Combination Chemotherapy in Treating Children With Newly Diagnosed Malignant Germ Cell Tumors

Sponsor

Children's Oncology Group (Other)

Overall Status

Completed

CT.gov ID

NCT00066482

Collaborator

National Cancer Institute (NCI) (NIH)

Enrollment

Locations

Arm

0.2

Patients Per Site

Study Details

Study Description

Brief Summary

RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Combining more than one drug may kill more tumor cells.

PURPOSE: Phase I trial to study the effect on the body of combining cyclophosphamide with cisplatin, etoposide, and bleomycin in treating children who have newly diagnosed malignant germ cell tumors that are not in the brain and gonads.

Condition or Disease	Intervention/Treatment	Phase
Childhood Germ Cell Tumor Extragonadal Germ Cell Tumor	Biological: bleomycin sulfate Biological: filgrastim Drug: cisplatin Drug: cyclophosphamide Drug: etoposide Procedure: conventional surgery Biological: MESNA	N/A

Detailed Description

OBJECTIVES:

Determine the maximum tolerated dose and toxicity profile of cyclophosphamide in combination with bleomycin, etoposide, and cisplatin in pediatric patients with newly diagnosed high-risk extracranial, extragonadal malignant germ cell tumors.
Determine the response rate in patients treated with this regimen.

OUTLINE: This is a pilot, multicenter, dose-escalation study of cyclophosphamide.

Induction therapy: Patients receive bleomycin IV over 10-20 minutes on day 1, etoposide IV over 1 hour and cisplatin IV over 4 hours on days 1-5, and cyclophosphamide IV over 1 hour on day 1. Patients also receive filgrastim (G-CSF) subcutaneously once daily beginning on day 6 and continuing until blood counts recover. Treatment repeats every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity.

Cohorts of 6 patients receive escalating doses of cyclophosphamide until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 6 patients experience dose-limiting toxicity.

Patients are evaluated after 4 courses of therapy. Patients with partial response or stable disease undergo second-look surgery, receive 2 more courses of induction therapy, and are then re-evaluated. Patients who do not achieve complete response (CR) after a total of 6 courses may undergo a third surgery. Patients who still have tumor that cannot be removed are removed from study therapy. Patients who achieve a CR at anytime are followed.

Patients are followed monthly for 1 year, every 6 months for 1 year, and then annually for 3 years.

PROJECTED ACCRUAL: A total of 6-18 patients will be accrued for this study within 1.3 years.

Study Design

Study Type:

Interventional

Actual Enrollment :

19 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Pilot Study of Cisplatin, Etoposide, Bleomycin and Escalating Dose Cyclophosphamide Therapy for Children With High Risk Malignant Germ Cell Tumors

Study Start Date :

Jul 1, 2004

Actual Primary Completion Date :

