

• Stage IV disease with favorable histology with or without loss of heterozygosity (LOH) for 1p and 16q

• Stage III disease with favorable histology with LOH for 1p and 16q transferring from clinical trial COG-AREN0532

• Patients must begin therapy within 14 days after surgery or biopsy, unless medically contraindicated

• No bilateral Wilms' tumors (stage IV)

• Patients should be referred to COG-AREN0534

• Previously enrolled in clinical trial COG-AREN03B2

• Karnofsky performance status (PS) 50-100% (for patients > 16 years of age) OR Lansky PS 50-100% (for patients ≤ 16 years of age)

• Bilirubin ≤ 1.5 times upper limit of normal (ULN)

• AST or ALT < 2.5 times ULN

• Shortening fraction ≥ 27% by echocardiogram OR ejection fraction ≥ 50% by radionuclide angiogram

• Not pregnant or nursing

• Negative pregnancy test

• Fertile patients must use effective contraception

• No prior tumor-directed chemotherapy or radiotherapy unless transferring from clinical trial COG-AREN0532 OR treatment for emergent issues, as medically indicated

• No concurrent aprepitant

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Children's Hospital of Alabama	Birmingham	Alabama	United States	35233
2	University of Alabama at Birmingham	Birmingham	Alabama	United States	35294
3	University of South Alabama	Mobile	Alabama	United States	36604
4	Phoenix Childrens Hospital	Phoenix	Arizona	United States	85016
5	University of Arizona Health Sciences Center	Tucson	Arizona	United States	85724
6	University of Arkansas for Medical Sciences	Little Rock	Arkansas	United States	72205
7	Children's Oncology Group	Arcadia	California	United States	91006-3776
8	Southern California Permanente Medical Group	Downey	California	United States	90242
9	Loma Linda University Medical Center	Loma Linda	California	United States	92354
10	Miller Children's Hospital	Long Beach	California	United States	90806
11	Children's Hospital Los Angeles	Los Angeles	California	United States	90027
12	Cedars-Sinai Medical Center	Los Angeles	California	United States	90048
13	Children's Hospital Central California	Madera	California	United States	93636-8762
14	Children's Hospital and Research Center at Oakland	Oakland	California	United States	94609-1809
15	Kaiser Permanente-Oakland	Oakland	California	United States	94611
16	Childrens Hospital of Orange County	Orange	California	United States	92868-3874
17	Lucile Packard Children's Hospital Stanford University	Palo Alto	California	United States	94304
18	Sutter General Hospital	Sacramento	California	United States	95816
19	UC Davis Comprehensive Cancer Center	Sacramento	California	United States	95817
20	Rady Children's Hospital - San Diego	San Diego	California	United States	92123
21	University of California San Francisco Medical Center-Parnassus	San Francisco	California	United States	94143
22	Children's Hospital Colorado	Aurora	Colorado	United States	80045
23	Rocky Mountain Hospital for Children-Presbyterian Saint Luke's Medical Center	Denver	Colorado	United States	80218
24	Connecticut Children's Medical Center	Hartford	Connecticut	United States	06106
25	Yale University	New Haven	Connecticut	United States	06520-8032
26	Alfred I duPont Hospital for Children	Wilmington	Delaware	United States	19803
27	Children's National Medical Center	Washington	District of Columbia	United States	20010
28	Lombardi Comprehensive Cancer Center at Georgetown University	Washington	District of Columbia	United States	20057
29	Broward Health Medical Center	Fort Lauderdale	Florida	United States	33316
30	Lee Memorial Health System	Fort Myers	Florida	United States	33901
31	University of Florida	Gainesville	Florida	United States	32610
32	Memorial Healthcare System - Joe DiMaggio Children's Hospital	Hollywood	Florida	United States	33021
33	Nemours Children's Clinic - Jacksonville	Jacksonville	Florida	United States	32207-8426
34	University of Miami Miller School of Medicine-Sylvester Cancer Center	Miami	Florida	United States	33136
35	Miami Children's Hospital	Miami	Florida	United States	33155
36	Baptist Hospital of Miami	Miami	Florida	United States	33176
37	Florida Hospital	Orlando	Florida	United States	32803
38	M D Anderson Cancer Center- Orlando	Orlando	Florida	United States	32806
39	Nemours Childrens Clinic - Orlando	Orlando	Florida	United States	32806
40	Nemours Children's Clinic - Pensacola	Pensacola	Florida	United States	32504
41	All Children's Hospital	Saint Petersburg	Florida	United States	33701
42	Saint Joseph Children's Hospital of Tampa	Tampa	Florida	United States	33607
43	Saint Mary's Hospital	West Palm Beach	Florida	United States	33407
44	Children's Healthcare of Atlanta - Egleston	Atlanta	Georgia	United States	30322
45	Memorial Health University Medical Center	Savannah	Georgia	United States	31403
46	University of Hawaii	Honolulu	Hawaii	United States	96813
47	Tripler Army Medical Center	Honolulu	Hawaii	United States	96859
48	Saint Luke's Mountain States Tumor Institute	Boise	Idaho	United States	83712
49	University of Illinois	Chicago	Illinois	United States	60612
50	Childrens Memorial Hospital	Chicago	Illinois	United States	60614
51	University of Chicago Comprehensive Cancer Center	Chicago	Illinois	United States	60637-1470
52	Loyola University Medical Center	Maywood	Illinois	United States	60153
53	Advocate Hope Children's Hospital	Oak Lawn	Illinois	United States	60453
54	Advocate Lutheran General Hospital	Park Ridge	Illinois	United States	60068
55	Saint Jude Midwest Affiliate	Peoria	Illinois	United States	61602
56	Southern Illinois University	Springfield	Illinois	United States	62702
57	Riley Hospital for Children	Indianapolis	Indiana	United States	46202
58	Saint Vincent Hospital and Health Services	Indianapolis	Indiana	United States	46260
59	Raymond Blank Children's Hospital	Des Moines	Iowa	United States	50309
