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

Primary Purpose

Sarcoma

Status
Completed
Phase
Phase 1
Locations
International
Study Type
Interventional
Intervention
cisplatin
dexrazoxane hydrochloride
doxorubicin hydrochloride
etoposide
ifosfamide
leucovorin calcium
methotrexate
zoledronic acid
adjuvant therapy
neoadjuvant therapy
therapeutic conventional surgery
filgrastim
Mesna
Sponsored by
Children's Oncology Group
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Sarcoma focused on measuring metastatic osteosarcoma

Eligibility Criteria

undefined - 40 Years (Child, Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • UAB Comprehensive Cancer Center
  • Arkansas Cancer Research Center at University of Arkansas for Medical Sciences
  • Southern California Permanente Medical Group
  • Jonathan Jaques Children's Cancer Center at Miller Children's Hospital
  • Childrens Hospital Los Angeles
  • Children's Hospital Central California
  • Children's Hospital and Research Center Oakland
  • Children's Hospital of Orange County
  • Lucile Packard Children's Hospital Stanford University
  • Rady Children's Hospital - San Diego
  • UCSF Helen Diller Family Comprehensive Cancer Center
  • Carole and Ray Neag Comprehensive Cancer Center at the University of Connecticut Health Center
  • Alfred I. duPont Hospital for Children
  • Children's National Medical Center
  • Nemours Children's Clinic
  • Nemours Children's Clinic - Orlando
  • Sacred Heart Cancer Center at Sacred Heart Hospital
  • All Children's Hospital
  • St. Joseph's Cancer Institute at St. Joseph's Hospital
  • Kaplan Cancer Center at St. Mary's Medical Center
  • AFLAC Cancer Center and Blood Disorders Service of Children's Healthcare of Atlanta - Egleston Campus
  • Cancer Research Center of Hawaii
  • Mountain States Tumor Institute at St. Luke's Regional Medical Center
  • Children's Memorial Hospital - Chicago
  • Keyser Family Cancer Center at Advocate Hope Children's Hospital
  • Indiana University Melvin and Bren Simon Cancer Center
  • Holden Comprehensive Cancer Center at University of Iowa
  • Kansas Masonic Cancer Research Institute at the University of Kansas Medical Center
  • Lucille P. Markey Cancer Center at University of Kentucky
  • Kosair Children's Hospital
  • Maine Children's Cancer Program at Barbara Bush Children's Hospital
  • Alvin and Lois Lapidus Cancer Institute at Sinai Hospital
  • Dana-Farber/Harvard Cancer Center at Dana-Farber Cancer Institute
  • C.S. Mott Children's Hospital at University of Michigan Medical Center
  • Barbara Ann Karmanos Cancer Institute
  • Butterworth Hospital at Spectrum Health
  • CCOP - Kalamazoo
  • Breslin Cancer Center at Ingham Regional Medical Center
  • Masonic Cancer Center at University of Minnesota
  • Mayo Clinic Cancer Center
  • University of Mississippi Cancer Clinic
  • Children's Mercy Hospital
  • Siteman Cancer Center at Barnes-Jewish Hospital - Saint Louis
  • Hackensack University Medical Center Cancer Center
  • Overlook Hospital
  • Cancer Institute of New Jersey at UMDNJ - Robert Wood Johnson Medical School
  • University of New Mexico Cancer Center
  • NYU Cancer Institute at New York University Medical Center
  • Herbert Irving Comprehensive Cancer Center at Columbia University Medical Center
  • SUNY Upstate Medical University Hospital
  • Blumenthal Cancer Center at Carolinas Medical Center
  • Presbyterian Cancer Center at Presbyterian Hospital
  • Duke Comprehensive Cancer Center
  • Wake Forest University Comprehensive Cancer Center
  • Akron Children's Hospital
  • Cincinnati Children's Hospital Medical Center
  • Rainbow Babies and Children's Hospital
  • Cleveland Clinic Taussig Cancer Center
  • Nationwide Children's Hospital
  • Dayton Children's - Dayton
  • Oklahoma University Cancer Institute
  • Knight Cancer Institute at Oregon Health and Science University
  • Penn State Children's Hospital
  • Palmetto Health South Carolina Cancer Center
  • T.C. Thompson Children's Hospital
  • East Tennessee Children's Hospital
  • Driscoll Children's Hospital
  • Medical City Dallas Hospital
  • Cook Children's Medical Center - Fort Worth
  • University of Texas Health Science Center at San Antonio
  • Methodist Children's Hospital of South Texas
  • Primary Children's Medical Center
  • Children's Hospital of The King's Daughters
  • Children's Hospital and Regional Medical Center - Seattle
  • Providence Cancer Center at Sacred Heart Medical Center
  • West Virginia University Health Sciences Center - Charleston
  • Marshfield Clinic - Marshfield Center
  • Princess Margaret Hospital for Children
  • Alberta Children's Hospital
  • Children's & Women's Hospital of British Columbia
  • CancerCare Manitoba
  • Janeway Children's Health and Rehabilitation Centre
  • IWK Health Centre
  • McMaster Children's Hospital at Hamilton Health Sciences
  • Hospital for Sick Children
  • Hopital Sainte Justine
  • Saskatoon Cancer Centre at the University of Saskatchewan
  • San Jorge Children's Hospital

