Clinical trial NCT00742924: Zoledronic Acid and Combination Chemotherapy in Treating Patients With Newly Diagnosed Metastatic Osteosarcoma
Official title: Feasibility and Dose Discovery Analysis of Zoledronic Acid With Concurrent Chemotherapy in the Treatment of Newly Diagnosed Metastatic Osteosarcoma
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Sarcoma
Keywords: metastatic osteosarcoma
Lead sponsor: Children's Oncology Group
Sponsor class: NETWORK
Collaborators: name: National Cancer Institute (NCI)
First posted: 2008-08-28
Enrollment: 24
Sex: ALL
Maximum age (years): 40
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: RATIONALE: 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. Giving more than one drug (combination chemotherapy) may kill more tumor cells.

PURPOSE: This clinical trial is studying the side effects and best dose of zoledronic acid when given together with combination chemotherapy in treating patients with newly diagnosed metastatic osteosarcoma.

Detailed description: OBJECTIVES:

Primary:

* To assess the feasibility and safety of zoledronic acid when administered in combination with standard chemotherapy in patients with newly diagnosed metastatic osteosarcoma.
* To determine the maximum tolerated dose of zoledronic acid when administered in combination with standard chemotherapy in these patients.

Secondary:

- To compare the histologic response and event-free survival of patients treated with this regimen versus patients treated on INT-0133 or CCG-7943.

OUTLINE: This is a multicenter, dose-escalation study of zoledronic acid.

* Induction therapy (weeks 1-11): Patients receive dexrazoxane hydrochloride IV slowly over 5-15 minutes, doxorubicin hydrochloride IV over 15 minutes, and cisplatin IV over 1 hour on days 1 and 2 of weeks 1 and 6; zoledronic acid IV at the assigned dose level over 30 minutes on day 4 of weeks 1 and 6; high-dose methotrexate IV over 4 hours on day 1 of weeks 4, 5, 9, and 10; leucovorin calcium IV or orally every 6 hours starting on day 2 and continuing until clearance of methotrexate of weeks 4, 5, 9, and 10; and filgrastim (G-CSF) subcutaneously (SC) once daily beginning on day 3 of weeks 1 and 6 and continuing until blood counts recover.
* Surgery (week 12): Patients undergo definitive surgery (limb-salvage surgery or amputation) of the primary tumor in week 12.
* Maintenance therapy course 1 (weeks 13-25): Patients receive etoposide IV over 1 hour and ifosfamide IV over 4 hours on days 1-5 of weeks 13 and 21; zoledronic acid IV over 30 minutes on day 4 of week 17 and on day 7 of weeks 13 and 21; high-dose methotrexate IV over 4 hours on day 1 of weeks 16, 20, and 24; leucovorin calcium IV or orally every 6 hours starting on day 2 and continuing until clearance of methotrexate of weeks 16, 20, and 24; dexrazoxane hydrochloride IV slowly over 5-15 minutes, doxorubicin hydrochloride IV over 15 minutes, and cisplatin IV over 1 hour on days 1 and 2 of week 17; and G-CSF SC once daily beginning on day 6 of weeks 13, 17, and 21 and continuing until blood counts recover.
* Surgery (week 26): Patients may undergo surgical resection of primary metastases in week 26.
* Maintenance therapy course 2 (weeks 27-36): Patients receive dexrazoxane hydrochloride IV slowly over 5-15 minutes and doxorubicin hydrochloride IV over 15 minutes on days 1 and 2 of weeks 27 and 31; cisplatin IV over 1 hour on days 1 and 2 of week 27; zoledronic acid IV over 30 minutes on day 4 of week 27 and on day 7 of weeks 31 and 36; high-dose methotrexate IV over 4 hours on day 1 of weeks 30, 34, and 35; leucovorin calcium IV or orally every 6 hours starting on day 2 and continuing until clearance of methotrexate of weeks 30, 34, and 35; etoposide IV over 1 hour on days 1-5 of week 36; ifosfamide (1.8 gm/m2 ) IV over 1 hour on days 1-5 of week 31;ifosfamide (2.8 gm/m2)IV over 4 hours on days 1-5 of week 36; and G-CSF SC once daily beginning on day 3 of weeks 27, 31, and 36 and continuing until blood counts recover.

Mensa is a supportive care medicine used to prevent hemorrhagic cystitis caused by ifosfamide. It is always given when ifosfamide is given. It was used in all arms.

