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

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

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.

Study Overview

• Status: Completed
• Conditions: Extragonadal Germ Cell Tumor; Childhood Germ Cell Tumor
• Intervention / Treatment: Biological: bleomycin sulfate; Biological: filgrastim; Drug: cisplatin; Drug: cyclophosphamide; Drug: etoposide; Procedure: conventional surgery; Biological: MESNA

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 Type: Interventional
• Enrollment (Actual): 19
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Australia
  • Western Australia
    • Perth, Western Australia, Australia, 6001
      • Princess Margaret Hospital for Children
• Canada
  • British Columbia
    • Vancouver, British Columbia, Canada, V6H 3V4
      • Children's & Women's Hospital of British Columbia
  • Newfoundland and Labrador
    • St. John's, Newfoundland and Labrador, Canada, A1B 3V6
      • Janeway Children's Health and Rehabilitation Centre
  • Ontario
    • Hamilton, Ontario, Canada, L8N 3Z5
      • McMaster Children's Hospital at Hamilton Health Sciences
    • Toronto, Ontario, Canada, M5G 1X8
      • Hospital for sick children
  • Quebec
    • Montreal, Quebec, Canada, H3H 1P3
      • Montreal Children's Hospital at McGill University Health Center
    • Montreal, Quebec, Canada, H3T 1C5
      • Hopital Sainte Justine
    • Ste-Foy, Quebec, Canada, G1V 4G2
      • Centre Hospitalier Universitaire de Quebec
  • Saskatchewan
    • Regina, Saskatchewan, Canada, S4T 7T1
      • Allan Blair Cancer Centre at Pasqua Hospital
• Puerto Rico
  • Santurce, Puerto Rico, 00912
    • San Jorge Children's Hospital
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294
      • Comprehensive Cancer Center at University of Alabama at Birmingham
  • Arizona
    • Phoenix, Arizona, United States, 85016-7710
      • Phoenix Children's Hospital
  • Arkansas
    • Little Rock, Arkansas, United States, 72205
      • Arkansas Cancer Research Center at University of Arkansas for Medical Sciences
  • California
    • Downey, California, United States, 90242-2814
      • Southern California Permanente Medical Group
    • Loma Linda, California, United States, 92354
      • Loma Linda University Cancer Institute at Loma Linda University Medical Center
    • Los Angeles, California, United States, 90027
      • Children's Hospital Los Angeles
    • Madera, California, United States, 93638-8762
      • Children's Hospital Central California
    • Orange, California, United States, 92868
      • Children's Hospital of Orange County
    • Sacramento, California, United States, 95825
      • Kaiser Permanente Medical Center - Oakland
    • San Diego, California, United States, 92123-4282
      • Children's Hospital and Health Center - San Diego
    • Stanford, California, United States, 94305
      • Stanford Cancer Center at Stanford University Medical Center
  • Colorado
    • Denver, Colorado, United States, 80218-1088
      • Children's Hospital Cancer Center
  • Delaware
    • Wilmington, Delaware, United States, 19899
      • Alfred I. duPont Hospital for Children
  • District of Columbia
    • Washington, District of Columbia, United States, 20010-2970
      • Children's National Medical Center
  • Florida
    • Fort Myers, Florida, United States, 33901
      • Lee Cancer Care of Lee Memorial Health System
    • Gainesville, Florida, United States, 32610-0232
      • University of Florida Shands Cancer Center
    • Jacksonville, Florida, United States, 32207
      • Nemours Children's Clinic
    • Miami, Florida, United States, 33136
      • University of Miami Sylvester Comprehensive Cancer Center
    • Miami, Florida, United States, 33155
      • Miami Children's Hospital
    • Miami, Florida, United States, 33176
      • Baptist-South Miami Regional Cancer Program
    • Pensacola, Florida, United States, 32504
      • Sacred Heart Cancer Center at Sacred Heart Hospital
    • St. Petersburg, Florida, United States, 33701
      • All Children's Hospital
    • Tampa, Florida, United States, 33607
      • St. Joseph's Cancer Institute at St. Joseph's Hospital
    • West Palm Beach, Florida, United States, 33407
      • Kaplan Cancer Center at St. Mary's Medical Center
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Emory University Hospital - Atlanta
  • Hawaii
    • Honolulu, Hawaii, United States, 95813
      • Cancer Research Center of Hawaii
  • Illinois
    • Chicago, Illinois, United States, 60614
      • Children's Memorial Hospital - Chicago
    • Peoria, Illinois, United States, 61637
      • Saint Jude Midwest Affiliate
    • Springfield, Illinois, United States, 62794-9620
      • Southern Illinois University School of Medicine
  • Indiana
    • Indianapolis, Indiana, United States, 46260
      • St. Vincent Indianapolis Hospital
  • Kansas
    • Kansas City, Kansas, United States, 66160-7357
      • Kansas Masonic Cancer Research Institute at the University of Kansas Medical Center
  • Kentucky
    • Lexington, Kentucky, United States, 40536-0293
      • Markey Cancer Center at University of Kentucky Chandler Medical Center
  • Maine
    • Bangor, Maine, United States, 04401
      • CancerCare of Maine at Eastern Maine Medial Center
  • Maryland
    • Baltimore, Maryland, United States, 21215
      • Alvin and Lois Lapidus Cancer Institute at Sinai Hospital
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Dana-Farber/Harvard Cancer Center at Dana Farber Cancer Institute
  • Michigan
    • Ann Arbor, Michigan, United States, 48109-0238
      • C.S. Mott Children's Hospital at University of Michigan
    • Detroit, Michigan, United States, 48201-1379
      • Barbara Ann Karmanos Cancer Institute
    • Flint, Michigan, United States, 48503
      • Hurley Medical Center
    • Grand Rapids, Michigan, United States, 49503-2560