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Experimental

Experimental

Experimental

Experimental

Arm Label

Arm 1- Chemotherapy and 1.2 mg/m2 Zoledronic Acid

Arm 2 - Chemotherapy and 2.3 mg/m2 Zoledronic Acid

Arm 3 - Chemotherapy and 3.5 mg/m2 Zoledronic Acid

Chemotherapy and 2.3 mg/m2 Zoledronic Acid after MTD

Arm Description

(Weeks 1-11) Patients receive dexrazoxane hydrochloride IV; doxorubicin hydrochloride IV; cisplatin IV; zoledronic acid IV; high-dose methotrexate IV; leucovorin calcium IV or orally; and G-CSF SC. (Week 12) Patients undergo therapeutic conventional surgery . (Weeks 13-25): Patients receive etoposide IV; ifosfamide IV; zoledronic acid IV; high-dose methotrexate IV; leucovorin calcium IV or orally; dexrazoxane hydrochloride IV; doxorubicin hydrochloride IV; cisplatin IV; G-CSF SC. (Week 26) Patients may undergo surgical procedure. (Weeks 27-36): Patients receive dexrazoxane hydrochloride IV; doxorubicin hydrochloride IV; cisplatin IV; zoledronic acid IV; high-dose methotrexate IV; leucovorin calcium IV or orally; etoposide IV; ifosfamide IV; and filgrastim (G-CSF) SC. See Detailed Description.

(Weeks 1-11) Patients receive dexrazoxane hydrochloride IV; doxorubicin hydrochloride IV; cisplatin IV; zoledronic acid IV; high-dose methotrexate IV; leucovorin calcium IV or orally; and G-CSF SC. (Week 12) Patients undergo therapeutic conventional surgery. (Weeks 13-25): Patients receive etoposide IV; ifosfamide IV; zoledronic acid IV; high-dose methotrexate IV; leucovorin calcium IV or orally; dexrazoxane hydrochloride IV; doxorubicin hydrochloride IV; cisplatin IV; G-CSF SC. (Week 26) Patients may undergo surgical procedure. (Weeks 27-36): Patients receive dexrazoxane hydrochloride IV; doxorubicin hydrochloride IV; cisplatin IV; zoledronic acid IV; high-dose methotrexate IV; leucovorin calcium IV or orally; etoposide IV; ifosfamide IV; and filgrastim (G-CSF) SC. See Detailed Description.

(Weeks 1-11) Patients receive dexrazoxane hydrochloride IV; doxorubicin hydrochloride IV; cisplatin IV; zoledronic acid IV; high-dose methotrexate IV; leucovorin calcium IV or orally; and G-CSF SC. (Week 12) Patients undergo therapeutic conventional surgery. (Weeks 13-25): Patients receive etoposide IV; ifosfamide IV; zoledronic acid IV; high-dose methotrexate IV; leucovorin calcium IV or orally; dexrazoxane hydrochloride IV; doxorubicin hydrochloride IV; cisplatin IV; G-CSF SC. (Week 26) Patients may undergo surgical procedure. (Weeks 27-36): Patients receive dexrazoxane hydrochloride IV; doxorubicin hydrochloride IV; cisplatin IV; zoledronic acid IV; high-dose methotrexate IV; leucovorin calcium IV or orally; etoposide IV; ifosfamide IV; and filgrastim (G-CSF) SC. See Detailed Description.

