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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/show/NCT00742924




Registration number
NCT00742924
Ethics application status
Date submitted
27/08/2008
Date registered
28/08/2008
Date last updated
4/07/2014

Titles & IDs
Public title
Zoledronic Acid and Combination Chemotherapy in Treating Patients With Newly Diagnosed Metastatic Osteosarcoma
Scientific title
Feasibility and Dose Discovery Analysis of Zoledronic Acid With Concurrent Chemotherapy in the Treatment of Newly Diagnosed Metastatic Osteosarcoma
Secondary ID [1] 0 0
CDR0000612613
Secondary ID [2] 0 0
AOST06P1
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Sarcoma 0 0
Condition category
Condition code
Cancer 0 0 0 0
Bone
Cancer 0 0 0 0
Sarcoma (also see 'Bone') - soft tissue
Cancer 0 0 0 0
Children's - Other

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - cisplatin
Treatment: Drugs - dexrazoxane hydrochloride
Treatment: Drugs - doxorubicin hydrochloride
Treatment: Drugs - etoposide
Treatment: Drugs - ifosfamide
Treatment: Drugs - leucovorin calcium
Treatment: Drugs - methotrexate
Treatment: Drugs - zoledronic acid
Treatment: Surgery - adjuvant therapy
Treatment: Surgery - neoadjuvant therapy
Treatment: Surgery - therapeutic conventional surgery
Other interventions - filgrastim
Treatment: Drugs - Mesna

Experimental: Arm 1- Chemotherapy and 1.2 mg/m2 Zoledronic Acid - (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.

Experimental: Arm 2 - Chemotherapy and 2.3 mg/m2 Zoledronic Acid - (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.

Experimental: Arm 3 - Chemotherapy and 3.5 mg/m2 Zoledronic Acid - (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.

Experimental: Chemotherapy and 2.3 mg/m2 Zoledronic Acid after MTD - (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.


Treatment: Drugs: cisplatin
Given IV

Treatment: Drugs: dexrazoxane hydrochloride
Given IV

Treatment: Drugs: doxorubicin hydrochloride
Given IV

Treatment: Drugs: etoposide
Given IV

Treatment: Drugs: ifosfamide
Given IV

Treatment: Drugs: leucovorin calcium
Given IV or orally

Treatment: Drugs: methotrexate
Given IV

Treatment: Drugs: zoledronic acid
Given IV

Treatment: Surgery: adjuvant therapy


Treatment: Surgery: neoadjuvant therapy


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

Other interventions: filgrastim
Given SC

Treatment: Drugs: Mesna
Given IV

Intervention code [1] 0 0
Treatment: Drugs
Intervention code [2] 0 0
Treatment: Surgery
Intervention code [3] 0 0
Other interventions
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
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.
Timepoint [1] 0 0
Enrollment through the first 12 weeks of therapy.
Secondary outcome [1] 0 0
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.
Timepoint [1] 0 0
At definitive surgery planned for 12 weeks after the start of protocol therapy.
Secondary outcome [2] 0 0
Event-free Survival - The EFS and survival functions will be estimated by the Kaplan-Meier methodology.
Timepoint [2] 0 0
Time from study enrollment to disease recurrence, death without disease progression, diagnosis of a second malignant neoplasm, assessed up to 5 years
Secondary outcome [3] 0 0
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.
Timepoint [3] 0 0
After week 13 to the end of protocol therapy
Secondary outcome [4] 0 0
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.
Timepoint [4] 0 0
At baseline and at weeks 13 and 36

