Eribulin Mesylate in Treating Patients With Recurrent or Refractory Osteosarcoma

Study Overview
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Brief Summary
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This phase II trial studies how well eribulin mesylate works in treating patients with osteosarcoma that has come back after treatment (recurrent) or has not responded to treatment (refractory). Microtubule inhibitors, such as eribulin mesylate, may stop or slow the growth of tumor cells by disrupting the cell cycle.

Detailed Description
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PRIMARY OBJECTIVES: I. To estimate the 4 month progression free survival rate and objective response rate in patients with recurrent osteosarcoma who are administered eribulin (eribulin mesylate) therapy on day 1 and day 8 of 21 day cycles. SECONDARY OBJECTIVES: I. To investigate the pharmacokinetics (PK) of eribulin in subjects with recurrent osteosarcoma. II. To further describe the tolerability of single agent eribulin. OUTLINE: Patients receive eribulin mesylate intravenously (IV) over 2-5 minutes on days 1 and 8. Courses repeat every 21 days for up to 24 months in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up annually for 5 years.

Official Title
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A Phase II Study of Eribulin (NSC# 707389) in Recurrent or Refractory Osteosarcoma

Conditions
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Recurrent Osteosarcoma

Intervention / Treatment
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* Drug: Eribulin Mesylate
* Other: Pharmacological Study


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must have had histologic verification of osteosarcoma at original diagnosis Patients must have measurable disease, documented by clinical, radiographic, or histologic criteria, and have relapsed or become refractory to conventional therapy Patients must have a performance status corresponding to Eastern Cooperative Oncology Group (ECOG) scores of 0, 1 or 2; use Karnofsky for patients > 16 years of age and Lansky for patients =< 16 years of age Patients must have a life expectancy of >= 8 weeks Patients must have fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to entering this study Myelosuppressive chemotherapy: must not have received within 2 weeks of entry onto this study (6 weeks if prior nitrosourea) Biologic (anti-neoplastic agent): at least 7 days since the completion of therapy with a biologic agent Bisphosphonates: at least 4 weeks since the completion of therapy with a bisphosphonate Monoclonal antibodies: at least 3 half-lives must have elapsed since prior therapy that included a monoclonal antibody Radiation therapy (RT): >= 2 weeks (wks) for local palliative RT (small port); >= 6 months must have elapsed if prior craniospinal RT or if >= 50% radiation of pelvis; >= 6 weeks must have elapsed if other substantial bone marrow (BM) radiation Peripheral absolute neutrophil count (ANC) >= 1000/uL Platelet count >= 75,000/uL (transfusion independent) Hemoglobin >= 8.0 g/dL (may receive red blood cell [RBC] transfusions) Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70 mL/min/1.73 m^2 or A serum creatinine based on age/gender as follows: (threshold creatinine values were derived from the Schwartz formula for estimating GFR) Age (12 to < 13 years) - serum creatinine of 1.2 mg/dL Age (13 to < 16 years) - serum creatinine of 1.5 mg/dL (male) and 1.4 mg/dL (female) Age (>= 16 years) - serum creatinine of 1.7 mg/dL (male) and 1.4 mg/dL (female) Bilirubin (sum of conjugate + unconjugated) =< 1.5 x upper limit of normal (ULN) for age Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 110 units per liter (U/L); for the purpose of this study, the ULN for SGPT is 45 U/L Serum albumin > 2 g/dL Shortening fraction of >= 27% by echocardiogram Ejection fraction of >= 50% by radionuclide angiogram All patients and/or their parents or legal guardians must sign a written informed consent All institutional, Food and Drug Administration (FDA), and National Cancer Institute (NCI) requirements for human studies must be met Exclusion Criteria: Patients with congenital prolonged QT syndrome Patients with a baseline QT/corrected QT (QTc) interval >= 501 msec Patients who are receiving drugs that prolong the QTc are not eligible Patients who have previously received eribulin, halichondrin B, or analogues of halichondrin B Patients who have grade >= 2 peripheral neuropathy Patients who are receiving other cancer directed therapy at the time of enrollment Patients who have had major surgery within 3 weeks prior to enrollment are not eligible; procedures such as placement of a central vascular catheter, or limited tumor biopsy, are not considered major surgery Pregnancy and breast feeding Female patients who are pregnant are ineligible Lactating females are not eligible unless they have agreed not to breastfeed their infants Female patients of childbearing potential are not eligible unless a negative pregnancy test result has been obtained Sexually active patients of reproductive potential are not eligible unless they have agreed to use an effective contraceptive method for the duration of their study participation