(Weeks 1-11) Patients receive dexrazoxane hydrochloride IV; doxorubicin hydrochloride IV; cisplatin IV; zoledronic acid IV; high-dose methotrexate IV; leucovorin calcium IV or orally; and G-CSF SC. (Week 12) Patients undergo therapeutic conventional surgery. (Weeks 13-25): Patients receive etoposide IV; ifosfamide IV; zoledronic acid IV; high-dose methotrexate IV; leucovorin calcium IV or orally; dexrazoxane hydrochloride IV; doxorubicin hydrochloride IV; cisplatin IV; G-CSF SC. (Week 26) Patients may undergo surgical procedure. (Weeks 27-36): Patients receive dexrazoxane hydrochloride IV; doxorubicin hydrochloride IV; cisplatin IV; zoledronic acid IV; high-dose methotrexate IV; leucovorin calcium IV or orally; etoposide IV; ifosfamide IV; and filgrastim (G-CSF) SC. See Detailed Description.

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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.
Event-free Survival
The EFS and survival functions will be estimated by the Kaplan-Meier methodology.
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.
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.

Full Information

First Posted
August 27, 2008
Last Updated
June 4, 2014
Sponsor
Children's Oncology Group
Collaborators
National Cancer Institute (NCI)
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1. Study Identification

Unique Protocol Identification Number
NCT00742924
Brief Title
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

2. Study Status

Record Verification Date
June 2014
Overall Recruitment Status
Completed
Study Start Date
August 2008 (undefined)
Primary Completion Date
April 2012 (Actual)
Study Completion Date
undefined (undefined)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Children's Oncology Group
Collaborators
National Cancer Institute (NCI)

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Sarcoma
Keywords
metastatic osteosarcoma