Eligibility
Key inclusion 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
Minimum age
No limit
Maximum age
40 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
Phase
Phase 1
Type of endpoint(s)
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
WA
Recruitment hospital [1] 0 0
Princess Margaret Hospital for Children - Perth
Recruitment postcode(s) [1] 0 0
6001 - Perth
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
Alabama
Country [2] 0 0
United States of America
State/province [2] 0 0
Arkansas
Country [3] 0 0
United States of America
State/province [3] 0 0
California
Country [4] 0 0
United States of America
State/province [4] 0 0
Connecticut
Country [5] 0 0
United States of America
State/province [5] 0 0
Delaware
Country [6] 0 0
United States of America
State/province [6] 0 0
District of Columbia
Country [7] 0 0
United States of America
State/province [7] 0 0
Florida
Country [8] 0 0
United States of America
State/province [8] 0 0
Georgia
Country [9] 0 0
United States of America
State/province [9] 0 0
Hawaii
Country [10] 0 0
United States of America
State/province [10] 0 0
Idaho
Country [11] 0 0
United States of America
State/province [11] 0 0
Illinois
Country [12] 0 0
United States of America
State/province [12] 0 0
Indiana
Country [13] 0 0
United States of America
State/province [13] 0 0
Iowa
Country [14] 0 0
United States of America
State/province [14] 0 0
Kansas
Country [15] 0 0
United States of America
State/province [15] 0 0
Kentucky
Country [16] 0 0
United States of America
State/province [16] 0 0
Maine
Country [17] 0 0
United States of America
State/province [17] 0 0
Maryland
Country [18] 0 0
United States of America
State/province [18] 0 0
Massachusetts
Country [19] 0 0
United States of America
State/province [19] 0 0
Michigan
Country [20] 0 0
United States of America
State/province [20] 0 0
Minnesota
Country [21] 0 0
United States of America
State/province [21] 0 0
Mississippi
Country [22] 0 0
United States of America
State/province [22] 0 0
Missouri
Country [23] 0 0
United States of America
State/province [23] 0 0
New Jersey
Country [24] 0 0
United States of America
State/province [24] 0 0
New Mexico
Country [25] 0 0
United States of America
State/province [25] 0 0
New York
Country [26] 0 0
United States of America
State/province [26] 0 0
North Carolina
Country [27] 0 0
United States of America
State/province [27] 0 0
Ohio
Country [28] 0 0
United States of America
State/province [28] 0 0
Oklahoma
Country [29] 0 0
United States of America
State/province [29] 0 0
Oregon
Country [30] 0 0
United States of America
State/province [30] 0 0
Pennsylvania
Country [31] 0 0
United States of America
State/province [31] 0 0
South Carolina
Country [32] 0 0
United States of America
State/province [32] 0 0
Tennessee
Country [33] 0 0
United States of America
State/province [33] 0 0
Texas
Country [34] 0 0
United States of America
State/province [34] 0 0
Utah
Country [35] 0 0
United States of America
State/province [35] 0 0
Virginia
Country [36] 0 0
United States of America
State/province [36] 0 0
Washington
Country [37] 0 0
United States of America
State/province [37] 0 0
West Virginia
Country [38] 0 0
United States of America
State/province [38] 0 0
Wisconsin
Country [39] 0 0
Canada
State/province [39] 0 0
Alberta
Country [40] 0 0
Canada
State/province [40] 0 0
British Columbia
Country [41] 0 0
Canada
State/province [41] 0 0
Manitoba
Country [42] 0 0
Canada
State/province [42] 0 0
Newfoundland and Labrador
Country [43] 0 0
Canada
State/province [43] 0 0
Nova Scotia
Country [44] 0 0
Canada
State/province [44] 0 0
Ontario
Country [45] 0 0
Canada
State/province [45] 0 0
Quebec
Country [46] 0 0
Canada
State/province [46] 0 0
Saskatchewan
Country [47] 0 0
Puerto Rico
State/province [47] 0 0
Santurce

Funding & Sponsors
Primary sponsor type
Other
Name
Children's Oncology Group
Address
Country
Other collaborator category [1] 0 0
Government body
Name [1] 0 0
National Cancer Institute (NCI)
Address [1] 0 0
Country [1] 0 0

Ethics approval
Ethics application status

Summary
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.
Trial website
https://clinicaltrials.gov/show/NCT00742924
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Robert Goldsby, MD
Address 0 0
University of California, San Francisco
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries

Summary results
Other publications