Sarcoma
Conditions
Keywords
metastatic osteosarcoma
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.
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.
Interventions
DRUGdoxorubicin hydrochloride
Given IV
DRUGetoposide
Given IV
DRUGifosfamide
Given IV
DRUGleucovorin calcium
Given IV or orally
DRUGmethotrexate
Given IV
DRUGdexrazoxane hydrochloride
Given IV
DRUGcisplatin
Given IV
DRUGzoledronic acid
Given IV
PROCEDUREadjuvant therapy
PROCEDUREneoadjuvant therapy
PROCEDUREtherapeutic conventional surgery
Surgery of the primary tumor is scheduled for 12 weeks after the commencement of chemotherapy.
BIOLOGICALfilgrastim
Given SC
DRUGMesna
Given IV
Sponsors
National Cancer Institute (NCI)
Children's Oncology Group
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
No minimum to 40 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Limiting Toxicity | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Histologic Response as Assessed in the Primary Tumor and in Resected Metastases | 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 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 | 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 | 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. |
Countries
Australia, Canada, Puerto Rico, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 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.
cisplatin: Given IV
dexrazoxane hydrochloride: Given IV
doxorubicin hydrochloride: Given IV
etoposide: Given IV
ifosfamide: Given IV
leucovorin calcium: Given IV or orally | 6 |
| 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.
cisplatin: Given IV
dexrazoxane hydrochloride: Given IV
doxorubicin hydrochloride: Given IV
etoposide: Given IV
ifosfamide: Given IV
leucovorin calcium: Given IV or orally | 6 |
| 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.
cisplatin: Given IV
dexrazoxane hydrochloride: Given IV
doxorubicin hydrochloride: Given IV
etoposide: Given IV
ifosfamide: Given IV
leucovorin calcium: Given IV or orally | 6 |
| 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.
cisplatin: Given IV
dexrazoxane hydrochloride: Given IV
doxorubicin hydrochloride: Given IV
etoposide: Given IV
ifosfamide: Given IV
leucovorin calcium: Given IV or orally | 6 |
| Total | 24 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 1 | 1 |
| Overall Study | Lack of Efficacy | 5 | 1 | 2 | 4 |
| Overall Study | Physician Decision | 0 | 0 | 0 | 1 |
| Overall Study | Withdrawal by Subject | 0 | 1 | 1 | 0 |
Baseline characteristics
| Characteristic | Total | Chemotherapy and 2.3 mg/m2 Zoledronic Acid After MTD | Arm 2 - Chemotherapy and 2.3 mg/m2 Zoledronic Acid | Arm 3 - Chemotherapy and 3.5 mg/m2 Zoledronic Acid | Arm 1- Chemotherapy and 1.2 mg/m2 Zoledronic Acid |
|---|---|---|---|---|---|
| Age, Continuous | 13.5 years | 14.5 years | 15.5 years | 14 years | 11.5 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants | 2 Participants | 0 Participants | 1 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 20 Participants | 4 Participants | 5 Participants | 5 Participants | 6 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 7 Participants | 1 Participants | 1 Participants | 3 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 3 Participants | 1 Participants | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) White | 13 Participants | 3 Participants | 4 Participants | 2 Participants | 4 Participants |
| Region of Enrollment Canada | 4 participants | 0 participants | 1 participants | 1 participants | 2 participants |
| Region of Enrollment United States | 20 participants | 6 participants | 5 participants | 5 participants | 4 participants |
| Sex: Female, Male Female | 16 Participants | 5 Participants | 4 Participants | 2 Participants | 5 Participants |
| Sex: Female, Male Male | 8 Participants | 1 Participants | 2 Participants | 4 Participants | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 6 / 6 | 6 / 6 | 6 / 6 | 5 / 6 |
| serious Total, serious adverse events | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 |
Outcome results
Primary
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.
Time frame: Enrollment through the first 12 weeks of therapy.
Population: Patients found not to meet the eligibility requirements are by group policy not followed for adverse events or outcome
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm 1- Chemotherapy and 1.2 mg/m2 Zoledronic Acid | Limiting Toxicity | 1 participants |
| Arm 2 - Chemotherapy and 2.3 mg/m2 Zoledronic Acid | Limiting Toxicity | 1 participants |
| Arm 3 - Chemotherapy and 3.5 mg/m2 Zoledronic Acid | Limiting Toxicity | 3 participants |
| Chemotherapy and 2.3 mg/m2 Zoledronic Acid After MTD | Limiting Toxicity | 2 participants |
Secondary
Event-free Survival
The EFS and survival functions will be estimated by the Kaplan-Meier methodology.
Time frame: Time from study enrollment to disease recurrence, death without disease progression, diagnosis of a second malignant neoplasm, assessed up to 5 years
Secondary
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.
Time frame: At definitive surgery planned for 12 weeks after the start of protocol therapy.
Secondary
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.
Time frame: At baseline and at weeks 13 and 36
Secondary
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.
Time frame: After week 13 to the end of protocol therapy