Ages Eligible for Study
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Minimum Age: 12 Years
Maximum Age: 49 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (eribulin mesylate)<br>Patients receive eribulin mesylate IV over 2-5 minutes on days 1 and 8. Courses repeat every 21 days for up to 24 months in the absence of disease progression or unacceptable toxicity. | Drug: Eribulin Mesylate<br>* Given IV<br>* Other names: Halichondrin B Analog;Other: Pharmacological Study<br>* Correlative studies<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease Control Success | The number of patients who do not experience disease progression or death in the four months following enrollment on AOST1322. | 4 Months | 
| Response Evaluation Criteria in Solid Tumors (RECIST) Response | The number of patients who experience a complete or partial response according to the RECIST criteria as defined in Eisenhauer et al. Eur J Cancer 45:228-47, 2009. | 4 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Cycles Where a Dose Limiting Toxicity Was Identified | Each cycle where the patient receives eribulin and does not receive non-protocol anticancer therapy will be considered in the analysis. A dose limiting toxicity is defined to be: day 8 eribulin dose is held due to grade 3 or grade 4 non-hematological toxicity attributable to the investigational drug and does not resolve to meet eligibility or baseline criteria by day 11. Any >= grade 3 non-hematological toxicity attributable to the investigational drug with the specific exclusion of: grade 3 nausea and vomiting < 3 days duration grade 3 liver enzyme elevation, including alanine aminotransferase (ALT)/aspartate aminotransferase (AST)/gamma-glutamyltransferase (GGT), that returns to grade =< 1 or baseline prior to the time for the next treatment cycle. | 4 months | 
| Area Under the Curve 0-infinity of Eribulin Mesylate in Ng-hr/ml | Data from all patients who provide samples for pharmacokinetic analysis will be aggregated. The sample mean and variance of the area under the curve will be reported The analytic unit will be the patient-cycle: Each cycle where the patient receives eribulin and does not receive non-protocol anticancer therapy will be considered in the analysis. | Cycle 1 day 1 and cycle 2 day 1 at the end of infusion, 0.5-6 hours, and 24-120 hours post infusion; cycle 1 day 8 and cycle 2 day 8 prior to the dose of eribulin and at the end of infusion | 
| Clearance of Eribulin Mesylate in L/hr | Data from all patients who provide samples for pharmacokinetic analysis will be aggregated. The sample mean and variance of the clearance will be reported. The analytic unit will be the patient-cycle: Each cycle where the patient receives eribulin and does not receive non-protocol anticancer therapy will be considered in the analysis. | Cycle 1 day 1 and cycle 2 day 1 at the end of infusion, 0.5-6 hours, and 24-120 hours post infusion; cycle 1 day 8 and cycle 2 day 8 prior to the dose of eribulin and at the end of infusion. | 
| A Half Life of Eribulin Mesylate in hr | Data from all patients who provide samples for pharmacokinetic analysis will be aggregated. The sample mean and variance of the half life will be reported. The analytic unit will be the patient-cycle: Each cycle where the patient receives eribulin and does not receive non-protocol anticancer therapy will be considered in the analysis. | 1 day 1 and cycle 2 day 1 at the end of infusion, 0.5-6 hours, and 24-120 hours post infusion; cycle 1 day 8 and cycle 2 day 8 prior to the dose of eribulin and at the end of infusion |