Apr 1, 2007

Arms and Interventions

Arm	Intervention/Treatment
Experimental: combination chemotherapy Induction therapy: bleomycin sulfate IV over 10-20 minutes on day 1, etoposide IV over 1 hour and cisplatin IV over 4 hours on days 1-5, and cyclophosphamide IV over 1 hour on day 1. MESNA & Filgrastim (G-CSF) subcutaneously once daily beginning on day 6 and continuing until blood counts recover. Treatment repeats every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity. 6 patients receive escalating doses of cyclophosphamide until the maximum tolerated dose (MTD) is determined. Evaluated after 4 courses of therapy. Partial response or stable disease undergo second-look conventional surgery & receive 2 more courses of induction therapy then re-evaluated. Those who do not achieve complete response (CR) after a total of 6 courses may undergo a third conventional surgery. Tumor that cannot be removed are removed from study therapy. Achievement of a CR at anytime are followed monthly for 1 year, every 6 months for 1 year, and then annually for 3 years.	Biological: bleomycin sulfate Given IV over 10 minutes. Children ≥ 12 months: 15 units/m2/dose Children < 12 months: 0.5 units/kg/dose Day 1 (Week 1, 4, 7, 10) Other Names: BLEO BLM Blenoxane NSC #125066 Biological: filgrastim Given SQ once daily 5 micrograms/kg/dose Starting on Day 6 (Week 1, 4, 7, 10) Daily until ANC > 5,000/uL Other Names: GRANULOCYTE COLONY-STIMULATING FACTOR r-metHuG-CSF G-CSF Neupogen NSC #614629 Drug: cisplatin Children ≥ 12 months: Given IV over one hour Dose: 20 mg/m2/dose Days 1-5 (Week 1,4,7,10) Children < 12 months: Given IV over 4 hours, 0.67 mg/kg/dose Days 1-5 (Week 1,4,7,10) Other Names: Cis-diamminedichloroplatinum II Platinol-AQ NSC #119875 Drug: cyclophosphamide Given IV over 1 hour. Children ≥ 12 months: Level 1: 1.2 g/m2/dose Level 2: 1.8 g/m2/dose Level 3: 2.4 g/m2/dose Children < 12 months: Level 1: 40 mg/kg/dose Level 2: 60 mg/kg/dose Level 3: 80 mg/kg/dose Day 1 (Week 1, 4, 7, 10) Other Names: Cytoxan NSC #026271 Drug: etoposide Given IV over 1 hour. Children ≥ 12 months: 100 mg/m2/dose Children < 12 months: 3.3 mg/kg/dose Day 1-5 (Week 1, 4, 7, 10) Other Names: VP-16 VePesid Etopophos NSC #141540 Procedure: conventional surgery Stage III/IV extragonadal tumors: biopsy followed by a definitive surgical excision after maximal chemotherapy effect, likely after 4 cycles of therapy Biological: MESNA Given IV or oral. The total daily MESNA dose is equal to at least 80% of the daily CPM dose. The oral dose of MESNA is 2x the IV dose. Day 1 (Week 1,4,7,10) To be given with CPM. Other Names: sodium 2-mercaptoethane sulfonate Mesnex NSC #113891

Arm

Intervention/Treatment

Experimental: combination chemotherapy

Induction therapy: bleomycin sulfate IV over 10-20 minutes on day 1, etoposide IV over 1 hour and cisplatin IV over 4 hours on days 1-5, and cyclophosphamide IV over 1 hour on day 1. MESNA & Filgrastim (G-CSF) subcutaneously once daily beginning on day 6 and continuing until blood counts recover. Treatment repeats every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity. 6 patients receive escalating doses of cyclophosphamide until the maximum tolerated dose (MTD) is determined. Evaluated after 4 courses of therapy. Partial response or stable disease undergo second-look conventional surgery & receive 2 more courses of induction therapy then re-evaluated. Those who do not achieve complete response (CR) after a total of 6 courses may undergo a third conventional surgery. Tumor that cannot be removed are removed from study therapy. Achievement of a CR at anytime are followed monthly for 1 year, every 6 months for 1 year, and then annually for 3 years.

Biological: bleomycin sulfate

Given IV over 10 minutes. Children ≥ 12 months: 15 units/m2/dose Children < 12 months: 0.5 units/kg/dose Day 1 (Week 1, 4, 7, 10)

Other Names:

BLEO

BLM

Blenoxane

NSC #125066

Biological: filgrastim

Given SQ once daily 5 micrograms/kg/dose Starting on Day 6 (Week 1, 4, 7, 10) Daily until ANC > 5,000/uL

Other Names:

GRANULOCYTE COLONY-STIMULATING FACTOR

r-metHuG-CSF

G-CSF

Neupogen

NSC #614629

Drug: cisplatin

Children ≥ 12 months: Given IV over one hour Dose: 20 mg/m2/dose Days 1-5 (Week 1,4,7,10) Children < 12 months: Given IV over 4 hours, 0.67 mg/kg/dose Days 1-5 (Week 1,4,7,10)

Other Names:

Cis-diamminedichloroplatinum II

Platinol-AQ

NSC #119875

Drug: cyclophosphamide

Given IV over 1 hour. Children ≥ 12 months: Level 1: 1.2 g/m2/dose Level 2: 1.8 g/m2/dose Level 3: 2.4 g/m2/dose Children < 12 months: Level 1: 40 mg/kg/dose Level 2: 60 mg/kg/dose Level 3: 80 mg/kg/dose Day 1 (Week 1, 4, 7, 10)