60	University of Iowa Hospitals and Clinics	Iowa City	Iowa	United States	52242
61	University of Kentucky	Lexington	Kentucky	United States	40536
62	Kosair Children's Hospital	Louisville	Kentucky	United States	40202
63	Tulane University Health Sciences Center	New Orleans	Louisiana	United States	70112
64	Children's Hospital-Main Campus	New Orleans	Louisiana	United States	70118
65	Ochsner Clinic Foundation	New Orleans	Louisiana	United States	70121
66	Eastern Maine Medical Center	Bangor	Maine	United States	04401
67	University of Maryland Greenebaum Cancer Center	Baltimore	Maryland	United States	21201-1595
68	Sinai Hospital of Baltimore	Baltimore	Maryland	United States	21215
69	Johns Hopkins University	Baltimore	Maryland	United States	21287-8936
70	Walter Reed National Military Medical Center	Bethesda	Maryland	United States	20889-5600
71	Floating Hospital for Children at Tufts Medical Center	Boston	Massachusetts	United States	02111
72	Massachusetts General Hospital Cancer Center	Boston	Massachusetts	United States	02114
73	Dana-Farber Cancer Institute	Boston	Massachusetts	United States	02115
74	University of Massachusetts Medical School	Worcester	Massachusetts	United States	01655
75	C S Mott Children's Hospital	Ann Arbor	Michigan	United States	48109
76	Wayne State University	Detroit	Michigan	United States	48202
77	Saint John Hospital and Medical Center	Detroit	Michigan	United States	48236
78	Hurley Medical Center	Flint	Michigan	United States	48502
79	Helen DeVos Children's Hospital at Spectrum Health	Grand Rapids	Michigan	United States	49503
80	Bronson Methodist Hospital	Kalamazoo	Michigan	United States	49007
81	Kalamazoo Center for Medical Studies	Kalamazoo	Michigan	United States	49008
82	Michigan State University - Breslin Cancer Center	Lansing	Michigan	United States	48910
83	William Beaumont Hospital	Royal Oak	Michigan	United States	48073
84	Children's Hospitals and Clinics of Minnesota - Minneapolis	Minneapolis	Minnesota	United States	55404
85	University of Minnesota Medical Center-Fairview	Minneapolis	Minnesota	United States	55455
86	Mayo Clinic	Rochester	Minnesota	United States	55905
87	University of Mississippi Medical Center	Jackson	Mississippi	United States	39216
88	University of Missouri-Columbia	Columbia	Missouri	United States	65212
89	The Childrens Mercy Hospital	Kansas City	Missouri	United States	64108
90	Cardinal Glennon Children's Medical Center	Saint Louis	Missouri	United States	63104
91	Saint John's Mercy Medical Center	Saint Louis	Missouri	United States	63141
92	Children's Hospital and Medical Center of Omaha	Omaha	Nebraska	United States	68114
93	University of Nebraska Medical Center	Omaha	Nebraska	United States	68198
94	Nevada Cancer Research Foundation CCOP	Las Vegas	Nevada	United States	89106
95	Dartmouth Hitchcock Medical Center	Lebanon	New Hampshire	United States	03756
96	Hackensack University Medical Center	Hackensack	New Jersey	United States	07601
97	Morristown Memorial Hospital	Morristown	New Jersey	United States	07962
98	Saint Peter's University Hospital	New Brunswick	New Jersey	United States	08901
99	UMDNJ - Robert Wood Johnson University Hospital	New Brunswick	New Jersey	United States	08903
100	Newark Beth Israel Medical Center	Newark	New Jersey	United States	07112
101	Saint Joseph's Regional Medical Center	Paterson	New Jersey	United States	07503
102	Overlook Hospital	Summit	New Jersey	United States	07902
103	University of New Mexico Cancer Center	Albuquerque	New Mexico	United States	87106
104	Albany Medical Center	Albany	New York	United States	12208
105	Montefiore Medical Center	Bronx	New York	United States	10467-2490
106	Brooklyn Hospital Center	Brooklyn	New York	United States	11201
107	Roswell Park Cancer Institute	Buffalo	New York	United States	14263
108	Winthrop University Hospital	Mineola	New York	United States	11501
109	The Steven and Alexandra Cohen Children's Medical Center of New York	New Hyde Park	New York	United States	11040
110	Columbia University Medical Center	New York	New York	United States	10032
111	Memorial Sloan Kettering Cancer Center	New York	New York	United States	10065
112	Weill Medical College of Cornell University	New York	New York	United States	10065
113	University of Rochester	Rochester	New York	United States	14642
114	Stony Brook University Medical Center	Stony Brook	New York	United States	11794
115	State University of New York Upstate Medical University	Syracuse	New York	United States	13210
116	New York Medical College	Valhalla	New York	United States	10595
117	Mission Hospitals Inc	Asheville	North Carolina	United States	28801
118	University of North Carolina	Chapel Hill	North Carolina	United States	27599
119	Carolinas Medical Center	Charlotte	North Carolina	United States	28203
120	Presbyterian Hospital	Charlotte	North Carolina	United States	28204
121	Duke University Medical Center	Durham	North Carolina	United States	27710
122	East Carolina University	Greenville	North Carolina	United States	27858
123	Wake Forest University Health Sciences	Winston-Salem	North Carolina	United States	27157
124	Sanford Medical Center-Fargo	Fargo	North Dakota	United States	58122
125	Children's Hospital Medical Center of Akron	Akron	Ohio	United States	44308
126	Cincinnati Children's Hospital Medical Center	Cincinnati	Ohio	United States	45229
127	Rainbow Babies and Childrens Hospital	Cleveland	Ohio	United States	44106
128	Cleveland Clinic Foundation	Cleveland	Ohio	United States	44195
129	Nationwide Children's Hospital	Columbus	Ohio	United States	43205
130	The Children's Medical Center of Dayton	Dayton	Ohio	United States	45404
131	The Toledo Hospital/Toledo Children's Hospital	Toledo	Ohio	United States	43606
132	Mercy Children's Hospital	Toledo	Ohio	United States	43608
133	University of Oklahoma Health Sciences Center	Oklahoma City	Oklahoma	United States	73104
134	Natalie W Bryant Cancer Center	Tulsa	Oklahoma	United States	74136
135	Legacy Emanuel Children's Hospital	Portland	Oregon	United States	97227
136	Legacy Emanuel Hospital and Health Center	Portland	Oregon	United States	97227
137	Oregon Health and Science University	Portland	Oregon	United States	97239
138	Lehigh Valley Hospital - Muhlenberg	Bethlehem	Pennsylvania	United States	18017
139	Geisinger Medical Center	Danville	Pennsylvania	United States	17822-2001
140	Penn State Hershey Children's Hospital	Hershey	Pennsylvania	United States	17033
141	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania	United States	19104
142	Saint Christopher's Hospital for Children	Philadelphia	Pennsylvania	United States	19134
143	Children's Hospital of Pittsburgh of UPMC	Pittsburgh	Pennsylvania	United States	15224
144	Rhode Island Hospital	Providence	Rhode Island	United States	02903
145	Medical University of South Carolina	Charleston	South Carolina	United States	29425
146	Palmetto Health Richland	Columbia	South Carolina	United States	29203
147	BI-LO Charities Children's Cancer Center	Greenville	South Carolina	United States	29605
148	Greenville Cancer Treatment Center	Greenville	South Carolina	United States	29605
149	Sanford USD Medical Center - Sioux Falls	Sioux Falls	South Dakota	United States	57117-5134
150	T C Thompson Children's Hospital	Chattanooga	Tennessee	United States	37403
151	East Tennessee Childrens Hospital	Knoxville	Tennessee	United States	37916
152	St. Jude Children's Research Hospital	Memphis	Tennessee	United States	38105
153	Vanderbilt-Ingram Cancer Center	Nashville	Tennessee	United States	37232
154	Texas Tech University Health Science Center-Amarillo	Amarillo	Texas	United States	79106
155	Dell Children's Medical Center of Central Texas	Austin	Texas	United States	78723
156	Driscoll Children's Hospital	Corpus Christi	Texas	United States	78411
157	Medical City Dallas Hospital	Dallas	Texas	United States	75230
158	University of Texas Southwestern Medical Center	Dallas	Texas	United States	75390
159	Brooke Army Medical Center	Fort Sam Houston	Texas	United States	78234
160	Cook Children's Medical Center	Fort Worth	Texas	United States	76104
161	Baylor College of Medicine	Houston	Texas	United States	77030
162	Covenant Children's Hospital	Lubbock	Texas	United States	79410
163	University of Texas Health Science Center at San Antonio	San Antonio	Texas	United States	78229-3900
164	Methodist Children's Hospital of South Texas	San Antonio	Texas	United States	78229
165	Scott and White Memorial Hospital	Temple	Texas	United States	76508
166	Primary Children's Medical Center	Salt Lake City	Utah	United States	84113
167	University of Vermont	Burlington	Vermont	United States	05401
168	University of Virginia	Charlottesville	Virginia	United States	22908
169	Inova Fairfax Hospital	Falls Church	Virginia	United States	22042
170	Childrens Hospital-King's Daughters	Norfolk	Virginia	United States	23507
171	Virginia Commonwealth University	Richmond	Virginia	United States	23298
172	Carilion Clinic Children's Hospital	Roanoke	Virginia	United States	24014
173	Seattle Children's Hospital	Seattle	Washington	United States	98105
174	Providence Sacred Heart Medical Center and Children's Hospital	Spokane	Washington	United States	99204
175	Mary Bridge Children's Hospital and Health Center	Tacoma	Washington	United States	98405
176	Madigan Army Medical Center	Tacoma	Washington	United States	98431
177	West Virginia University Charleston	Charleston	West Virginia	United States	25304
178	University of Wisconsin Hospital and Clinics	Madison	Wisconsin	United States	53792
179	Marshfield Clinic	Marshfield	Wisconsin	United States	54449
180	Midwest Children's Cancer Center	Milwaukee	Wisconsin	United States	53226
181	Sydney Children's Hospital	Randwick	New South Wales	Australia	2031
182	The Children's Hospital at Westmead	Sydney	New South Wales	Australia	2145
183	Royal Brisbane and Women's Hospital	Herston	Queensland	Australia	4029
184	Royal Childrens Hospital	Herston	Queensland	Australia	4029
185	Women's and Children's Hospital-Adelaide	North Adelaide	South Australia	Australia	5006
186	Royal Children's Hospital	Parkville	Victoria	Australia	3052
187	Princess Margaret Hospital for Children	Perth	Western Australia	Australia	6008
188	Alberta Children's Hospital	Calgary	Alberta	Canada	T3B 6A8
189	University of Alberta Hospital	Edmonton	Alberta	Canada	T6G 2B7
190	British Columbia Children's Hospital	Vancouver	British Columbia	Canada	V6H 3V4
191	CancerCare Manitoba	Winnipeg	Manitoba	Canada	R3E 0V9
192	Janeway Child Health Centre	Saint John's	Newfoundland and Labrador	Canada	A1B 3V6
193	IWK Health Centre	Halifax	Nova Scotia	Canada	B3J 3G9
194	McMaster Children's Hospital at Hamilton Health Sciences	Hamilton	Ontario	Canada	L8N 3Z5
195	Chedoke-McMaster Hospitals	Hamilton	Ontario	Canada	L8S 4L8
196	Cancer Centre of Southeastern Ontario at Kingston General Hospital	Kingston	Ontario	Canada	K7L 5P9
197	Children's Hospital	London	Ontario	Canada	N6A 5W9
198	Children's Hospital of Eastern Ontario	Ottawa	Ontario	Canada	K1H 8L1
199	Hospital for Sick Children	Toronto	Ontario	Canada	M5G 1X8
200	The Montreal Children's Hospital of the MUHC	Montreal	Quebec	Canada	H3H 1P3
201	Hospital Sainte-Justine	Montreal	Quebec	Canada	H3T 1C5
202	Centre Hospitalier Universitaire de Quebec	Ste-Foy	Quebec	Canada	G1V 4G2
203	Saskatoon Cancer Centre	Saskatoon	Saskatchewan	Canada	S7N 4H4
204	Schneider Children's Medical Center of Israel	Petah	Tikua	Israel	49202
205	Starship Children's Hospital	Grafton	Auckland	New Zealand	1145
206	San Jorge Children's Hospital	Santurce		Puerto Rico	00912
207	Swiss Pediatric Oncology Group - Bern	Bern		Switzerland	3010