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
24 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Arm 1- Chemotherapy and 1.2 mg/m2 Zoledronic Acid
Arm Type
Experimental
Arm Description
(Weeks 1-11) Patients receive dexrazoxane hydrochloride IV; doxorubicin hydrochloride IV; cisplatin IV; zoledronic acid IV; high-dose methotrexate IV; leucovorin calcium IV or orally; and G-CSF SC. (Week 12) Patients undergo therapeutic conventional surgery . (Weeks 13-25): Patients receive etoposide IV; ifosfamide IV; zoledronic acid IV; high-dose methotrexate IV; leucovorin calcium IV or orally; dexrazoxane hydrochloride IV; doxorubicin hydrochloride IV; cisplatin IV; G-CSF SC. (Week 26) Patients may undergo surgical procedure. (Weeks 27-36): Patients receive dexrazoxane hydrochloride IV; doxorubicin hydrochloride IV; cisplatin IV; zoledronic acid IV; high-dose methotrexate IV; leucovorin calcium IV or orally; etoposide IV; ifosfamide IV; and filgrastim (G-CSF) SC. See Detailed Description.
Arm Title
Arm 2 - Chemotherapy and 2.3 mg/m2 Zoledronic Acid
Arm Type
Experimental
Arm Description
(Weeks 1-11) Patients receive dexrazoxane hydrochloride IV; doxorubicin hydrochloride IV; cisplatin IV; zoledronic acid IV; high-dose methotrexate IV; leucovorin calcium IV or orally; and G-CSF SC. (Week 12) Patients undergo therapeutic conventional surgery. (Weeks 13-25): Patients receive etoposide IV; ifosfamide IV; zoledronic acid IV; high-dose methotrexate IV; leucovorin calcium IV or orally; dexrazoxane hydrochloride IV; doxorubicin hydrochloride IV; cisplatin IV; G-CSF SC. (Week 26) Patients may undergo surgical procedure. (Weeks 27-36): Patients receive dexrazoxane hydrochloride IV; doxorubicin hydrochloride IV; cisplatin IV; zoledronic acid IV; high-dose methotrexate IV; leucovorin calcium IV or orally; etoposide IV; ifosfamide IV; and filgrastim (G-CSF) SC. See Detailed Description.
Arm Title
Arm 3 - Chemotherapy and 3.5 mg/m2 Zoledronic Acid
Arm Type
Experimental
Arm Description
(Weeks 1-11) Patients receive dexrazoxane hydrochloride IV; doxorubicin hydrochloride IV; cisplatin IV; zoledronic acid IV; high-dose methotrexate IV; leucovorin calcium IV or orally; and G-CSF SC. (Week 12) Patients undergo therapeutic conventional surgery. (Weeks 13-25): Patients receive etoposide IV; ifosfamide IV; zoledronic acid IV; high-dose methotrexate IV; leucovorin calcium IV or orally; dexrazoxane hydrochloride IV; doxorubicin hydrochloride IV; cisplatin IV; G-CSF SC. (Week 26) Patients may undergo surgical procedure. (Weeks 27-36): Patients receive dexrazoxane hydrochloride IV; doxorubicin hydrochloride IV; cisplatin IV; zoledronic acid IV; high-dose methotrexate IV; leucovorin calcium IV or orally; etoposide IV; ifosfamide IV; and filgrastim (G-CSF) SC. See Detailed Description.
Arm Title
Chemotherapy and 2.3 mg/m2 Zoledronic Acid after MTD
Arm Type
Experimental
Arm Description
(Weeks 1-11) Patients receive dexrazoxane hydrochloride IV; doxorubicin hydrochloride IV; cisplatin IV; zoledronic acid IV; high-dose methotrexate IV; leucovorin calcium IV or orally; and G-CSF SC. (Week 12) Patients undergo therapeutic conventional surgery. (Weeks 13-25): Patients receive etoposide IV; ifosfamide IV; zoledronic acid IV; high-dose methotrexate IV; leucovorin calcium IV or orally; dexrazoxane hydrochloride IV; doxorubicin hydrochloride IV; cisplatin IV; G-CSF SC. (Week 26) Patients may undergo surgical procedure. (Weeks 27-36): Patients receive dexrazoxane hydrochloride IV; doxorubicin hydrochloride IV; cisplatin IV; zoledronic acid IV; high-dose methotrexate IV; leucovorin calcium IV or orally; etoposide IV; ifosfamide IV; and filgrastim (G-CSF) SC. See Detailed Description.