Other Names:

Cytoxan

NSC #026271

Drug: etoposide

Given IV over 1 hour. Children ≥ 12 months: 100 mg/m2/dose Children < 12 months: 3.3 mg/kg/dose Day 1-5 (Week 1, 4, 7, 10)

Other Names:

VP-16

VePesid

Etopophos

NSC #141540

Procedure: conventional surgery

Stage III/IV extragonadal tumors: biopsy followed by a definitive surgical excision after maximal chemotherapy effect, likely after 4 cycles of therapy

Biological: MESNA

Given IV or oral. The total daily MESNA dose is equal to at least 80% of the daily CPM dose. The oral dose of MESNA is 2x the IV dose. Day 1 (Week 1,4,7,10) To be given with CPM.

Other Names:

sodium 2-mercaptoethane sulfonate

Mesnex

NSC #113891

Outcome Measures

Primary Outcome Measures

Feasibility of adding cyclophosphamide to a PEB backbone [2 years]

Secondary Outcome Measures

Maximum tolerated dose [21 days]
Maximum tolerated dose (MTD) and toxicity profile of cyclophosphamide combined with cisplatin, etoposide, bleomycin (C-PEB) in previously untreated children with high-risk malignant germ cell tumors (MGCT).
Estimate the response rate [Length of study]
To estimate the response rate in this group of patients to a regimen of cyclophosphamide combined with cisplatin, etoposide, bleomycin (C-PEB).

Eligibility Criteria

Criteria

Ages Eligible for Study:

N/A to 21 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

DISEASE CHARACTERISTICS:

Histologically confirmed newly diagnosed extracranial germ cell tumors, including 1 of the following types:
Yolk sac carcinoma (endodermal sinus tumor)
Embryonal carcinoma
Choriocarcinoma
Teratoma with mixed malignant elements (malignant teratoma)
High-risk disease, defined as stage III or IV extragonadal germ cell tumors
Must be enrolled on study within 21 days of diagnostic surgical procedure

PATIENT CHARACTERISTICS:

Age

21 and under (at original diagnosis)

Performance status

ECOG 0-2
Karnofsky 50-100% (in patients over 16 years of age)
Lansky 50-100% (in patients 16 years of age and under)

Life expectancy

At least 2 months

Hematopoietic

Absolute neutrophil count at least 1,000/mm^3
Platelet count at least 100,000/mm^3 (transfusion independent)
Hemoglobin at least 10.0 g/dL (transfusion allowed)

Hepatic

Not specified

Renal

Creatinine clearance or radioisotope glomerular filtration rate at least 70 mL/min OR
Creatinine based on age as follows:
No greater than 0.8 mg/dL (5 years and under)
No greater than 1.0 mg/dL (6-10 years)
No greater than 1.2 mg/dL (11-15 years)
No greater than 1.5 mg/dL (over 15 years)

Pulmonary

FEV_1/FVC greater than 60% OR
Children who are uncooperative must meet all of the following criteria:
No dyspnea at rest
No exercise intolerance
Pulse oximetry greater than 94%

Other

Not pregnant or nursing
Fertile patients must use effective contraception

PRIOR CONCURRENT THERAPY:

Biologic therapy

Not specified

Chemotherapy

No prior chemotherapy

Endocrine therapy

Not specified

Radiotherapy

No prior radiotherapy

Surgery

See Disease Characteristics

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Comprehensive Cancer Center at University of Alabama at Birmingham	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	Children's Hospital Los Angeles	Los Angeles	California	United States	90027
7	Children's Hospital Central California	Madera	California	United States	93638-8762
8	Children's Hospital of Orange County	Orange	California	United States	92868
9	Kaiser Permanente Medical Center - Oakland	Sacramento	California	United States	95825
10	Children's Hospital and Health Center - San Diego	San Diego	California	United States	92123-4282
11	Stanford Cancer Center at Stanford University Medical Center	Stanford	California	United States	94305
12	Children's Hospital Cancer Center	Denver	Colorado	United States	80218-1088
13	Alfred I. duPont Hospital for Children	Wilmington	Delaware	United States	19899
14	Children's National Medical Center	Washington	District of Columbia	United States	20010-2970
15	Lee Cancer Care of Lee Memorial Health System	Fort Myers	Florida	United States	33901
16	University of Florida Shands Cancer Center	Gainesville	Florida	United States	32610-0232
17	Nemours Children's Clinic	Jacksonville	Florida	United States	32207
18	University of Miami Sylvester Comprehensive Cancer Center	Miami	Florida	United States	33136
19	Miami Children's Hospital	Miami	Florida	United States	33155
20	Baptist-South Miami Regional Cancer Program	Miami	Florida	United States	33176
21	Sacred Heart Cancer Center at Sacred Heart Hospital	Pensacola	Florida	United States	32504
22	All Children's Hospital	St. Petersburg	Florida	United States	33701
23	St. Joseph's Cancer Institute at St. Joseph's Hospital	Tampa	Florida	United States	33607
24	Kaplan Cancer Center at St. Mary's Medical Center	West Palm Beach	Florida	United States	33407
25	Emory University Hospital - Atlanta	Atlanta	Georgia	United States	30322
26	Cancer Research Center of Hawaii	Honolulu	Hawaii	United States	95813
27	Children's Memorial Hospital - Chicago	Chicago	Illinois	United States	60614
28	Saint Jude Midwest Affiliate	Peoria	Illinois	United States	61637
29	Southern Illinois University School of Medicine	Springfield	Illinois	United States	62794-9620
30	St. Vincent Indianapolis Hospital	Indianapolis	Indiana	United States	46260
31	Kansas Masonic Cancer Research Institute at the University of Kansas Medical Center	Kansas City	Kansas	United States	66160-7357
32	Markey Cancer Center at University of Kentucky Chandler Medical Center	Lexington	Kentucky	United States	40536-0293
33	CancerCare of Maine at Eastern Maine Medial Center	Bangor	Maine	United States	04401
34	Alvin and Lois Lapidus Cancer Institute at Sinai Hospital	Baltimore	Maryland	United States	21215
35	Dana-Farber/Harvard Cancer Center at Dana Farber Cancer Institute	Boston	Massachusetts	United States	02115
36	C.S. Mott Children's Hospital at University of Michigan	Ann Arbor	Michigan	United States	48109-0238
37	Barbara Ann Karmanos Cancer Institute	Detroit	Michigan	United States	48201-1379
38	Hurley Medical Center	Flint	Michigan	United States	48503
39	Spectrum Health Cancer Care - Butterworth Campus	Grand Rapids	Michigan	United States	49503-2560
40	Van Elslander Cancer Center at St. John Hospital and Medical Center	Grosse Pointe Woods	Michigan	United States	48236
41	Breslin Cancer Center at Ingham Regional Medical Center	Lansing	Michigan	United States	48910
42	Children's Hospital of Minnesota - Minneapolis	Minneapolis	Minnesota	United States	55404
43	Fairview University Medical Center - University Campus	Minneapolis	Minnesota	United States	55455
44	Mayo Clinic Cancer Center	Rochester	Minnesota	United States	55905
45	University of Mississippi Medical Center	Jackson	Mississippi	United States	39216-4505
46	Ellis Fischel Cancer Center at University of Missouri - Columbia	Columbia	Missouri	United States	65203
47	Children's Mercy Hospital	Kansas City	Missouri	United States	64108
48	Siteman Cancer Center at Barnes-Jewish Hospital	St. Louis	Missouri	United States	63110
49	Hackensack University Medical Center Cancer Center	Hackensack	New Jersey	United States	07601
