Zoledronic Acid and Combination Chemotherapy in Treating Patients With Newly Diagnosed Metastatic Osteosarcoma

Sarcoma Clinical Trial

Official title:

Feasibility and Dose Discovery Analysis of Zoledronic Acid With Concurrent Chemotherapy in the Treatment of Newly Diagnosed Metastatic Osteosarcoma

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00742924
• Other study ID #: AOST06P1
• Secondary ID: CDR0000612613COG
• Status: Completed
• Phase: Phase 1
• First received: August 27, 2008
• Last updated: June 4, 2014
• Start date: August 2008

Study information

• Verified date: June 2014
• Source: Children's Oncology Group
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Federal Government
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 24
• Est. primary completion date: April 2012
• Accepts healthy volunteers: No
• Gender: Both
• Age group: N/A to 40 Years

Eligibility

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

Study Design

Allocation: Non-Randomized, Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Osteosarcoma
• Sarcoma

Intervention

Drug:
• cisplatin
Given IV
• dexrazoxane hydrochloride
Given IV
• doxorubicin hydrochloride
Given IV
• etoposide
Given IV
• ifosfamide
Given IV
• leucovorin calcium
Given IV or orally
• methotrexate
Given IV
• zoledronic acid
Given IV

Procedure:
• adjuvant therapy

• neoadjuvant therapy

• therapeutic conventional surgery
Surgery of the primary tumor is scheduled for 12 weeks after the commencement of chemotherapy.