Intervention Type
Drug
Intervention Name(s)
cisplatin
Other Intervention Name(s)
Cis-diamminedichloroplatinum II, CDDP, cis-DDP, Platinol-AQ, NSC #119875
Intervention Description
Given IV
Intervention Type
Drug
Intervention Name(s)
dexrazoxane hydrochloride
Other Intervention Name(s)
ICRF-187, ADR-529, ZINECARD, NSC #169780
Intervention Description
Given IV
Intervention Type
Drug
Intervention Name(s)
doxorubicin hydrochloride
Other Intervention Name(s)
Adriamycin, NSC #123127
Intervention Description
Given IV
Intervention Type
Drug
Intervention Name(s)
etoposide
Other Intervention Name(s)
VePesid, Etopophos, VP-16, NSC #141540
Intervention Description
Given IV
Intervention Type
Drug
Intervention Name(s)
ifosfamide
Other Intervention Name(s)
Isophosphamide, Iphosphamide, Z4942, Ifex, NSC #109724
Intervention Description
Given IV
Intervention Type
Drug
Intervention Name(s)
leucovorin calcium
Other Intervention Name(s)
LCV, Wellcovorin, citrovorum factor, folinic acid, NSC #003590
Intervention Description
Given IV or orally
Intervention Type
Drug
Intervention Name(s)
methotrexate
Other Intervention Name(s)
MTX, amethopterin, Trexall, NSC #000740
Intervention Description
Given IV
Intervention Type
Drug
Intervention Name(s)
zoledronic acid
Other Intervention Name(s)
1-Hydroxy-2-imidazol-1-ylethylidene - diphosphonic acid, zoledronate, Zometa, Aclasta, NSC# 721517
Intervention Description
Given IV
Intervention Type
Procedure
Intervention Name(s)
adjuvant therapy
Intervention Type
Procedure
Intervention Name(s)
neoadjuvant therapy
Intervention Type
Procedure
Intervention Name(s)
therapeutic conventional surgery
Intervention Description
Surgery of the primary tumor is scheduled for 12 weeks after the commencement of chemotherapy.
Intervention Type
Biological
Intervention Name(s)
filgrastim
Other Intervention Name(s)
Granulocyte Colony-Stimulating Factor, r-metHuG-CSF, G-CSF, Neupogen, NSC #614629
Intervention Description
Given SC
Intervention Type
Drug
Intervention Name(s)
Mesna
Other Intervention Name(s)
sodium 2-mercaptoethane sulfonate, UCB 3983, Mesnex, NSC #113891
Intervention Description
Given IV
Primary Outcome Measure Information:
Title
Limiting Toxicity
Description
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.
Time Frame
Enrollment through the first 12 weeks of therapy.
Secondary Outcome Measure Information:
Title
Histologic Response as Assessed in the Primary Tumor and in Resected Metastases
Description
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.
Time Frame
At definitive surgery planned for 12 weeks after the start of protocol therapy.
Title
Event-free Survival
Description
The EFS and survival functions will be estimated by the Kaplan-Meier methodology.
Time Frame
Time from study enrollment to disease recurrence, death without disease progression, diagnosis of a second malignant neoplasm, assessed up to 5 years
Title
Secondary Limiting Toxicity
Description
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.
Time Frame
After week 13 to the end of protocol therapy
Title
Prognostic Value of Bone Resorption Markers
Description
Blood will be collected for quantification of c-telopeptide and urine will be collected for quantification of n-telopeptide.
Time Frame
At baseline and at weeks 13 and 36