Sponsors and Collaborators

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

Investigators

• Principal Investigator: David Dix, MD, Children's Oncology Group

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: NCT00379340
• Other Study ID Numbers: AREN0533; NCI-2009-00419; CDR0000496508; U10CA098543; COG-AREN0533
• First Posted: Sep 21, 2006
• Last Update Posted: Mar 25, 2022
• Last Verified: Mar 1, 2022

• Additional relevant MeSH terms: Neoplasms; Wilms Tumor; Dactinomycin; Cactinomycin; Cyclophosphamide; Doxorubicin; Liposomal doxorubicin; Etoposide; Vincristine; Etoposide phosphate

Study Results

Participant Flow

Pre-assignment Detail	The 15 discrepant patients were ineligible to the study. They were excluded in the Participant Flow table because none of them were treated by the protocol and their group designations were unknown.

Arm/Group Title	Stage IV and Rapid Complete Response (RCR) of Lung Metastases	Stage IV and Slow Incomplete Response (SIR) of Lung Metastases	Stage III/IV With LOH 1p and 16q Treated With Regimen M	Stage IV With Non-lung Disease Treated With Regimen M	Stage IV With Lung Metastases
Arm/Group Description	Stage IV and rapid complete response (RCR) of lung metastases continuously treated with DD4A after 6 weeks of DD4A.	Stage IV and slow incomplete response (SIR) of lung metastases treated with Regimen M after 6 weeks of DD4A.	Stage III/IV with LOH 1p and 16q treated with Regimen M.	Stage IV with non-lung disease treated with Regimen M.	Stage IV with lung metastases treated with DD4A for less than 6 weeks and/or response inevaluable at week 6.
Period Title: Overall Study
STARTED	120	135	52	50	23
COMPLETED	107	132	50	37	9
NOT COMPLETED	13	3	2	13	14

Baseline Characteristics

Arm/Group Title	Stage IV and Rapid Complete Response (RCR) of Lung Metastases	Stage IV and Slow Incomplete Response (SIR) of Lung Metastases	Stage III/IV With LOH 1p and 16q Treated With Regimen M	Stage IV With Non-lung Disease Treated With Regimen M	Stage IV With Lung Metastases	Total
Arm/Group Description	Stage IV and rapid complete response (RCR) of lung metastases continuously treated with DD4A after 6 weeks of DD4A.	Stage IV and slow incomplete response (SIR) of lung metastases treated with Regimen M after 6 weeks of DD4A.	Stage III/IV with LOH 1p and 16q treated with Regimen M.	Stage IV with non-lung disease treated with Regimen M.	Stage IV with lung metastases treated with DD4A for less than 6 weeks and/or response inevaluable at week 6.	Total of all reporting groups
Overall Participants	120	135	52	50	23	380
Age (Months) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Months]	54.94 (36.27)	55.07 (27.16)	52.16 (28.64)	69.58 (39.24)	56.06 (23.71)	56.60 (32.29)
Sex: Female, Male (Count of Participants)
Female	65 54.2%	71 52.6%	30 57.7%	31 62%	8 34.8%	205 53.9%
Male	55 45.8%	64 47.4%	22 42.3%	19 38%	15 65.2%	175 46.1%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	12 10%	18 13.3%	6 11.5%	12 24%	3 13%	51 13.4%
Not Hispanic or Latino	104 86.7%	108 80%	42 80.8%	36 72%	18 78.3%	308 81.1%
Unknown or Not Reported	4 3.3%	9 6.7%	4 7.7%	2 4%	2 8.7%	21 5.5%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	1 0.8%	0 0%	0 0%	0 0%	0 0%	1 0.3%
Asian	2 1.7%	2 1.5%	0 0%	2 4%	1 4.3%	7 1.8%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Black or African American	21 17.5%	22 16.3%	10 19.2%	4 8%	1 4.3%	58 15.3%
White	80 66.7%	94 69.6%	38 73.1%	39 78%	18 78.3%	269 70.8%
More than one race	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	16 13.3%	17 12.6%	4 7.7%	5 10%	3 13%	45 11.8%

Outcome Measures

1. Primary Outcome

Title	Event Free Survival Probability
Description	Probability of no relapse, secondary malignancy, or death after 4 year in the study.
Time Frame	4 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Stage IV and Rapid Complete Response (RCR) of Lung Metastases
Arm/Group Description	Stage IV and rapid complete response (RCR) of lung metastases continuously treated with DD4A after 6 weeks of DD4A.
Measure Participants	120
Number (95% Confidence Interval) [Probability]	0.79

2. Primary Outcome

Title	Event Free Survival (EFS) Probability
Description	Probability of no relapse, secondary malignancy, or death after 4 year in the study.
Time Frame	At 4 years

Outcome Measure Data

Analysis Population Description

Analysis includes only eligible patients.

Arm/Group Title	Stage IV and Slow Incomplete Response (SIR) of Lung Metastases
Arm/Group Description	Stage IV and slow incomplete response (SIR) of lung metastases treated with Regimen M after 6 weeks of DD4A doxorubicin hydrochloride: Given IV liposomal vincristine sulfate: Given IV conventional surgery 3-dimensional conformal radiation therapy dactinomycin: Given IV cyclophosphamide: Given IV etoposide: Given IV
Measure Participants	135
Number (95% Confidence Interval) [Probability of EFS at 4 years]	0.89

3. Primary Outcome

Title	Event Free Survival Probability
Description	Probability of no relapse, secondary malignancy, or death after 4 year in the study
Time Frame	At 4 years

Outcome Measure Data

Analysis Population Description

All eligible patients were included in this analysis.

Arm/Group Title	Stage III/IV With LOH 1p and 16q Treated With Regimen M	Stage IV With Non-lung Disease Treated With Regimen M
Arm/Group Description	Stage III/IV with LOH 1p and 16q treated with Regimen M doxorubicin hydrochloride: Given IV liposomal vincristine sulfate: Given IV conventional surgery 3-dimensional conformal radiation therapy dactinomycin: Given IV cyclophosphamide: Given IV etoposide: Given IV	Stage IV with non-lung disease treated with Regimen M doxorubicin hydrochloride: Given IV liposomal vincristine sulfate: Given IV conventional surgery dactinomycin: Given IV cyclophosphamide: Given IV etoposide: Given IV
Measure Participants	52	50
Number (95% Confidence Interval) [Probability of EFS at 4 years]	0.90	0.73

4. Secondary Outcome

Title	Event Free Survival Associated With the Burden of Pulmonary Metastatic Disease
Description	Probability of no relapse, secondary malignancy, or death after 4 year in the study.
Time Frame	At 4 years

Outcome Measure Data

Analysis Population Description

Analysis population is eligible stage (stg) IV patients (pts) with lung mets only. On Participant Flow table, these pts include 120 RCR, 135 SIR, 21 stg IV with LOH (of 52 when including stg III), and 23 stg IV with lung mets (off therapy before week 6). A total of 299 stg IV pts, exceeding the total number of participant (297) analyzed for OM 4.

Arm/Group Title	Lung Mets <= 1cm	Lung Mets > 1cm
Arm/Group Description	Lung mets <= 1cm	Lung mets > 1cm
Measure Participants	147	150
Number (95% Confidence Interval) [Probability]	0.88	0.82

Adverse Events

Arm/Group Title	Stage IV and Rapid Complete Response (RCR) of Lung Metastases		Stage IV and Slow Incomplete Response (SIR) of Lung Metastases		Stage III/IV With LOH 1p and 16q Treated With Regimen M		Stage IV With Non-lung Disease Treated With Regimen M		Stage IV With Lung Metastases
Arm/Group Description	Stage IV and rapid complete response (RCR) of lung metastases continuously treated with DD4A after 6 weeks of DD4A.		Stage IV and slow incomplete response (SIR) of lung metastases treated with Regimen M after 6 weeks of DD4A.		Stage III/IV with LOH 1p and 16q treated with Regimen M.		Stage IV with non-lung disease treated with Regimen M.		Stage IV with lung metastases treated with DD4A for less than 6 weeks and/or response inevaluable at week 6.
All Cause Mortality
	Stage IV and Rapid Complete Response (RCR) of Lung Metastases		Stage IV and Slow Incomplete Response (SIR) of Lung Metastases		Stage III/IV With LOH 1p and 16q Treated With Regimen M		Stage IV With Non-lung Disease Treated With Regimen M		Stage IV With Lung Metastases
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Stage IV and Rapid Complete Response (RCR) of Lung Metastases		Stage IV and Slow Incomplete Response (SIR) of Lung Metastases		Stage III/IV With LOH 1p and 16q Treated With Regimen M		Stage IV With Non-lung Disease Treated With Regimen M		Stage IV With Lung Metastases
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/120 (2.5%)		10/135 (7.4%)		3/52 (5.8%)		11/50 (22%)		0/23 (0%)
Blood and lymphatic system disorders
Bone marrow hypocellular	0/120 (0%)	0	0/135 (0%)	0	0/52 (0%)	0	1/50 (2%)	1	0/23 (0%)	0
Cardiac disorders
Cardiac arrest	1/120 (0.8%)	1	0/135 (0%)	0	0/52 (0%)	0	0/50 (0%)	0	0/23 (0%)	0
Pericardial effusion	0/120 (0%)	0	1/135 (0.7%)	1	0/52 (0%)	0	0/50 (0%)	0	0/23 (0%)	0
Gastrointestinal disorders
Ileus	0/120 (0%)	0	0/135 (0%)	0	0/52 (0%)	0	1/50 (2%)	1	0/23 (0%)	0
Intra-abdominal hemorrhage	0/120 (0%)	0	0/135 (0%)	0	0/52 (0%)	0	1/50 (2%)	1	0/23 (0%)	0
Small intestinal obstruction	0/120 (0%)	0	1/135 (0.7%)	1	0/52 (0%)	0	0/50 (0%)	0	0/23 (0%)	0
General disorders
Death NOS	2/120 (1.7%)	2	3/135 (2.2%)	3	2/52 (3.8%)	2	3/50 (6%)	3	0/23 (0%)	0
Hepatobiliary disorders
Hepatobiliary disorders - Other specify	0/120 (0%)	0	1/135 (0.7%)	1	0/52 (0%)	0	1/50 (2%)	1	0/23 (0%)	0
Infections and infestations
Infections and infestations - Other specify	0/120 (0%)	0	0/135 (0%)	0	0/52 (0%)	0	2/50 (4%)	2	0/23 (0%)	0
Sepsis	0/120 (0%)	0	2/135 (1.5%)	2	0/52 (0%)	0	0/50 (0%)	0	0/23 (0%)	0
Injury, poisoning and procedural complications
Postoperative hemorrhage	0/120 (0%)	0	0/135 (0%)	0	0/52 (0%)	0	1/50 (2%)	1	0/23 (0%)	0
Investigations
Cardiac troponin I increased	0/120 (0%)	0	0/135 (0%)	0	0/52 (0%)	0	1/50 (2%)	1	0/23 (0%)	0
CPK increased	0/120 (0%)	0	0/135 (0%)	0	0/52 (0%)	0	1/50 (2%)	1	0/23 (0%)	0
Neutrophil count decreased	0/120 (0%)	0	0/135 (0%)	0	0/52 (0%)	0	1/50 (2%)	1	0/23 (0%)	0
Platelet count decreased	0/120 (0%)	0	1/135 (0.7%)	1	0/52 (0%)	0	1/50 (2%)	1	0/23 (0%)	0
White blood cell decreased	0/120 (0%)	0	1/135 (0.7%)	1	0/52 (0%)	0	0/50 (0%)	0	0/23 (0%)	0
Metabolism and nutrition disorders
Tumor lysis syndrome	0/120 (0%)	0	0/135 (0%)	0	0/52 (0%)	0	1/50 (2%)	1	0/23 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Neoplasms benign malignant and unspecified (incl cy	0/120 (0%)	0	1/135 (0.7%)	1	0/52 (0%)	0	0/50 (0%)	0	0/23 (0%)	0