50	St. Barnabas Medical Center	Livingston	New Jersey	United States	07039
51	Albert Einstein Cancer Center at Albert Einstein College of Medicine	Bronx	New York	United States	10461
52	James P. Wilmot Cancer Center at University of Rochester Medical Center	Rochester	New York	United States	14642
53	SUNY Upstate Medical University Hospital	Syracuse	New York	United States	13210
54	New York Medical College	Valhalla	New York	United States	10595
55	Blumenthal Cancer Center at Carolinas Medical Center	Charlotte	North Carolina	United States	28232-2861
56	Presbyterian Cancer Center at Presbyterian Hospital	Charlotte	North Carolina	United States	28233-3549
57	Duke Comprehensive Cancer Center	Durham	North Carolina	United States	27710
58	Children's Hospital Medical Center of Akron	Akron	Ohio	United States	44308-1062
59	Cincinnati Children's Hospital Medical Center	Cincinnati	Ohio	United States	45229-3039
60	Children's Medical Center - Dayton	Dayton	Ohio	United States	45404-1815
61	Tod Children's Hospital - Forum Health	Youngstown	Ohio	United States	44501
62	Oklahoma University Medical Center	Oklahoma City	Oklahoma	United States	73104
63	Penn State Cancer Institute at Milton S. Hershey Medical Center	Hershey	Pennsylvania	United States	17033-0850
64	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania	United States	19104-9786
65	St. Christopher's Hospital for Children	Philadelphia	Pennsylvania	United States	19134-1095
66	Hollings Cancer Center at Medical University of South Carolina	Charleston	South Carolina	United States	29425
67	Greenville Hospital System Cancer Center	Greenville	South Carolina	United States	29605
68	East Tennessee Children's Hospital	Knoxville	Tennessee	United States	37916
69	St. Jude Children's Research Hospital	Memphis	Tennessee	United States	38105
70	Texas Tech University Health Sciences Center School of Medicine	Amarillo	Texas	United States	79106
71	Children's Hospital of Austin	Austin	Texas	United States	78701
72	Driscoll Children's Hospital	Corpus Christi	Texas	United States	78466
73	Medical City Dallas Hospital	Dallas	Texas	United States	75230
74	Simmons Comprehensive Cancer Center at University of Texas Southwestern Medical Center - Dallas	Dallas	Texas	United States	75390
75	Cook Children's Medical Center - Fort Worth	Fort Worth	Texas	United States	76104-9958
76	Baylor University Medical Center - Houston	Houston	Texas	United States	77030-2399
77	M.D. Anderson Cancer Center at University of Texas	Houston	Texas	United States	77030-4009
78	Covenant Children's Hospital	Lubbock	Texas	United States	79410
79	University of Texas Health Science Center at San Antonio	San Antonio	Texas	United States	78229-3900
80	Methodist Children's Hospital of South Texas	San Antonio	Texas	United States	78229-3993
81	Primary Children's Medical Center	Salt Lake City	Utah	United States	84113-1100
82	INOVA Fairfax Hospital	Fairfax	Virginia	United States	22031
83	Carilion Cancer Center of Western Virginia	Roanoke	Virginia	United States	24029
84	West Virginia University - Robert C. Byrd Health Sciences Center - Charleston Division	Charleston	West Virginia	United States	25302
85	St. Vincent Hospital Regional Cancer Center	Green Bay	Wisconsin	United States	54307-3508
86	University of Wisconsin Comprehensive Cancer Center	Madison	Wisconsin	United States	53792-6164
87	Marshfield Clinic - Marshfield Center	Marshfield	Wisconsin	United States	54449
88	Midwest Children's Cancer Center	Milwaukee	Wisconsin	United States	53226
89	Princess Margaret Hospital for Children	Perth	Western Australia	Australia	6001
90	Children's & Women's Hospital of British Columbia	Vancouver	British Columbia	Canada	V6H 3V4
91	Janeway Children's Health and Rehabilitation Centre	St. John's	Newfoundland and Labrador	Canada	A1B 3V6
92	McMaster Children's Hospital at Hamilton Health Sciences	Hamilton	Ontario	Canada	L8N 3Z5
93	Hospital for Sick Children	Toronto	Ontario	Canada	M5G 1X8
94	Montreal Children's Hospital at McGill University Health Center	Montreal	Quebec	Canada	H3H 1P3
95	Hopital Sainte Justine	Montreal	Quebec	Canada	H3T 1C5
96	Centre Hospitalier Universitaire de Quebec	Ste-Foy	Quebec	Canada	G1V 4G2
97	Allan Blair Cancer Centre at Pasqua Hospital	Regina	Saskatchewan	Canada	S4T 7T1
98	San Jorge Children's Hospital	Santurce		Puerto Rico	00912