      • Spectrum Health Cancer Care - Butterworth Campus
    • Grosse Pointe Woods, Michigan, United States, 48236
      • Van Elslander Cancer Center at St. John Hospital and Medical Center
    • Lansing, Michigan, United States, 48910
      • Breslin Cancer Center at Ingham Regional Medical Center
  • Minnesota
    • Minneapolis, Minnesota, United States, 55455
      • Fairview University Medical Center - University Campus
    • Minneapolis, Minnesota, United States, 55404
      • Children's Hospital of Minnesota - Minneapolis
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic Cancer Center
  • Mississippi
    • Jackson, Mississippi, United States, 39216-4505
      • University of Mississippi Medical Center
  • Missouri
    • Columbia, Missouri, United States, 65203
      • Ellis Fischel Cancer Center at University of Missouri - Columbia
    • Kansas City, Missouri, United States, 64108
      • Children's Mercy Hospital
    • St. Louis, Missouri, United States, 63110
      • Siteman Cancer Center at Barnes-Jewish Hospital
  • New Jersey
    • Hackensack, New Jersey, United States, 07601
      • Hackensack University Medical Center Cancer Center
    • Livingston, New Jersey, United States, 07039
      • St. Barnabas Medical Center
  • New York
    • Bronx, New York, United States, 10461
      • Albert Einstein Cancer Center at Albert Einstein College of Medicine
    • Rochester, New York, United States, 14642
      • James P. Wilmot Cancer Center at University of Rochester Medical Center
    • Syracuse, New York, United States, 13210
      • SUNY Upstate Medical University Hospital
    • Valhalla, New York, United States, 10595
      • New York Medical College
  • North Carolina
    • Charlotte, North Carolina, United States, 28232-2861
      • Blumenthal Cancer Center at Carolinas Medical Center
    • Charlotte, North Carolina, United States, 28233-3549
      • Presbyterian Cancer Center at Presbyterian Hospital
    • Durham, North Carolina, United States, 27710
      • Duke Comprehensive Cancer Center
  • Ohio
    • Akron, Ohio, United States, 44308-1062
      • Children's Hospital Medical Center of Akron
    • Cincinnati, Ohio, United States, 45229-3039
      • Cincinnati Children's Hospital Medical Center
    • Dayton, Ohio, United States, 45404-1815
      • Children's Medical Center - Dayton
    • Youngstown, Ohio, United States, 44501
      • Tod Children's Hospital - Forum Health
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73104
      • Oklahoma University Medical Center
  • Pennsylvania
    • Hershey, Pennsylvania, United States, 17033-0850
      • Penn State Cancer Institute at Milton S. Hershey Medical Center
    • Philadelphia, Pennsylvania, United States, 19134-1095
      • St. Christopher's Hospital for Children
    • Philadelphia, Pennsylvania, United States, 19104-9786
      • Children's Hospital of Philadelphia
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Hollings Cancer Center at Medical University of South Carolina
    • Greenville, South Carolina, United States, 29605
      • Greenville Hospital System Cancer Center
  • Tennessee
    • Knoxville, Tennessee, United States, 37916
      • East Tennessee Children's Hospital
    • Memphis, Tennessee, United States, 38105
      • St. Jude Children's Research Hospital
  • Texas
    • Amarillo, Texas, United States, 79106
      • Texas Tech University Health Sciences Center School of Medicine
    • Austin, Texas, United States, 78701
      • Children's Hospital of Austin
    • Corpus Christi, Texas, United States, 78466
      • Driscoll Children's Hospital
    • Dallas, Texas, United States, 75230
      • Medical City Dallas Hospital
    • Dallas, Texas, United States, 75390
      • Simmons Comprehensive Cancer Center at University of Texas Southwestern Medical Center - Dallas
    • Fort Worth, Texas, United States, 76104-9958
      • Cook Children's Medical Center - Fort Worth
    • Houston, Texas, United States, 77030-2399
      • Baylor University Medical Center - Houston
    • Houston, Texas, United States, 77030-4009
      • M.D. Anderson Cancer Center at University of Texas
    • Lubbock, Texas, United States, 79410
      • Covenant Children's Hospital
    • San Antonio, Texas, United States, 78229-3993
      • Methodist Children's Hospital of South Texas
    • San Antonio, Texas, United States, 78229-3900
      • University of Texas Health Science Center at San Antonio
  • Utah
    • Salt Lake City, Utah, United States, 84113-1100
      • Primary Children's Medical Center
  • Virginia
    • Fairfax, Virginia, United States, 22031
      • Inova Fairfax Hospital
    • Roanoke, Virginia, United States, 24029
      • Carilion Cancer Center of Western Virginia
  • West Virginia
    • Charleston, West Virginia, United States, 25302
      • West Virginia University - Robert C. Byrd Health Sciences Center - Charleston Division
  • Wisconsin
    • Green Bay, Wisconsin, United States, 54307-3508
      • St. Vincent Hospital Regional Cancer Center
    • Madison, Wisconsin, United States, 53792-6164
      • University of Wisconsin Comprehensive Cancer Center
    • Marshfield, Wisconsin, United States, 54449
      • Marshfield Clinic - Marshfield Center
    • Milwaukee, Wisconsin, United States, 53226
      • Midwest Children's Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 21 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / 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: BLM; Blenoxane; NSC #125066; BLEO; 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: G-CSF; r-metHuG-CSF; Neupogen; NSC #614629; GRANULOCYTE COLONY-STIMULATING FACTOR; 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: Platinol-AQ; Cis-diamminedichloroplatinum II; 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; Etopophos; VePesid; 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: Mesnex; sodium 2-mercaptoethane sulfonate; NSC #113891