After completion of study treatment, patients are followed periodically for up to 5 years.

Eligibility criteria: DISEASE CHARACTERISTICS:

* Biopsy-proven high-grade osteosarcoma within the past 6 weeks

  * Newly diagnosed disease
  * Metastatic disease
* Resectable disease OR expected to become resectable after initial chemotherapy
* Disease has arisen outside of areas of Paget's disease

PATIENT CHARACTERISTICS:

* ECOG performance status (PS) 0-2 OR Karnofsky PS 50-100% (for patients \> 16 years of age) OR Lansky PS 50-100% (for patients ≤ 16 years of age)
* Creatinine clearance or radioisotope glomerular filtration rate ≥ 70 mL/min OR maximum serum creatinine based on age/gender as follows:

  * 0.4 mg/dL (for patients 1 to 5 months of age)
  * 0.5 mg/dL (for patients 6 to 11 months of age)
  * 0.6 mg/dL (for patients 1 year of age)
  * 0.8 mg/dL (for patients 2 to 5 years of age)
  * 1 mg/dL (for patients 6 to 9 years of age)
  * 1.2 mg/dL (for patients 10 to 12 years of age)
  * 1.5 mg/dL (males) or 1.4 mg/dL (females) (for patients 13 to 15 years of age)
  * 1.7 mg/dL (males) or 1.4 mg/dL (females) (for patients ≥ 16 years of age)
* Total bilirubin ≤ 1.5 times upper limit of normal (ULN) for age
* AST or ALT \< 2.5 times ULN for age
* Shortening fraction ≥ 28% by echocardiogram OR ejection fraction ≥ 50% by radionuclide angiogram
* ANC ≥ 1,000/mm³
* Platelet count ≥ 100,000/mm³ (transfusion independent)
* Hemoglobin ≥ 10 g/dL (RBC transfusion allowed)
* Not pregnant or nursing
* Negative pregnancy test
* Fertile patients must use contraception
* No known HIV infection
* No history of pericarditis, myocarditis, symptomatic arrhythmia, or conduction disturbances

PRIOR CONCURRENT THERAPY:

* No prior chemotherapy or radiotherapy
* No other concurrent anticancer chemotherapy
* No concurrent immunomodulating agents
* Steroids for anti-emetic allowed