10. Eligibility

Sex
All
Maximum Age & Unit of Time
40 Years
Accepts Healthy Volunteers
No
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Robert Goldsby, MD
Organizational Affiliation
University of California, San Francisco
Official's Role
Study Chair
Facility Information:
Facility Name
UAB Comprehensive Cancer Center
City
Birmingham
State/Province
Alabama
ZIP/Postal Code
35294
Country
United States
Facility Name
Arkansas Cancer Research Center at University of Arkansas for Medical Sciences
City
Little Rock
State/Province
Arkansas
ZIP/Postal Code
72205
Country
United States
Facility Name
Southern California Permanente Medical Group
City
Downey
State/Province
California
ZIP/Postal Code
90027
Country
United States
Facility Name
Jonathan Jaques Children's Cancer Center at Miller Children's Hospital
City
Long Beach
State/Province
California
ZIP/Postal Code
90801
Country
United States
Facility Name
Childrens Hospital Los Angeles
City
Los Angeles
State/Province
California
ZIP/Postal Code
90027
Country
United States
Facility Name
Children's Hospital Central California
City
Madera
State/Province
California
ZIP/Postal Code
93638-8762
Country
United States
Facility Name
Children's Hospital and Research Center Oakland
City
Oakland
State/Province
California
ZIP/Postal Code
94609
Country
United States
Facility Name
Children's Hospital of Orange County
City
Orange
State/Province
California
ZIP/Postal Code
92868
Country
United States
Facility Name
Lucile Packard Children's Hospital Stanford University
City
Palo Alto
State/Province
California
ZIP/Postal Code
94304
Country
United States
Facility Name
Rady Children's Hospital - San Diego
City
San Diego
State/Province
California
ZIP/Postal Code
92123-4282
Country
United States
Facility Name
UCSF Helen Diller Family Comprehensive Cancer Center
City
San Francisco
State/Province
California
ZIP/Postal Code
94115
Country
United States
Facility Name
Carole and Ray Neag Comprehensive Cancer Center at the University of Connecticut Health Center
City
Farmington
State/Province
Connecticut
ZIP/Postal Code
06360-2875
Country
United States
Facility Name
Alfred I. duPont Hospital for Children
City
Wilmington
State/Province
Delaware
ZIP/Postal Code
19803
Country
United States
Facility Name
Children's National Medical Center
City
Washington
State/Province
District of Columbia
ZIP/Postal Code
20010-2970
Country
United States
Facility Name
Nemours Children's Clinic
City
Jacksonville
State/Province
Florida
ZIP/Postal Code
32207
Country
United States
Facility Name
Nemours Children's Clinic - Orlando
City
Orlando
State/Province
Florida
ZIP/Postal Code
32806
Country
United States
Facility Name
Sacred Heart Cancer Center at Sacred Heart Hospital
City
Pensacola
State/Province
Florida
ZIP/Postal Code
32504
Country
United States
Facility Name
All Children's Hospital
City
Saint Petersburg
State/Province
Florida
ZIP/Postal Code
33701
Country
United States
Facility Name
St. Joseph's Cancer Institute at St. Joseph's Hospital
City
Tampa
State/Province
Florida
ZIP/Postal Code
33607
Country
United States
Facility Name
Kaplan Cancer Center at St. Mary's Medical Center
City
West Palm Beach
State/Province
Florida
ZIP/Postal Code
33407
Country
United States
Facility Name
AFLAC Cancer Center and Blood Disorders Service of Children's Healthcare of Atlanta - Egleston Campus
City
Atlanta
State/Province
Georgia
ZIP/Postal Code
30322
Country
United States
Facility Name
Cancer Research Center of Hawaii
City
Honolulu
State/Province
Hawaii
ZIP/Postal Code
96813
Country
United States
Facility Name
Mountain States Tumor Institute at St. Luke's Regional Medical Center
City
Boise
State/Province
Idaho
ZIP/Postal Code
83712-6297
Country
United States
Facility Name
Children's Memorial Hospital - Chicago
City
Chicago
State/Province
Illinois
ZIP/Postal Code
60614
Country
United States
Facility Name
Keyser Family Cancer Center at Advocate Hope Children's Hospital
City
Oak Lawn
State/Province
Illinois
ZIP/Postal Code
60453
Country
United States
Facility Name
Indiana University Melvin and Bren Simon Cancer Center
City
Indianapolis
State/Province
Indiana
ZIP/Postal Code
46202-5289
Country
United States
Facility Name
Holden Comprehensive Cancer Center at University of Iowa
City
Iowa City
State/Province
Iowa
ZIP/Postal Code
52242-1002
Country
United States
Facility Name
Kansas Masonic Cancer Research Institute at the University of Kansas Medical Center
City