Treatment related secondary malignancy	0/120 (0%)	0	0/135 (0%)	0	0/52 (0%)	0	1/50 (2%)	1	0/23 (0%)	0
Renal and urinary disorders
Proteinuria	0/120 (0%)	0	1/135 (0.7%)	1	0/52 (0%)	0	0/50 (0%)	0	0/23 (0%)	0
Urinary tract obstruction	0/120 (0%)	0	0/135 (0%)	0	0/52 (0%)	0	1/50 (2%)	1	0/23 (0%)	0
Respiratory, thoracic and mediastinal disorders
Pneumonitis	0/120 (0%)	0	1/135 (0.7%)	1	0/52 (0%)	0	1/50 (2%)	1	0/23 (0%)	0
Pulmonary hypertension	0/120 (0%)	0	0/135 (0%)	0	0/52 (0%)	0	1/50 (2%)	1	0/23 (0%)	0
Respiratory failure	0/120 (0%)	0	0/135 (0%)	0	1/52 (1.9%)	1	0/50 (0%)	0	0/23 (0%)	0
Respiratory thoracic and mediastinal disorders - Ot	0/120 (0%)	0	0/135 (0%)	0	0/52 (0%)	0	1/50 (2%)	2	0/23 (0%)	0
Other (Not Including Serious) Adverse Events
	Stage IV and Rapid Complete Response (RCR) of Lung Metastases		Stage IV and Slow Incomplete Response (SIR) of Lung Metastases		Stage III/IV With LOH 1p and 16q Treated With Regimen M		Stage IV With Non-lung Disease Treated With Regimen M		Stage IV With Lung Metastases
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	11/120 (9.2%)		90/135 (66.7%)		35/52 (67.3%)		37/50 (74%)		1/23 (4.3%)
Blood and lymphatic system disorders
Anemia	0/120 (0%)	0	3/135 (2.2%)	4	2/52 (3.8%)	2	2/50 (4%)	2	0/23 (0%)	0
Blood and lymphatic system disorders - Other specif	1/120 (0.8%)	1	0/135 (0%)	0	0/52 (0%)	0	0/50 (0%)	0	0/23 (0%)	0
Febrile neutropenia	0/120 (0%)	0	53/135 (39.3%)	77	21/52 (40.4%)	27	20/50 (40%)	23	1/23 (4.3%)	2
Cardiac disorders
Cardiac arrest	0/120 (0%)	0	0/135 (0%)	0	0/52 (0%)	0	1/50 (2%)	1	0/23 (0%)	0
Left ventricular systolic dysfunction	0/120 (0%)	0	0/135 (0%)	0	0/52 (0%)	0	1/50 (2%)	1	0/23 (0%)	0
Sinus tachycardia	0/120 (0%)	0	0/135 (0%)	0	0/52 (0%)	0	2/50 (4%)	2	0/23 (0%)	0
Ear and labyrinth disorders
Ear pain	0/120 (0%)	0	0/135 (0%)	0	1/52 (1.9%)	1	0/50 (0%)	0	0/23 (0%)	0
Middle ear inflammation	0/120 (0%)	0	0/135 (0%)	0	1/52 (1.9%)	1	0/50 (0%)	0	0/23 (0%)	0
Gastrointestinal disorders
Abdominal pain	0/120 (0%)	0	1/135 (0.7%)	1	1/52 (1.9%)	1	2/50 (4%)	2	0/23 (0%)	0
Colitis	0/120 (0%)	0	2/135 (1.5%)	2	0/52 (0%)	0	1/50 (2%)	1	0/23 (0%)	0
Diarrhea	0/120 (0%)	0	2/135 (1.5%)	2	1/52 (1.9%)	1	2/50 (4%)	2	0/23 (0%)	0
Enterocolitis	0/120 (0%)	0	0/135 (0%)	0	1/52 (1.9%)	1	1/50 (2%)	1	0/23 (0%)	0
Gastroparesis	0/120 (0%)	0	1/135 (0.7%)	1	0/52 (0%)	0	0/50 (0%)	0	0/23 (0%)	0
Ileal obstruction	0/120 (0%)	0	0/135 (0%)	0	0/52 (0%)	0	1/50 (2%)	1	0/23 (0%)	0
Ileus	2/120 (1.7%)	2	2/135 (1.5%)	2	0/52 (0%)	0	2/50 (4%)	2	0/23 (0%)	0
Jejunal obstruction	0/120 (0%)	0	1/135 (0.7%)	1	0/52 (0%)	0	0/50 (0%)	0	0/23 (0%)	0
Mucositis oral	1/120 (0.8%)	1	4/135 (3%)	4	2/52 (3.8%)	2	3/50 (6%)	3	0/23 (0%)	0
Nausea	0/120 (0%)	0	5/135 (3.7%)	5	2/52 (3.8%)	3	4/50 (8%)	4	0/23 (0%)	0
Oral pain	0/120 (0%)	0	0/135 (0%)	0	0/52 (0%)	0	1/50 (2%)	1	0/23 (0%)	0
Small intestinal obstruction	0/120 (0%)	0	3/135 (2.2%)	3	0/52 (0%)	0	1/50 (2%)	1	0/23 (0%)	0
Typhlitis	0/120 (0%)	0	2/135 (1.5%)	2	0/52 (0%)	0	0/50 (0%)	0	0/23 (0%)	0
Vomiting	0/120 (0%)	0	3/135 (2.2%)	3	3/52 (5.8%)	3	6/50 (12%)	7	1/23 (4.3%)	1
General disorders
Fatigue	0/120 (0%)	0	1/135 (0.7%)	1	1/52 (1.9%)	1	0/50 (0%)	0	0/23 (0%)	0
Fever	0/120 (0%)	0	5/135 (3.7%)	6	0/52 (0%)	0	1/50 (2%)	1	0/23 (0%)	0
Infusion related reaction	0/120 (0%)	0	1/135 (0.7%)	2	0/52 (0%)	0	0/50 (0%)	0	0/23 (0%)	0
Pain	0/120 (0%)	0	0/135 (0%)	0	1/52 (1.9%)	1	1/50 (2%)	1	0/23 (0%)	0
Hepatobiliary disorders
Cholecystitis	1/120 (0.8%)	1	0/135 (0%)	0	0/52 (0%)	0	0/50 (0%)	0	0/23 (0%)	0
Hepatobiliary disorders - Other specify	0/120 (0%)	0	1/135 (0.7%)	1	1/52 (1.9%)	1	1/50 (2%)	1	0/23 (0%)	0
Immune system disorders
