A Placebo-Controlled Study of Saracatinib (AZD0530) in Patients With Recurrent Osteosarcoma Localized to the Lung

Study Overview
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Brief Summary
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The purpose of this study is to determine how long patients who undergo complete surgical removal of recurrent osteosarcoma in the lung will remain free of cancer after taking Saracatinib compared to patients taking placebo (a sugar pill).

Detailed Description
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Further details provided by SARC (Sarcoma Alliance for Research through Collaboration): After complete surgical removal of their cancer, patients will be randomly assigned to receive either Saracatinib or placebo (a sugar pill) throughout the study. Patients will take Saracatinib (or placebo) once daily by mouth for a total of 364 days. The duration of treatment is divided into 13 cycles, 28 days each cycle with no breaks in between. Patients will be seen for interim medical history, physical exam and laboratory studies prior to each cycle. To monitor for recurrence of tumor, patients will undergo thoracic CT scans at 3-4 weeks, 6-8 weeks, at 3 months, at 6 months, at 9 months, at 12 months, then every 6 months up to 2 years, and then every year up to 5 years after starting treatment. An electrocardiogram (ECG) will be taken at 3 months, and a bone scan will be performed at 12 months. Patients who recur in the lung while on-study and who are thought to be amenable to complete surgical resection will be able to find out if they were receiving placebo or saracatinib. Those patients who were receiving placebo may then have the option of undergoing surgical resection. If fully resected of all recurrent disease,they will be given the option of receiving oral therapy with saracatinib. Saracatinib will be administered as a once daily, oral dose of 175 mg, for a 28-day cycle, with no breaks between cycles. The duration of treatment with saracatinib will be thirteen 28-day cycles (364 days total). If complete resection of all lung nodules is not achieved, the patient will be removed from the study. Patients who recur in locations other than the lung while on-study will be taken off study at that time. Blood and tumor samples for research purposes will be collected at the time the tumor is removed. After completing all 13 cycles, patients will be followed for approximately every 3 months until 2 years from starting treatment, then approximately every 6 months until 4 years from starting treatment, and once at year 5.

Official Title
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A Randomized, Double-Blinded, Placebo-Controlled, Multi-Institutional, Cross-over, Phase II.5 Study of Saracatinib (AZD0530), a Selective Src Kinase Inhibitor, In Patients With Recurrent Osteosarcoma Localized to the Lung

Conditions
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Osteosarcoma

Intervention / Treatment
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* Drug: Saracatinib
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patient had recurrence of osteosarcoma, localized to the lungs, had complete surgical removal of all lung nodules are eligible for enrollment. Patient with suspected recurrence of osteosarcoma but who has not had surgery is eligible for enrollment but will not be randomized to receive study medication until deemed fully eligible following surgical removal of all lung nodules. Patient had histological confirmed diagnosis of osteosarcoma of the recurrent sample. Patient had recurrence of osteosarcoma in the lung following standard therapy including: adriamycin, cisplatin, ifosfamide and methotrexate. Patient is ≥ 15 and < 75 years of age. Weight ≥ 34 kg. ECOG performance score of 0-2. Adequate bone marrow function. Adequate renal function. Adequate hepatic function. Adequate cardiac function. Women of childbearing potential must have had a negative pregnancy test (urine or serum) ≤ 7 days prior to enrollment, and willingness to use an acceptable method of contraception during participation in the study and for 3 months after the last dose. Randomization must occur ≤ 6 weeks after complete surgical resection. Patient or legal guardian has signed informed consent. Exclusion Criteria: Presence of metastatic disease in other locations in addition to the lung. Disruption of the lung pleura by tumor. Paget's disease. Patient currently using, or has previously used CYP3A4 inducers or inhibitors within 2 to 14 days prior to the initiation of oral therapy. Known hypersensitivity to other Src/Abl non-receptor kinase inhibitors. Evidence of interstitial lung disease. Any concurrent condition which in the investigator's opinion makes it undesirable for the patient to participate in the trial or which would jeopardize compliance with the protocol. Myocardial infarction within one year prior to study entry. Bleeding diathesis, resulting in symptomatic bleeding. Patient is pregnant or nursing/breast-feeding. Patient received chemotherapy, biological or investigational agent ≤ 28 days prior to enrollment. Patient experiencing unresolved toxicity ≥ CTCAE grade 2 (except alopecia) from previous agents.

Ages Eligible for Study
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Minimum Age: 15 Years
Maximum Age: 74 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: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Saracatinib<br>Saracatinib will be administered as a once daily, oral dose of 175 mg, for a 28-day cycle, with no breaks between cycles. The duration of treatment with saracatinib will be 13 cycles. | Drug: Saracatinib<br>* Oral Agent<br>|
| Placebo Comparator: Placebo<br>Placebo will be administered as a once daily, oral dose of 175 mg, for a 28-day cycle, with no breaks between cycles. The duration of treatment with placebo will be 13 cycles. | Drug: Placebo<br>* Oral Agent<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival Rate Among Patients Treated With Saracatinib and Placebo. | To determine if the addition of saracatinib to pulmonary metastasectomy, versus placebo and pulmonary metastasectomy, results in a change in progression free survival. | Evaluation for recurrence/progression will be made every 3 months for the 1st year, then every 6 months up to 2 years, then every year up to 5 years after starting treatment. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Overall Survival With the Addition of Saracatinib to Pulmonary Metastasectomy, Versus Placebo and Pulmonary Metastasectomy | To determine if the addition of saracatinib to pulmonary metastasectomy, versus placebo and pulmonary metastasectomy, results in a change in overall survival. | 5 year overall survival | 
| Change in Time to Treatment Failure With the Addition of Saracatinib to Pulmonary Metastasectomy, Versus Placebo and Pulmonary Metastasectomy | To determine if the addition of saracatinib to pulmonary metastasectomy, versus placebo and pulmonary metastasectomy, results in a change in the time to treatment failure. Time to treatment failure is the time from randomization to treatment discontinuation. | Up to 12 months | 
| Number of Genes Identified for Prediction of Recurrence of Osteosarcoma | To perform microarray analysis of tumor samples to identify a gene signature that predicts for recurrence of osteosarcoma using methodology that relies on preparation of RNA, followed by cDNA. Fluorescent labeling followed by hybridization to a DNA chip allows for quantitative scanning for hybridized complexes. | Up to 12 months | 
| Biomarkers Related to Activation of Src and Src Substrates | To evaluate tumor samples for biomarkers related to activation of Src and Src substrates. | Up to 12 months | 
| Cell Lines and Murine Xenografts From Recurrent Tumor Samples | To establish cell lines and murine xenografts from recurrent tumor samples. | Up to 12 months | 
| Number of Mutations Identified That May be Causative For Recurrent Osteosarcoma | To perform sequencing analysis of DNA and RNA in tumor samples compared to normal blood to detect mutations that may be causative for recurrent osteosarcoma. The methodology uses transcriptome sequencing, exon re-sequencing and mate-pair end sequencing, allowing us to detect translocations. The availability of matched normal DNA in the blood will allow us to determine which changes are unique to the tumor. | Up to 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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AZD0530, Saracatinib, Osteosarcoma, Recurrent, Localized, to the Lung