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

This study has been completed.
Sponsor:
Collaborator:
Information provided by (Responsible Party):
Children's Oncology Group
ClinicalTrials.gov Identifier:
NCT00742924
First received: August 27, 2008
Last updated: June 4, 2014
Last verified: June 2014
  Purpose

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.


Condition Intervention Phase
Sarcoma
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
Phase 1

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Feasibility and Dose Discovery Analysis of Zoledronic Acid With Concurrent Chemotherapy in the Treatment of Newly Diagnosed Metastatic Osteosarcoma

Resource links provided by NLM:


Further study details as provided by Children's Oncology Group:

Primary Outcome Measures:
  • Limiting Toxicity [ Time Frame: Enrollment through the first 12 weeks of therapy. ] [ Designated as safety issue: Yes ]

    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 [ Time Frame: At definitive surgery planned for 12 weeks after the start of protocol therapy. ] [ Designated as safety issue: No ]

    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: Yes ]

    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 ] [ Designated as safety issue: No ]
    Blood will be collected for quantification of c-telopeptide and urine will be collected for quantification of n-telopeptide.


Enrollment: 24
Study Start Date: August 2008
Primary Completion Date: April 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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.

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 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.

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 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.

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: 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.

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

Detailed Description:

OBJECTIVES:

Primary:

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

Secondary:

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

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

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

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

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

  Eligibility

Ages Eligible for Study:   up to 40 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00742924

  Show 88 Study Locations
Sponsors and Collaborators
Children's Oncology Group
Investigators
Study Chair: Robert Goldsby, MD University of California, San Francisco
  More Information

Additional Information:
No publications provided by Children's Oncology Group

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Children's Oncology Group
ClinicalTrials.gov Identifier: NCT00742924     History of Changes
Other Study ID Numbers: AOST06P1, CDR0000612613, COG-AOST06P1
Study First Received: August 27, 2008
Results First Received: June 4, 2014
Last Updated: June 4, 2014
Health Authority: United States: Federal Government

Keywords provided by Children's Oncology Group:
metastatic osteosarcoma

Additional relevant MeSH terms:
Osteosarcoma
Sarcoma
Neoplasms, Bone Tissue
Neoplasms, Connective Tissue
Neoplasms, Connective and Soft Tissue
Neoplasms by Histologic Type
Neoplasms
Mesna
Levoleucovorin
Etoposide phosphate
Isophosphamide mustard
Cisplatin
Doxorubicin
Etoposide
Ifosfamide
Methotrexate
Razoxane
Leucovorin
Lenograstim
Zoledronic acid
Diphosphonates
Protective Agents
Physiological Effects of Drugs
Pharmacologic Actions
Antineoplastic Agents
Therapeutic Uses
Radiation-Sensitizing Agents
Antibiotics, Antineoplastic
Antineoplastic Agents, Phytogenic
Antineoplastic Agents, Alkylating

ClinicalTrials.gov processed this record on July 26, 2014