Biological:
• filgrastim
Given SC

Drug:
• Mesna
Given IV

Locations

Country	Name	City	State
Australia	Princess Margaret Hospital for Children	Perth	Western Australia
Canada	Alberta Children's Hospital	Calgary	Alberta
Canada	IWK Health Centre	Halifax	Nova Scotia
Canada	McMaster Children's Hospital at Hamilton Health Sciences	Hamilton	Ontario
Canada	Hopital Sainte Justine	Montreal	Quebec
Canada	Saskatoon Cancer Centre at the University of Saskatchewan	Saskatoon	Saskatchewan
Canada	Janeway Children's Health and Rehabilitation Centre	St. John's	Newfoundland and Labrador
Canada	Hospital for Sick Children	Toronto	Ontario
Canada	Children's & Women's Hospital of British Columbia	Vancouver	British Columbia
Canada	CancerCare Manitoba	Winnipeg	Manitoba
Puerto Rico	San Jorge Children's Hospital	Santurce
United States	Akron Children's Hospital	Akron	Ohio
United States	University of New Mexico Cancer Center	Albuquerque	New Mexico
United States	C.S. Mott Children's Hospital at University of Michigan Medical Center	Ann Arbor	Michigan
United States	AFLAC Cancer Center and Blood Disorders Service of Children's Healthcare of Atlanta - Egleston Campus	Atlanta	Georgia
United States	Alvin and Lois Lapidus Cancer Institute at Sinai Hospital	Baltimore	Maryland
United States	UAB Comprehensive Cancer Center	Birmingham	Alabama
United States	Mountain States Tumor Institute at St. Luke's Regional Medical Center	Boise	Idaho
United States	Dana-Farber/Harvard Cancer Center at Dana-Farber Cancer Institute	Boston	Massachusetts
United States	West Virginia University Health Sciences Center - Charleston	Charleston	West Virginia
United States	Blumenthal Cancer Center at Carolinas Medical Center	Charlotte	North Carolina
United States	Presbyterian Cancer Center at Presbyterian Hospital	Charlotte	North Carolina
United States	T.C. Thompson Children's Hospital	Chattanooga	Tennessee
United States	Children's Memorial Hospital - Chicago	Chicago	Illinois
United States	Cincinnati Children's Hospital Medical Center	Cincinnati	Ohio
United States	Cleveland Clinic Taussig Cancer Center	Cleveland	Ohio
United States	Rainbow Babies and Children's Hospital	Cleveland	Ohio
United States	Palmetto Health South Carolina Cancer Center	Columbia	South Carolina
United States	Nationwide Children's Hospital	Columbus	Ohio
United States	Driscoll Children's Hospital	Corpus Christi	Texas
United States	Medical City Dallas Hospital	Dallas	Texas
United States	Dayton Children's - Dayton	Dayton	Ohio
United States	Barbara Ann Karmanos Cancer Institute	Detroit	Michigan
United States	Southern California Permanente Medical Group	Downey	California
United States	Duke Comprehensive Cancer Center	Durham	North Carolina
United States	Carole and Ray Neag Comprehensive Cancer Center at the University of Connecticut Health Center	Farmington	Connecticut
United States	Cook Children's Medical Center - Fort Worth	Fort Worth	Texas
United States	Butterworth Hospital at Spectrum Health	Grand Rapids	Michigan
United States	Hackensack University Medical Center Cancer Center	Hackensack	New Jersey
United States	Penn State Children's Hospital	Hershey	Pennsylvania
United States	Cancer Research Center of Hawaii	Honolulu	Hawaii
United States	Indiana University Melvin and Bren Simon Cancer Center	Indianapolis	Indiana
United States	Holden Comprehensive Cancer Center at University of Iowa	Iowa City	Iowa
United States	University of Mississippi Cancer Clinic	Jackson	Mississippi
United States	Nemours Children's Clinic	Jacksonville	Florida
United States	CCOP - Kalamazoo	Kalamazoo	Michigan
United States	Children's Mercy Hospital	Kansas City	Missouri
United States	Kansas Masonic Cancer Research Institute at the University of Kansas Medical Center	Kansas City	Kansas
United States	East Tennessee Children's Hospital	Knoxville	Tennessee
United States	Breslin Cancer Center at Ingham Regional Medical Center	Lansing	Michigan
United States	Lucille P. Markey Cancer Center at University of Kentucky	Lexington	Kentucky
United States	Arkansas Cancer Research Center at University of Arkansas for Medical Sciences	Little Rock	Arkansas
United States	Jonathan Jaques Children's Cancer Center at Miller Children's Hospital	Long Beach	California
United States	Childrens Hospital Los Angeles	Los Angeles	California
United States	Kosair Children's Hospital	Louisville	Kentucky
United States	Children's Hospital Central California	Madera	California
United States	Marshfield Clinic - Marshfield Center	Marshfield	Wisconsin
United States	Masonic Cancer Center at University of Minnesota	Minneapolis	Minnesota
United States	Overlook Hospital	Morristown	New Jersey
United States	Cancer Institute of New Jersey at UMDNJ - Robert Wood Johnson Medical School	New Brunswick	New Jersey
United States	Herbert Irving Comprehensive Cancer Center at Columbia University Medical Center	New York	New York
United States	NYU Cancer Institute at New York University Medical Center	New York	New York
United States	Children's Hospital of The King's Daughters	Norfolk	Virginia
United States	Keyser Family Cancer Center at Advocate Hope Children's Hospital	Oak Lawn	Illinois
United States	Children's Hospital and Research Center Oakland	Oakland	California
United States	Oklahoma University Cancer Institute	Oklahoma City	Oklahoma
United States	Children's Hospital of Orange County	Orange	California
United States	Nemours Children's Clinic - Orlando	Orlando	Florida
United States	Lucile Packard Children's Hospital Stanford University	Palo Alto	California
United States	Sacred Heart Cancer Center at Sacred Heart Hospital	Pensacola	Florida
United States	Knight Cancer Institute at Oregon Health and Science University	Portland	Oregon
United States	Mayo Clinic Cancer Center	Rochester	Minnesota
United States	All Children's Hospital	Saint Petersburg	Florida
United States	Primary Children's Medical Center	Salt Lake City	Utah
United States	Methodist Children's Hospital of South Texas	San Antonio	Texas
United States	University of Texas Health Science Center at San Antonio	San Antonio	Texas
United States	Rady Children's Hospital - San Diego	San Diego	California
United States	UCSF Helen Diller Family Comprehensive Cancer Center	San Francisco	California
United States	Maine Children's Cancer Program at Barbara Bush Children's Hospital	Scarborough	Maine
United States	Children's Hospital and Regional Medical Center - Seattle	Seattle	Washington
United States	Providence Cancer Center at Sacred Heart Medical Center	Spokane	Washington
United States	Siteman Cancer Center at Barnes-Jewish Hospital - Saint Louis	St. Louis	Missouri
United States	SUNY Upstate Medical University Hospital	Syracuse	New York
United States	St. Joseph's Cancer Institute at St. Joseph's Hospital	Tampa	Florida
United States	Children's National Medical Center	Washington	District of Columbia
United States	Kaplan Cancer Center at St. Mary's Medical Center	West Palm Beach	Florida
United States	Alfred I. duPont Hospital for Children	Wilmington	Delaware
United States	Wake Forest University Comprehensive Cancer Center	Winston-Salem	North Carolina

Sponsors (2)

Lead Sponsor	Collaborator
Children's Oncology Group	National Cancer Institute (NCI)

Countries where clinical trial is conducted

United States,  Australia,  Canada,  Puerto Rico, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Limiting Toxicity	The occurrence of Limiting Toxicity defined as Any CTC AE version 4 Grade 3 and 4 non-hematologic toxicity thought to be possibly, probably or definitely related to zoledronic acid with the specific exclusion of: Grade 3 nausea and vomiting controlled with adequate antiemetic prophylaxis.; Grade 3 transaminase (AST/ALT) that occurs during the evaluation period but resolves to = Grade 2, before the planned dose of therapy after definitive surgery.; Grade 3 fever or infection.; Grade 3 or 4 hypocalcemia (see Section 5.1.1); Grade 3 mucositis.; Grade 3 fatigue that returns to = Grade 2, before the planned dose of therapy after definitive surgery.; Grade 3 joint range of motion, decreased or joint effusion that is related to the primary tumor.	Enrollment through the first 12 weeks of therapy.	Yes
Secondary	Histologic Response as Assessed in the Primary Tumor and in Resected Metastases	Histologic response as graded according to the system of Huvos across all specimens resected at the time of local control in the primary tumor and in resected metastases.; The best response, as quantified by maximum necrosis grading according to the system of Huvos across all specimens resected at the time of local control, will be used to quantify the effect of Induction chemotherapy.	At definitive surgery planned for 12 weeks after the start of protocol therapy.	No
Secondary	Event-free Survival	The EFS and survival functions will be estimated by the Kaplan-Meier methodology.	Time from study enrollment to disease recurrence, death without disease progression, diagnosis of a second malignant neoplasm, assessed up to 5 years	No
Secondary	Secondary Limiting Toxicity	Secondary limiting toxicity defined as Any CTC AE version 4 Grade 3 and 4 non-hematologic toxicity thought to be possibly, probably or definitely related to zoledronic acid with the specific exclusion of: Grade 3 nausea and vomiting controlled with adequate antiemetic prophylaxis.; Grade 3 transaminase (AST/ALT) that occurs during the evaluation period but resolves to = Grade 2, before the planned dose of therapy after definitive surgery.; Grade 3 fever or infection.; Grade 3 or 4 hypocalcemia (see Section 5.1.1); Grade 3 mucositis.; Grade 3 fatigue that returns to = Grade 2, before the planned dose of therapy after definitive surgery.; Grade 3 joint range of motion, decreased or joint effusion that is related to the primary tumor.; CTC AE version 4 hematologic toxicity will be based on time to blood count recovery to an ANC = 1000/µL and platelet count = 100,000/µL that delays definitive surgery by more than 2 weeks.	After week 13 to the end of protocol therapy	Yes
Secondary	Prognostic Value of Bone Resorption Markers	Blood will be collected for quantification of c-telopeptide and urine will be collected for quantification of n-telopeptide.	At baseline and at weeks 13 and 36	No