Primary outcomes:
measure: Limiting Toxicity
timeFrame: Enrollment through the first 12 weeks of therapy.
Secondary outcomes:
measure: Histologic Response as Assessed in the Primary Tumor and in Resected Metastases
timeFrame: At definitive surgery planned for 12 weeks after the start of protocol therapy.
measure: Event-free Survival
timeFrame: Time from study enrollment to disease recurrence, death without disease progression, diagnosis of a second malignant neoplasm, assessed up to 5 years
measure: Secondary Limiting Toxicity
timeFrame: After week 13 to the end of protocol therapy
measure: Prognostic Value of Bone Resorption Markers
timeFrame: At baseline and at weeks 13 and 36
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: UAB Comprehensive Cancer Center
state: Alabama
city: Little Rock
country: United States
facility: Arkansas Cancer Research Center at University of Arkansas for Medical Sciences
state: Arkansas
city: Downey
country: United States
facility: Southern California Permanente Medical Group
state: California
city: Long Beach
country: United States
facility: Jonathan Jaques Children's Cancer Center at Miller Children's Hospital
state: California
city: Los Angeles
country: United States
facility: Childrens Hospital Los Angeles
state: California
city: Madera
country: United States
facility: Children's Hospital Central California
state: California
city: Oakland
country: United States
facility: Children's Hospital and Research Center Oakland
state: California
city: Orange
country: United States
facility: Children's Hospital of Orange County
state: California
city: Palo Alto
country: United States
facility: Lucile Packard Children's Hospital Stanford University
state: California
city: San Diego
country: United States
facility: Rady Children's Hospital - San Diego
state: California
city: San Francisco
country: United States
facility: UCSF Helen Diller Family Comprehensive Cancer Center
state: California
city: Farmington
country: United States
facility: Carole and Ray Neag Comprehensive Cancer Center at the University of Connecticut Health Center
state: Connecticut
city: Wilmington
country: United States
facility: Alfred I. duPont Hospital for Children
state: Delaware
city: Washington
country: United States
facility: Children's National Medical Center
state: District of Columbia
city: Jacksonville
country: United States
facility: Nemours Children's Clinic
state: Florida
city: Orlando
country: United States
facility: Nemours Children's Clinic - Orlando
state: Florida
city: Pensacola
country: United States
facility: Sacred Heart Cancer Center at Sacred Heart Hospital
state: Florida
city: Saint Petersburg
country: United States
facility: All Children's Hospital
state: Florida
city: Tampa
country: United States
facility: St. Joseph's Cancer Institute at St. Joseph's Hospital
state: Florida
city: West Palm Beach
country: United States
facility: Kaplan Cancer Center at St. Mary's Medical Center
state: Florida
city: Atlanta
country: United States
facility: AFLAC Cancer Center and Blood Disorders Service of Children's Healthcare of Atlanta - Egleston Campus
state: Georgia
city: Honolulu
country: United States
facility: Cancer Research Center of Hawaii
state: Hawaii
city: Boise
country: United States
facility: Mountain States Tumor Institute at St. Luke's Regional Medical Center
state: Idaho
city: Chicago
country: United States
facility: Children's Memorial Hospital - Chicago
state: Illinois
city: Oak Lawn
country: United States
facility: Keyser Family Cancer Center at Advocate Hope Children's Hospital
state: Illinois
city: Indianapolis
country: United States
facility: Indiana University Melvin and Bren Simon Cancer Center
state: Indiana
city: Iowa City
country: United States
facility: Holden Comprehensive Cancer Center at University of Iowa
state: Iowa
city: Kansas City
country: United States
facility: Kansas Masonic Cancer Research Institute at the University of Kansas Medical Center
state: Kansas
city: Lexington
country: United States
facility: Lucille P. Markey Cancer Center at University of Kentucky
state: Kentucky
city: Louisville
country: United States
facility: Kosair Children's Hospital
state: Kentucky
city: Scarborough
country: United States
facility: Maine Children's Cancer Program at Barbara Bush Children's Hospital
state: Maine
city: Baltimore
country: United States
facility: Alvin and Lois Lapidus Cancer Institute at Sinai Hospital
state: Maryland
city: Boston
country: United States
facility: Dana-Farber/Harvard Cancer Center at Dana-Farber Cancer Institute
state: Massachusetts
city: Ann Arbor
country: United States
facility: C.S. Mott Children's Hospital at University of Michigan Medical Center
state: Michigan
city: Detroit
country: United States
facility: Barbara Ann Karmanos Cancer Institute
state: Michigan
city: Grand Rapids
country: United States
facility: Butterworth Hospital at Spectrum Health
state: Michigan
city: Kalamazoo
country: United States
facility: CCOP - Kalamazoo
state: Michigan
city: Lansing
country: United States
facility: Breslin Cancer Center at Ingham Regional Medical Center
state: Michigan
city: Minneapolis
country: United States
facility: Masonic Cancer Center at University of Minnesota
state: Minnesota
city: Rochester
country: United States
facility: Mayo Clinic Cancer Center
state: Minnesota
city: Jackson
country: United States
facility: University of Mississippi Cancer Clinic
state: Mississippi
city: Kansas City
country: United States