Kansas City
State/Province
Kansas
ZIP/Postal Code
66160-7357
Country
United States
Facility Name
Lucille P. Markey Cancer Center at University of Kentucky
City
Lexington
State/Province
Kentucky
ZIP/Postal Code
40536-0093
Country
United States
Facility Name
Kosair Children's Hospital
City
Louisville
State/Province
Kentucky
ZIP/Postal Code
40232
Country
United States
Facility Name
Maine Children's Cancer Program at Barbara Bush Children's Hospital
City
Scarborough
State/Province
Maine
ZIP/Postal Code
04074-9308
Country
United States
Facility Name
Alvin and Lois Lapidus Cancer Institute at Sinai Hospital
City
Baltimore
State/Province
Maryland
ZIP/Postal Code
21215
Country
United States
Facility Name
Dana-Farber/Harvard Cancer Center at Dana-Farber Cancer Institute
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02115
Country
United States
Facility Name
C.S. Mott Children's Hospital at University of Michigan Medical Center
City
Ann Arbor
State/Province
Michigan
ZIP/Postal Code
48109-0286
Country
United States
Facility Name
Barbara Ann Karmanos Cancer Institute
City
Detroit
State/Province
Michigan
ZIP/Postal Code
48201-1379
Country
United States
Facility Name
Butterworth Hospital at Spectrum Health
City
Grand Rapids
State/Province
Michigan
ZIP/Postal Code
49503-2560
Country
United States
Facility Name
CCOP - Kalamazoo
City
Kalamazoo
State/Province
Michigan
ZIP/Postal Code
49007-5381
Country
United States
Facility Name
Breslin Cancer Center at Ingham Regional Medical Center
City
Lansing
State/Province
Michigan
ZIP/Postal Code
48910
Country
United States
Facility Name
Masonic Cancer Center at University of Minnesota
City
Minneapolis
State/Province
Minnesota
ZIP/Postal Code
55455
Country
United States
Facility Name
Mayo Clinic Cancer Center
City
Rochester
State/Province
Minnesota
ZIP/Postal Code
55905
Country
United States
Facility Name
University of Mississippi Cancer Clinic
City
Jackson
State/Province
Mississippi
ZIP/Postal Code
39216-4505
Country
United States
Facility Name
Children's Mercy Hospital
City
Kansas City
State/Province
Missouri
ZIP/Postal Code
64108
Country
United States
Facility Name
Siteman Cancer Center at Barnes-Jewish Hospital - Saint Louis
City
St. Louis
State/Province
Missouri
ZIP/Postal Code
63110
Country
United States
Facility Name
Hackensack University Medical Center Cancer Center
City
Hackensack
State/Province
New Jersey
ZIP/Postal Code
07601
Country
United States
Facility Name
Overlook Hospital
City
Morristown
State/Province
New Jersey
ZIP/Postal Code
07962
Country
United States
Facility Name
Cancer Institute of New Jersey at UMDNJ - Robert Wood Johnson Medical School
City
New Brunswick
State/Province
New Jersey
ZIP/Postal Code
08903
Country
United States
Facility Name
University of New Mexico Cancer Center
City
Albuquerque
State/Province
New Mexico
ZIP/Postal Code
87131-5636
Country
United States
Facility Name
NYU Cancer Institute at New York University Medical Center
City
New York
State/Province
New York
ZIP/Postal Code
10016
Country
United States
Facility Name
Herbert Irving Comprehensive Cancer Center at Columbia University Medical Center
City
New York
State/Province
New York
ZIP/Postal Code
10032
Country
United States
Facility Name
SUNY Upstate Medical University Hospital
City
Syracuse
State/Province
New York
ZIP/Postal Code
13210
Country
United States
Facility Name
Blumenthal Cancer Center at Carolinas Medical Center
City
Charlotte
State/Province
North Carolina
ZIP/Postal Code
28232-2861
Country
United States
Facility Name
Presbyterian Cancer Center at Presbyterian Hospital
City
Charlotte
State/Province
North Carolina
ZIP/Postal Code
28233-3549
Country
United States
Facility Name
Duke Comprehensive Cancer Center
City
Durham
State/Province
North Carolina
ZIP/Postal Code
27710
Country
United States
Facility Name
Wake Forest University Comprehensive Cancer Center
City
Winston-Salem
State/Province
North Carolina
ZIP/Postal Code
27157-1096
Country
United States
Facility Name
Akron Children's Hospital
City
Akron
State/Province
Ohio
ZIP/Postal Code
44308-1062
Country
United States
Facility Name
Cincinnati Children's Hospital Medical Center
City
Cincinnati
State/Province
Ohio
ZIP/Postal Code
45229-3039
Country
United States
Facility Name
Rainbow Babies and Children's Hospital
City
Cleveland
State/Province
Ohio
ZIP/Postal Code
44106-5000
Country
United States
Facility Name
Cleveland Clinic Taussig Cancer Center
City
Cleveland