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Feasibility of adding cyclophosphamide to a PEB backbone	2 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximum tolerated dose	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).	21 days
Estimate the response rate	To estimate the response rate in this group of patients to a regimen of cyclophosphamide combined with cisplatin, etoposide, bleomycin (C-PEB).	Length of study

Collaborators and Investigators

• Sponsor: Children's Oncology Group
• Collaborators: National Cancer Institute (NCI)
• Investigators: Study Chair: Marcio A. Malogolowkin, MD, Children's Hospital Los Angeles

Study record dates

Study Major Dates

• Study Start: July 1, 2004
• Primary Completion (Actual): April 1, 2007

Study Registration Dates

• First Submitted: August 6, 2003
• First Submitted That Met QC Criteria: August 6, 2003
• First Posted (Estimate): August 7, 2003

Study Record Updates

• Last Update Posted (Estimate): October 17, 2013
• Last Update Submitted That Met QC Criteria: October 15, 2013
• Last Verified: October 1, 2013

More Information

Terms related to this study

• Keywords: childhood teratoma; childhood extragonadal germ cell tumor
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Neoplasms, Germ Cell and Embryonal; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Protective Agents; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Antineoplastic Agents, Phytogenic; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Adjuvants, Immunologic; Antibiotics, Antineoplastic; Cyclophosphamide; Etoposide; Cisplatin; Lenograstim; Bleomycin; Mesna
• Other Study ID Numbers: AGCT01P1; CDR0000316244 (Other Identifier: Clinical Trials.gov)