Anaphylaxis	0/120 (0%)	0	1/135 (0.7%)	1	1/52 (1.9%)	1	0/50 (0%)	0	0/23 (0%)	0
Infections and infestations
Abdominal infection	0/120 (0%)	0	0/135 (0%)	0	1/52 (1.9%)	1	1/50 (2%)	1	0/23 (0%)	0
Bladder infection	0/120 (0%)	0	0/135 (0%)	0	0/52 (0%)	0	1/50 (2%)	1	0/23 (0%)	0
Catheter related infection	0/120 (0%)	0	4/135 (3%)	4	1/52 (1.9%)	1	2/50 (4%)	2	0/23 (0%)	0
Device related infection	0/120 (0%)	0	1/135 (0.7%)	1	0/52 (0%)	0	0/50 (0%)	0	0/23 (0%)	0
Duodenal infection	0/120 (0%)	0	1/135 (0.7%)	1	0/52 (0%)	0	0/50 (0%)	0	0/23 (0%)	0
Enterocolitis infectious	0/120 (0%)	0	4/135 (3%)	4	1/52 (1.9%)	1	1/50 (2%)	1	0/23 (0%)	0
Infections and infestations - Other specify	2/120 (1.7%)	2	20/135 (14.8%)	22	11/52 (21.2%)	17	9/50 (18%)	11	0/23 (0%)	0
Lung infection	0/120 (0%)	0	4/135 (3%)	4	2/52 (3.8%)	2	1/50 (2%)	1	0/23 (0%)	0
Mucosal infection	0/120 (0%)	0	1/135 (0.7%)	1	0/52 (0%)	0	0/50 (0%)	0	0/23 (0%)	0
Otitis media	0/120 (0%)	0	2/135 (1.5%)	2	2/52 (3.8%)	2	0/50 (0%)	0	0/23 (0%)	0
Pharyngitis	0/120 (0%)	0	0/135 (0%)	0	1/52 (1.9%)	1	0/50 (0%)	0	0/23 (0%)	0
Sepsis	0/120 (0%)	0	3/135 (2.2%)	3	1/52 (1.9%)	1	0/50 (0%)	0	0/23 (0%)	0
Skin infection	0/120 (0%)	0	1/135 (0.7%)	1	0/52 (0%)	0	1/50 (2%)	1	0/23 (0%)	0
Stoma site infection	0/120 (0%)	0	1/135 (0.7%)	1	0/52 (0%)	0	0/50 (0%)	0	0/23 (0%)	0
Upper respiratory infection	0/120 (0%)	0	3/135 (2.2%)	4	2/52 (3.8%)	3	0/50 (0%)	0	0/23 (0%)	0
Urinary tract infection	1/120 (0.8%)	1	3/135 (2.2%)	3	2/52 (3.8%)	3	4/50 (8%)	5	0/23 (0%)	0
Vulval infection	0/120 (0%)	0	0/135 (0%)	0	0/52 (0%)	0	1/50 (2%)	1	0/23 (0%)	0
Wound infection	0/120 (0%)	0	0/135 (0%)	0	1/52 (1.9%)	1	0/50 (0%)	0	0/23 (0%)	0
Injury, poisoning and procedural complications
Vascular access complication	0/120 (0%)	0	0/135 (0%)	0	0/52 (0%)	0	1/50 (2%)	1	0/23 (0%)	0
Investigations
Activated partial thromboplastin time prolonged	0/120 (0%)	0	0/135 (0%)	0	0/52 (0%)	0	2/50 (4%)	2	0/23 (0%)	0
Alanine aminotransferase increased	0/120 (0%)	0	5/135 (3.7%)	6	3/52 (5.8%)	3	6/50 (12%)	6	1/23 (4.3%)	1
Aspartate aminotransferase increased	0/120 (0%)	0	2/135 (1.5%)	2	2/52 (3.8%)	2	3/50 (6%)	3	1/23 (4.3%)	1
Blood bilirubin increased	0/120 (0%)	0	0/135 (0%)	0	0/52 (0%)	0	3/50 (6%)	3	0/23 (0%)	0
Creatinine increased	0/120 (0%)	0	1/135 (0.7%)	1	0/52 (0%)	0	0/50 (0%)	0	0/23 (0%)	0
GGT increased	0/120 (0%)	0	2/135 (1.5%)	2	1/52 (1.9%)	1	2/50 (4%)	3	0/23 (0%)	0
Lipase increased	0/120 (0%)	0	0/135 (0%)	0	0/52 (0%)	0	2/50 (4%)	2	0/23 (0%)	0
Lymphocyte count decreased	0/120 (0%)	0	0/135 (0%)	0	0/52 (0%)	0	2/50 (4%)	2	0/23 (0%)	0
Neutrophil count decreased	1/120 (0.8%)	1	4/135 (3%)	6	3/52 (5.8%)	5	2/50 (4%)	2	0/23 (0%)	0
Platelet count decreased	0/120 (0%)	0	3/135 (2.2%)	4	3/52 (5.8%)	4	2/50 (4%)	2	0/23 (0%)	0
Weight loss	0/120 (0%)	0	1/135 (0.7%)	1	2/52 (3.8%)	2	3/50 (6%)	4	0/23 (0%)	0
White blood cell decreased	0/120 (0%)	0	2/135 (1.5%)	3	2/52 (3.8%)	2	1/50 (2%)	1	0/23 (0%)	0
Metabolism and nutrition disorders
Acidosis	0/120 (0%)	0	2/135 (1.5%)	2	2/52 (3.8%)	2	1/50 (2%)	1	0/23 (0%)	0
Anorexia	0/120 (0%)	0	10/135 (7.4%)	12	5/52 (9.6%)	7	9/50 (18%)	14	0/23 (0%)	0
Dehydration	0/120 (0%)	0	10/135 (7.4%)	10	3/52 (5.8%)	3	1/50 (2%)	1	0/23 (0%)	0
Hypercalcemia	0/120 (0%)	0	0/135 (0%)	0	1/52 (1.9%)	1	0/50 (0%)	0	0/23 (0%)	0
Hyperglycemia	1/120 (0.8%)	1	3/135 (2.2%)	3	3/52 (5.8%)	4	1/50 (2%)	1	0/23 (0%)	0
Hyperkalemia	0/120 (0%)	0	1/135 (0.7%)	1	1/52 (1.9%)	1	1/50 (2%)	1	0/23 (0%)	0
Hypoalbuminemia	0/120 (0%)	0	0/135 (0%)	0	1/52 (1.9%)	1	2/50 (4%)	2	0/23 (0%)	0
Hypocalcemia	2/120 (1.7%)	2	1/135 (0.7%)	1	3/52 (5.8%)	3	3/50 (6%)	3	0/23 (0%)	0
Hypokalemia	0/120 (0%)	0	6/135 (4.4%)	6	6/52 (11.5%)	6	3/50 (6%)	3	0/23 (0%)	0
