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

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ClinicalTrials.gov Identifier: NCT00742924
Recruitment Status : Completed
First Posted : August 28, 2008
Results First Posted : July 4, 2014
Last Update Posted : July 4, 2014
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Children's Oncology Group

August 27, 2008
August 28, 2008
June 4, 2014
July 4, 2014
July 4, 2014
August 2008
April 2012   (Final data collection date for primary outcome measure)
Limiting Toxicity [ Time Frame: Enrollment through the first 12 weeks of therapy. ]

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.
  • Safety
  • Dose-limiting toxicity and maximum tolerated dose of zoledronic acid
Complete list of historical versions of study NCT00742924 on ClinicalTrials.gov Archive Site
  • Histologic Response as Assessed in the Primary Tumor and in Resected Metastases [ Time Frame: At definitive surgery planned for 12 weeks after the start of protocol therapy. ]

    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 [ Time Frame: Time from study enrollment to disease recurrence, death without disease progression, diagnosis of a second malignant neoplasm, assessed up to 5 years ]
    The EFS and survival functions will be estimated by the Kaplan-Meier methodology.
  • Secondary Limiting Toxicity [ Time Frame: After week 13 to the end of protocol therapy ]

    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 [ Time Frame: At baseline and at weeks 13 and 36 ]
    Blood will be collected for quantification of c-telopeptide and urine will be collected for quantification of n-telopeptide.
  • Histologic response
  • Event-free survival
Not Provided
Not Provided
 
Zoledronic Acid and Combination Chemotherapy in Treating Patients With Newly Diagnosed Metastatic Osteosarcoma
Feasibility and Dose Discovery Analysis of Zoledronic Acid With Concurrent Chemotherapy in the Treatment of Newly Diagnosed Metastatic Osteosarcoma

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.

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.

Interventional
Phase 1
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Sarcoma
  • Drug: cisplatin
    Given IV
    Other Names:
    • Cis-diamminedichloroplatinum II
    • CDDP
    • cis-DDP
    • Platinol-AQ
    • NSC #119875
  • Drug: dexrazoxane hydrochloride
    Given IV
    Other Names:
    • ICRF-187
    • ADR-529
    • ZINECARD
    • NSC #169780
  • Drug: doxorubicin hydrochloride
    Given IV
    Other Names:
    • Adriamycin
    • NSC #123127
  • Drug: etoposide
    Given IV
    Other Names:
    • VePesid
    • Etopophos
    • VP-16
    • NSC #141540
  • Drug: ifosfamide
    Given IV
    Other Names:
    • Isophosphamide
    • Iphosphamide
    • Z4942
    • Ifex
    • NSC #109724
  • Drug: leucovorin calcium
    Given IV or orally
    Other Names:
    • LCV
    • Wellcovorin
    • citrovorum factor
    • folinic acid
    • NSC #003590
  • Drug: methotrexate
    Given IV
    Other Names:
    • MTX
    • amethopterin
    • Trexall
    • NSC #000740
  • Drug: zoledronic acid
    Given IV
    Other Names:
    • 1-Hydroxy-2-imidazol-1-ylethylidene - diphosphonic acid
    • zoledronate
    • Zometa
    • Aclasta
    • NSC# 721517
  • Procedure: adjuvant therapy
  • Procedure: neoadjuvant therapy
  • Procedure: therapeutic conventional surgery
    Surgery of the primary tumor is scheduled for 12 weeks after the commencement of chemotherapy.
  • Biological: filgrastim
    Given SC
    Other Names:
    • Granulocyte Colony-Stimulating Factor
    • r-metHuG-CSF
    • G-CSF
    • Neupogen
    • NSC #614629
  • Drug: Mesna
    Given IV
    Other Names:
    • sodium 2-mercaptoethane sulfonate
    • UCB 3983
    • Mesnex
    • NSC #113891
  • 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.

    Interventions:
    • Drug: cisplatin
    • Drug: dexrazoxane hydrochloride
    • Drug: doxorubicin hydrochloride
    • Drug: etoposide
    • Drug: ifosfamide
    • Drug: leucovorin calcium
    • Drug: methotrexate
    • Drug: zoledronic acid
    • Procedure: adjuvant therapy
    • Procedure: neoadjuvant therapy
    • Procedure: therapeutic conventional surgery
    • Biological: filgrastim
    • Drug: Mesna
  • 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.

    Interventions:
    • Drug: cisplatin
    • Drug: dexrazoxane hydrochloride
    • Drug: doxorubicin hydrochloride
    • Drug: etoposide
    • Drug: ifosfamide
    • Drug: leucovorin calcium
    • Drug: methotrexate
    • Drug: zoledronic acid
    • Procedure: adjuvant therapy
    • Procedure: neoadjuvant therapy
    • Procedure: therapeutic conventional surgery
    • Biological: filgrastim
    • Drug: Mesna
  • 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.

    Interventions:
    • Drug: cisplatin
    • Drug: dexrazoxane hydrochloride
    • Drug: doxorubicin hydrochloride
    • Drug: etoposide
    • Drug: ifosfamide
    • Drug: leucovorin calcium
    • Drug: methotrexate
    • Drug: zoledronic acid
    • Procedure: adjuvant therapy
    • Procedure: neoadjuvant therapy
    • Procedure: therapeutic conventional surgery
    • Biological: filgrastim
    • Drug: Mesna
  • 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.

    Interventions:
    • Drug: cisplatin
    • Drug: dexrazoxane hydrochloride
    • Drug: doxorubicin hydrochloride
    • Drug: etoposide
    • Drug: ifosfamide
    • Drug: leucovorin calcium
    • Drug: methotrexate
    • Drug: zoledronic acid
    • Procedure: adjuvant therapy
    • Procedure: neoadjuvant therapy
    • Procedure: therapeutic conventional surgery
    • Biological: filgrastim
    • Drug: Mesna
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.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Completed
24
30
Not Provided
April 2012   (Final data collection date for primary outcome measure)

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
Sexes Eligible for Study: All
up to 40 Years   (Child, Adult)
No
Contact information is only displayed when the study is recruiting subjects
Australia,   Canada,   Puerto Rico,   United States
 
 
NCT00742924
AOST06P1
CDR0000612613 ( Other Identifier: Clinical Trials.gov )
COG-AOST06P1 ( Other Identifier: Children's Oncology Group )
Yes
Not Provided
Not Provided
Children's Oncology Group
Children's Oncology Group
National Cancer Institute (NCI)
Study Chair: Robert Goldsby, MD University of California, San Francisco
Children's Oncology Group
June 2014

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP