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

Children's Oncology Group

Status and phase

Completed

Phase 1

Conditions

Sarcoma

Treatments

Drug: cisplatin

Procedure: neoadjuvant therapy

Procedure: adjuvant therapy

Biological: filgrastim

Drug: dexrazoxane hydrochloride

Drug: zoledronic acid

Drug: ifosfamide

Drug: Mesna

Drug: doxorubicin hydrochloride

Procedure: therapeutic conventional surgery

Drug: methotrexate

Drug: etoposide

Drug: leucovorin calcium

Study type

Interventional

Funder types

NETWORK

NIH

Identifiers

NCT00742924

AOST06P1

COG-AOST06P1 (Other Identifier)

CDR0000612613 (Other Identifier)

Details and patient eligibility

About

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.

Full 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.

Enrollment

24 patients

Sex

All

Ages

Under 40 years old

Volunteers

No Healthy Volunteers

Inclusion and exclusion 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

Trial design

Primary purpose

Treatment

Allocation

Non-Randomized

Interventional model

Single Group Assignment

Masking

None (Open label)

24 participants in 4 patient groups

Arm 1- Chemotherapy and 1.2 mg/m2 Zoledronic Acid

Experimental group

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.

Treatment:

Drug: leucovorin calcium

Drug: etoposide

Drug: methotrexate

Procedure: therapeutic conventional surgery

Procedure: neoadjuvant therapy

Procedure: adjuvant therapy

Drug: doxorubicin hydrochloride

Drug: Mesna

Drug: zoledronic acid

Drug: ifosfamide

Drug: dexrazoxane hydrochloride

Biological: filgrastim

Drug: cisplatin

Arm 2 - Chemotherapy and 2.3 mg/m2 Zoledronic Acid

Experimental group

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.

Treatment:

Drug: leucovorin calcium

Drug: etoposide

Drug: methotrexate

Procedure: therapeutic conventional surgery

Procedure: neoadjuvant therapy

Procedure: adjuvant therapy

Drug: doxorubicin hydrochloride

Drug: Mesna

Drug: zoledronic acid

Drug: ifosfamide

Drug: dexrazoxane hydrochloride

Biological: filgrastim

Drug: cisplatin

Arm 3 - Chemotherapy and 3.5 mg/m2 Zoledronic Acid

Experimental group

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.

Treatment:

Drug: leucovorin calcium

Drug: etoposide

Drug: methotrexate

Procedure: therapeutic conventional surgery

Procedure: neoadjuvant therapy

Procedure: adjuvant therapy

Drug: doxorubicin hydrochloride

Drug: Mesna

Drug: zoledronic acid

Drug: ifosfamide

Drug: dexrazoxane hydrochloride

Biological: filgrastim

Drug: cisplatin

Chemotherapy and 2.3 mg/m2 Zoledronic Acid after MTD

Experimental group

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.

Treatment:

Drug: leucovorin calcium

Drug: etoposide

Drug: methotrexate

Procedure: therapeutic conventional surgery

Procedure: neoadjuvant therapy

Procedure: adjuvant therapy

Drug: doxorubicin hydrochloride

Drug: Mesna

Drug: zoledronic acid

Drug: ifosfamide

Drug: dexrazoxane hydrochloride