State/Province
Ohio
ZIP/Postal Code
44195
Country
United States
Facility Name
Nationwide Children's Hospital
City
Columbus
State/Province
Ohio
ZIP/Postal Code
43205-2696
Country
United States
Facility Name
Dayton Children's - Dayton
City
Dayton
State/Province
Ohio
ZIP/Postal Code
45404-1815
Country
United States
Facility Name
Oklahoma University Cancer Institute
City
Oklahoma City
State/Province
Oklahoma
ZIP/Postal Code
73104
Country
United States
Facility Name
Knight Cancer Institute at Oregon Health and Science University
City
Portland
State/Province
Oregon
ZIP/Postal Code
97239-3098
Country
United States
Facility Name
Penn State Children's Hospital
City
Hershey
State/Province
Pennsylvania
ZIP/Postal Code
17033-0850
Country
United States
Facility Name
Palmetto Health South Carolina Cancer Center
City
Columbia
State/Province
South Carolina
ZIP/Postal Code
29203
Country
United States
Facility Name
T.C. Thompson Children's Hospital
City
Chattanooga
State/Province
Tennessee
ZIP/Postal Code
37403
Country
United States
Facility Name
East Tennessee Children's Hospital
City
Knoxville
State/Province
Tennessee
ZIP/Postal Code
37901
Country
United States
Facility Name
Driscoll Children's Hospital
City
Corpus Christi
State/Province
Texas
ZIP/Postal Code
78411
Country
United States
Facility Name
Medical City Dallas Hospital
City
Dallas
State/Province
Texas
ZIP/Postal Code
75230
Country
United States
Facility Name
Cook Children's Medical Center - Fort Worth
City
Fort Worth
State/Province
Texas
ZIP/Postal Code
76104
Country
United States
Facility Name
University of Texas Health Science Center at San Antonio
City
San Antonio
State/Province
Texas
ZIP/Postal Code
78207
Country
United States
Facility Name
Methodist Children's Hospital of South Texas
City
San Antonio
State/Province
Texas
ZIP/Postal Code
78229-3993
Country
United States
Facility Name
Primary Children's Medical Center
City
Salt Lake City
State/Province
Utah
ZIP/Postal Code
84113-1100
Country
United States
Facility Name
Children's Hospital of The King's Daughters
City
Norfolk
State/Province
Virginia
ZIP/Postal Code
23507-1971
Country
United States
Facility Name
Children's Hospital and Regional Medical Center - Seattle
City
Seattle
State/Province
Washington
ZIP/Postal Code
98105
Country
United States
Facility Name
Providence Cancer Center at Sacred Heart Medical Center
City
Spokane
State/Province
Washington
ZIP/Postal Code
99220-2555
Country
United States
Facility Name
West Virginia University Health Sciences Center - Charleston
City
Charleston
State/Province
West Virginia
ZIP/Postal Code
25302
Country
United States
Facility Name
Marshfield Clinic - Marshfield Center
City
Marshfield
State/Province
Wisconsin
ZIP/Postal Code
54449
Country
United States
Facility Name
Princess Margaret Hospital for Children
City
Perth
State/Province
Western Australia
ZIP/Postal Code
6001
Country
Australia
Facility Name
Alberta Children's Hospital
City
Calgary
State/Province
Alberta
ZIP/Postal Code
T3B 6A8
Country
Canada
Facility Name
Children's & Women's Hospital of British Columbia
City
Vancouver
State/Province
British Columbia
ZIP/Postal Code
V6H 3V4
Country
Canada
Facility Name
CancerCare Manitoba
City
Winnipeg
State/Province
Manitoba
ZIP/Postal Code
R3E 0V9
Country
Canada
Facility Name
Janeway Children's Health and Rehabilitation Centre
City
St. John's
State/Province
Newfoundland and Labrador
ZIP/Postal Code
A1B 3V6
Country
Canada
Facility Name
IWK Health Centre
City
Halifax
State/Province
Nova Scotia
ZIP/Postal Code
B3K 6R8
Country
Canada
Facility Name
McMaster Children's Hospital at Hamilton Health Sciences
City
Hamilton
State/Province
Ontario
ZIP/Postal Code
L8N 3Z5
Country
Canada
Facility Name
Hospital for Sick Children
City
Toronto
State/Province
Ontario
ZIP/Postal Code
M5G 1X8
Country
Canada
Facility Name
Hopital Sainte Justine
City
Montreal
State/Province
Quebec
ZIP/Postal Code
H3T 1C5
Country
Canada
Facility Name
Saskatoon Cancer Centre at the University of Saskatchewan
City
Saskatoon
State/Province
Saskatchewan
ZIP/Postal Code
S7N 4H4
Country
Canada
Facility Name
San Jorge Children's Hospital
City
Santurce
ZIP/Postal Code
00912
Country
Puerto Rico

12. IPD Sharing Statement

Citations:
PubMed Identifier
23664013
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.
Results Reference
derived

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

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