facility: Children's Mercy Hospital
state: Missouri
city: St. Louis
country: United States
facility: Siteman Cancer Center at Barnes-Jewish Hospital - Saint Louis
state: Missouri
city: Hackensack
country: United States
facility: Hackensack University Medical Center Cancer Center
state: New Jersey
city: Morristown
country: United States
facility: Overlook Hospital
state: New Jersey
city: New Brunswick
country: United States
facility: Cancer Institute of New Jersey at UMDNJ - Robert Wood Johnson Medical School
state: New Jersey
city: Albuquerque
country: United States
facility: University of New Mexico Cancer Center
state: New Mexico
city: New York
country: United States
facility: NYU Cancer Institute at New York University Medical Center
state: New York
city: New York
country: United States
facility: Herbert Irving Comprehensive Cancer Center at Columbia University Medical Center
state: New York
city: Syracuse
country: United States
facility: SUNY Upstate Medical University Hospital
state: New York
city: Charlotte
country: United States
facility: Blumenthal Cancer Center at Carolinas Medical Center
state: North Carolina
city: Charlotte
country: United States
facility: Presbyterian Cancer Center at Presbyterian Hospital
state: North Carolina
city: Durham
country: United States
facility: Duke Comprehensive Cancer Center
state: North Carolina
city: Winston-Salem
country: United States
facility: Wake Forest University Comprehensive Cancer Center
state: North Carolina
city: Akron
country: United States
facility: Akron Children's Hospital
state: Ohio
city: Cincinnati
country: United States
facility: Cincinnati Children's Hospital Medical Center
state: Ohio
city: Cleveland
country: United States
facility: Rainbow Babies and Children's Hospital
state: Ohio
city: Cleveland
country: United States
facility: Cleveland Clinic Taussig Cancer Center
state: Ohio
city: Columbus
country: United States
facility: Nationwide Children's Hospital
state: Ohio
city: Dayton
country: United States
facility: Dayton Children's - Dayton
state: Ohio
city: Oklahoma City
country: United States
facility: Oklahoma University Cancer Institute
state: Oklahoma
city: Portland
country: United States
facility: Knight Cancer Institute at Oregon Health and Science University
state: Oregon
city: Hershey
country: United States
facility: Penn State Children's Hospital
state: Pennsylvania
city: Columbia
country: United States
facility: Palmetto Health South Carolina Cancer Center
state: South Carolina
city: Chattanooga
country: United States
facility: T.C. Thompson Children's Hospital
state: Tennessee
city: Knoxville
country: United States
facility: East Tennessee Children's Hospital
state: Tennessee
city: Corpus Christi
country: United States
facility: Driscoll Children's Hospital
state: Texas
city: Dallas
country: United States
facility: Medical City Dallas Hospital
state: Texas
city: Fort Worth
country: United States
facility: Cook Children's Medical Center - Fort Worth
state: Texas
city: San Antonio
country: United States
facility: University of Texas Health Science Center at San Antonio
state: Texas
city: San Antonio
country: United States
facility: Methodist Children's Hospital of South Texas
state: Texas
city: Salt Lake City
country: United States
facility: Primary Children's Medical Center
state: Utah
city: Norfolk
country: United States
facility: Children's Hospital of The King's Daughters
state: Virginia
city: Seattle
country: United States
facility: Children's Hospital and Regional Medical Center - Seattle
state: Washington
city: Spokane
country: United States
facility: Providence Cancer Center at Sacred Heart Medical Center
state: Washington
city: Charleston
country: United States
facility: West Virginia University Health Sciences Center - Charleston
state: West Virginia
city: Marshfield
country: United States
facility: Marshfield Clinic - Marshfield Center
state: Wisconsin
city: Perth
country: Australia
facility: Princess Margaret Hospital for Children
state: Western Australia
city: Calgary
country: Canada
facility: Alberta Children's Hospital
state: Alberta
city: Vancouver
country: Canada
facility: Children's & Women's Hospital of British Columbia
state: British Columbia
city: Winnipeg
country: Canada
facility: CancerCare Manitoba
state: Manitoba
city: St. John's
country: Canada
facility: Janeway Children's Health and Rehabilitation Centre
state: Newfoundland and Labrador
city: Halifax
country: Canada
facility: IWK Health Centre
state: Nova Scotia
city: Hamilton
country: Canada
facility: McMaster Children's Hospital at Hamilton Health Sciences
state: Ontario
city: Toronto
country: Canada
facility: Hospital for Sick Children
state: Ontario
city: Montreal
country: Canada
facility: Hopital Sainte Justine
state: Quebec
city: Saskatoon
country: Canada
facility: Saskatoon Cancer Centre at the University of Saskatchewan
state: Saskatchewan
city: Santurce
country: Puerto Rico
facility: San Jorge Children's Hospital
Study officials:
affiliation: University of California, San Francisco
name: Robert Goldsby, MD
role: STUDY_CHAIR
References:
citation: Goldsby RE, Fan TM, Villaluna D, Wagner LM, Isakoff MS, Meyer J, Randall RL, Lee S, Kim G, Bernstein M, Gorlick R, Krailo M, Marina N. Feasibility and dose discovery analysis of zoledronic acid with concurrent chemotherapy in the treatment of newly diagnosed metastatic osteosarcoma: a report from the Children's Oncology Group. Eur J Cancer. 2013 Jul;49(10):2384-91. doi: 10.1016/j.ejca.2013.03.018. Epub 2013 May 7.