Hyponatremia	0/120 (0%)	0	3/135 (2.2%)	3	1/52 (1.9%)	1	3/50 (6%)	4	0/23 (0%)	0
Hypophosphatemia	0/120 (0%)	0	1/135 (0.7%)	1	2/52 (3.8%)	2	0/50 (0%)	0	0/23 (0%)	0
Obesity	0/120 (0%)	0	0/135 (0%)	0	0/52 (0%)	0	1/50 (2%)	1	0/23 (0%)	0
Musculoskeletal and connective tissue disorders
Bone pain	0/120 (0%)	0	0/135 (0%)	0	0/52 (0%)	0	1/50 (2%)	1	0/23 (0%)	0
Buttock pain	0/120 (0%)	0	0/135 (0%)	0	0/52 (0%)	0	1/50 (2%)	1	0/23 (0%)	0
Chest wall pain	0/120 (0%)	0	1/135 (0.7%)	1	0/52 (0%)	0	0/50 (0%)	0	0/23 (0%)	0
Generalized muscle weakness	0/120 (0%)	0	1/135 (0.7%)	1	1/52 (1.9%)	1	0/50 (0%)	0	0/23 (0%)	0
Muscle weakness lower limb	0/120 (0%)	0	1/135 (0.7%)	1	0/52 (0%)	0	0/50 (0%)	0	0/23 (0%)	0
Muscle weakness upper limb	0/120 (0%)	0	1/135 (0.7%)	1	0/52 (0%)	0	0/50 (0%)	0	0/23 (0%)	0
Pain in extremity	0/120 (0%)	0	0/135 (0%)	0	0/52 (0%)	0	1/50 (2%)	1	0/23 (0%)	0
Soft tissue necrosis lower limb	0/120 (0%)	0	0/135 (0%)	0	0/52 (0%)	0	1/50 (2%)	1	0/23 (0%)	0
Nervous system disorders
Headache	0/120 (0%)	0	1/135 (0.7%)	1	0/52 (0%)	0	0/50 (0%)	0	0/23 (0%)	0
Peripheral motor neuropathy	0/120 (0%)	0	4/135 (3%)	5	3/52 (5.8%)	4	2/50 (4%)	5	1/23 (4.3%)	1
Peripheral sensory neuropathy	0/120 (0%)	0	1/135 (0.7%)	1	1/52 (1.9%)	1	1/50 (2%)	2	0/23 (0%)	0
Seizure	0/120 (0%)	0	2/135 (1.5%)	2	0/52 (0%)	0	0/50 (0%)	0	0/23 (0%)	0
Syncope	0/120 (0%)	0	1/135 (0.7%)	1	0/52 (0%)	0	1/50 (2%)	1	0/23 (0%)	0
Psychiatric disorders
Depression	0/120 (0%)	0	0/135 (0%)	0	1/52 (1.9%)	1	0/50 (0%)	0	0/23 (0%)	0
Suicidal ideation	0/120 (0%)	0	0/135 (0%)	0	1/52 (1.9%)	1	0/50 (0%)	0	0/23 (0%)	0
Renal and urinary disorders
Acute kidney injury	0/120 (0%)	0	2/135 (1.5%)	2	0/52 (0%)	0	0/50 (0%)	0	0/23 (0%)	0
Cystitis noninfective	0/120 (0%)	0	1/135 (0.7%)	1	0/52 (0%)	0	0/50 (0%)	0	0/23 (0%)	0
Hematuria	0/120 (0%)	0	1/135 (0.7%)	1	1/52 (1.9%)	1	0/50 (0%)	0	0/23 (0%)	0
Proteinuria	0/120 (0%)	0	0/135 (0%)	0	1/52 (1.9%)	1	0/50 (0%)	0	0/23 (0%)	0
Urinary tract obstruction	0/120 (0%)	0	2/135 (1.5%)	2	0/52 (0%)	0	1/50 (2%)	2	0/23 (0%)	0
Urinary tract pain	0/120 (0%)	0	1/135 (0.7%)	1	0/52 (0%)	0	0/50 (0%)	0	0/23 (0%)	0
Respiratory, thoracic and mediastinal disorders
Adult respiratory distress syndrome	0/120 (0%)	0	2/135 (1.5%)	3	0/52 (0%)	0	0/50 (0%)	0	0/23 (0%)	0
Dyspnea	0/120 (0%)	0	1/135 (0.7%)	1	0/52 (0%)	0	2/50 (4%)	2	0/23 (0%)	0
Epistaxis	0/120 (0%)	0	1/135 (0.7%)	1	0/52 (0%)	0	0/50 (0%)	0	0/23 (0%)	0
Hypoxia	0/120 (0%)	0	2/135 (1.5%)	2	0/52 (0%)	0	2/50 (4%)	2	0/23 (0%)	0
Pneumonitis	0/120 (0%)	0	0/135 (0%)	0	1/52 (1.9%)	1	2/50 (4%)	2	0/23 (0%)	0
Pneumothorax	0/120 (0%)	0	0/135 (0%)	0	0/52 (0%)	0	2/50 (4%)	2	0/23 (0%)	0
Pulmonary hypertension	0/120 (0%)	0	0/135 (0%)	0	0/52 (0%)	0	2/50 (4%)	2	0/23 (0%)	0
Respiratory failure	0/120 (0%)	0	1/135 (0.7%)	1	0/52 (0%)	0	0/50 (0%)	0	0/23 (0%)	0
Skin and subcutaneous tissue disorders
Pruritus	0/120 (0%)	0	1/135 (0.7%)	1	0/52 (0%)	0	0/50 (0%)	0	0/23 (0%)	0
Rash maculo-papular	0/120 (0%)	0	0/135 (0%)	0	0/52 (0%)	0	1/50 (2%)	1	0/23 (0%)	0
Vascular disorders
Hematoma	0/120 (0%)	0	0/135 (0%)	0	0/52 (0%)	0	1/50 (2%)	1	0/23 (0%)	0
Hypertension	0/120 (0%)	0	3/135 (2.2%)	5	0/52 (0%)	0	3/50 (6%)	4	0/23 (0%)	0
Hypotension	0/120 (0%)	0	2/135 (1.5%)	2	2/52 (3.8%)	2	1/50 (2%)	1	0/23 (0%)	0
Thromboembolic event	0/120 (0%)	0	0/135 (0%)	0	0/52 (0%)	0	2/50 (4%)	3	0/23 (0%)	0
Vascular disorders - Other specify	0/120 (0%)	0	2/135 (1.5%)	2	0/52 (0%)	0	1/50 (2%)	1	0/23 (0%)	0

Limitations/Caveats

[Not Specified]

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Certain Agreements

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

Must obtain prior Sponsor approval.