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

Study Overview
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Brief Summary
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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
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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.

Official Title
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Feasibility and Dose Discovery Analysis of Zoledronic Acid With Concurrent Chemotherapy in the Treatment of Newly Diagnosed Metastatic Osteosarcoma

Conditions
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Sarcoma

Intervention / Treatment
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* 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


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Maximum Age: 40 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm 1- Chemotherapy and 1.2 mg/m2 Zoledronic Acid<br>(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<br>* Given IV<br>* Other names: NSC #119875;Drug: dexrazoxane hydrochloride<br>* Given IV<br>* Other names: NSC #169780;Drug: doxorubicin hydrochloride<br>* Given IV<br>* Other names: NSC #123127;Drug: etoposide<br>* Given IV<br>* Other names: NSC #141540;Drug: ifosfamide<br>* Given IV<br>* Other names: NSC #109724;Drug: leucovorin calcium<br>* Given IV or orally<br>* Other names: NSC #003590;Drug: methotrexate<br>* Given IV<br>* Other names: NSC #000740;Drug: zoledronic acid<br>* Given IV<br>* Other names: NSC# 721517;Procedure: adjuvant therapy<br> <br> Procedure: neoadjuvant therapy<br> <br> Procedure: therapeutic conventional surgery<br>* Surgery of the primary tumor is scheduled for 12 weeks after the commencement of chemotherapy.<br>Biological: filgrastim<br>* Given SC<br>* Other names: NSC #614629;Drug: Mesna<br>* Given IV<br>* Other names: NSC #113891;|
| Experimental: Arm 2 - Chemotherapy and 2.3 mg/m2 Zoledronic Acid<br>(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<br>* Given IV<br>* Other names: NSC #119875;Drug: dexrazoxane hydrochloride<br>* Given IV<br>* Other names: NSC #169780;Drug: doxorubicin hydrochloride<br>* Given IV<br>* Other names: NSC #123127;Drug: etoposide<br>* Given IV<br>* Other names: NSC #141540;Drug: ifosfamide<br>* Given IV<br>* Other names: NSC #109724;Drug: leucovorin calcium<br>* Given IV or orally<br>* Other names: NSC #003590;Drug: methotrexate<br>* Given IV<br>* Other names: NSC #000740;Drug: zoledronic acid<br>* Given IV<br>* Other names: NSC# 721517;Procedure: adjuvant therapy<br> <br> Procedure: neoadjuvant therapy<br> <br> Procedure: therapeutic conventional surgery<br>* Surgery of the primary tumor is scheduled for 12 weeks after the commencement of chemotherapy.<br>Biological: filgrastim<br>* Given SC<br>* Other names: NSC #614629;Drug: Mesna<br>* Given IV<br>* Other names: NSC #113891;|
| Experimental: Arm 3 - Chemotherapy and 3.5 mg/m2 Zoledronic Acid<br>(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<br>* Given IV<br>* Other names: NSC #119875;Drug: dexrazoxane hydrochloride<br>* Given IV<br>* Other names: NSC #169780;Drug: doxorubicin hydrochloride<br>* Given IV<br>* Other names: NSC #123127;Drug: etoposide<br>* Given IV<br>* Other names: NSC #141540;Drug: ifosfamide<br>* Given IV<br>* Other names: NSC #109724;Drug: leucovorin calcium<br>* Given IV or orally<br>* Other names: NSC #003590;Drug: methotrexate<br>* Given IV<br>* Other names: NSC #000740;Drug: zoledronic acid<br>* Given IV<br>* Other names: NSC# 721517;Procedure: adjuvant therapy<br> <br> Procedure: neoadjuvant therapy<br> <br> Procedure: therapeutic conventional surgery<br>* Surgery of the primary tumor is scheduled for 12 weeks after the commencement of chemotherapy.<br>Biological: filgrastim<br>* Given SC<br>* Other names: NSC #614629;Drug: Mesna<br>* Given IV<br>* Other names: NSC #113891;|
| Experimental: Chemotherapy and 2.3 mg/m2 Zoledronic Acid after MTD<br>(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<br>* Given IV<br>* Other names: NSC #119875;Drug: dexrazoxane hydrochloride<br>* Given IV<br>* Other names: NSC #169780;Drug: doxorubicin hydrochloride<br>* Given IV<br>* Other names: NSC #123127;Drug: etoposide<br>* Given IV<br>* Other names: NSC #141540;Drug: ifosfamide<br>* Given IV<br>* Other names: NSC #109724;Drug: leucovorin calcium<br>* Given IV or orally<br>* Other names: NSC #003590;Drug: methotrexate<br>* Given IV<br>* Other names: NSC #000740;Drug: zoledronic acid<br>* Given IV<br>* Other names: NSC# 721517;Procedure: adjuvant therapy<br> <br> Procedure: neoadjuvant therapy<br> <br> Procedure: therapeutic conventional surgery<br>* Surgery of the primary tumor is scheduled for 12 weeks after the commencement of chemotherapy.<br>Biological: filgrastim<br>* Given SC<br>* Other names: NSC #614629;Drug: Mesna<br>* Given IV<br>* Other names: NSC #113891;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Enrollment through the first 12 weeks of therapy. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | At definitive surgery planned for 12 weeks after the start of protocol therapy. | 
| Event-free Survival | The EFS and survival functions will be estimated by the Kaplan-Meier methodology. | Time from study enrollment to disease recurrence, death without disease progression, diagnosis of a second malignant neoplasm, assessed up to 5 years | 
| 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. | After week 13 to the end of protocol therapy | 
| 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. | At baseline and at weeks 13 and 36 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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metastatic osteosarcoma