Study of Continuous Dosing of Sunitinib in Non GIST Sarcomas With Concomitant Radiotherapy

Study Overview
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Brief Summary
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The purpose of this study is to determine the safety of continuous dosing of sunitinib in association with radiotherapy in patients with non GIST (gastro intestinal stromal tumor) sarcomas who cannot be treated by surgery. The primary objective of the study is to determine the maximum tolerated dose (MTD) of continuous dosing of sunitinib in association with radiotherapy in patients with non GIST sarcomas who cannot be treated by surgery. This study is a multicentre, open-label phase I with dose escalation : 2 dose levels. 3-6 patients will be included at each dose level.3-18 patients will be included in the study.

Detailed Description
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Study design : 2 dose levels Step 1 : 25 mg once daily Step 2 : 37.5 mg once daily 3-6 patients will be included at each of the sunitinib dose levels, depending on the number of DLTs (dose limiting toxicity) occurring in 14 weeks after start of treatment DLT is defined as : any grade 3 or 4 musculoskeletal or cutaneous toxicity within the field of radiation any other toxicity > or = 4 Secondary objectives are : to evaluate the safety with late toxicities to estimate the response rate at 6 months to estimate the progression free survival to evaluate the proportion of patients with an operable tumour after treatment Exploratory objectives are : to study evolution during treatment of neo-angiogenesis measured by dynamic contrast enhanced-ultrasonography (DCE-US) to study the correlation between clinical response and changes of tumor perfusion measured by DCE-US

Official Title
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Phase I Study of Continuous Dosing of Sunitinib in Non GIST Sarcomas With Concomitant Radiotherapy

Conditions
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Non GIST Sarcomas

Intervention / Treatment
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* Drug: sunitinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female patients > 18 years of age Histologically or cytologically (in case of recurrence) confirmed connective tissue neoplasm, including any of the following subtypes: Liposarcomas Fibrosarcoma, myxofibrosarcoma Undifferentiated pleomorphic sarcoma Leiomyosarcomas Pleomorphic rhabdomyosarcomas only Angiosarcomas Uncertain differentiated tumors: synovial sarcomas, epithelioid sarcomas, alveolar sarcomas, clear cells sarcomas. or osteosarcoma diagnosis, chondrosarcoma or chordoma. Locally advanced or locally recurrent inoperable tumor without previous irradiation [inoperable status must be assessed by staff including a surgeon specialized in sarcoma]. No prior treatment by sunitinib malate Life expectancy > 6 months ECOG performance status ≤ 2 Blood tests, renal and liver functions in the normal range with, in the 7 days prior to study entry, blood or serum values as follows: Absolute neutrophil count ≥ 1.,5 G/L Platelet count ≥ 100 G/L Bilirubin ≤ 1.5 mg/dL PT and INR ≤ 1.5 times upper limit of normal [Patients under preventive anticoagulant therapy are allowed to participate] AST and ALT ≤ 2.5 times upper limit of normal Creatinine ≤ 150 umol/L Calcium ≤ 12 mg/dL Blood glucose < 150 mg/dL Fertile patients must use effective contraception prior to, during, and for 28 days after completion of study therapy Ability to swallow oral medications Mandatory affiliation with a health insurance company Signed written informed consent. Exclusion Criteria: GIST, Ewing sarcoma or embryonic rhabdomyosarcomas Radiation field including lung, bowel, or central nervous system Pre-existing thyroid abnormality, defined as abnormal thyroid function tests despite medication NCI grade ≥ 3 hemorrhage within the past 4 weeks prior to study drug administration Significant cardiovascular disease (New York Heart Association (NYHA) > grade 2 congestive cardiac failure, myocardial infarction within 6 months prior to inclusion, unstable angina, severe cardiac arrhythmia, severe cerebrovascular accident within 6 months prior to inclusion, history of severe thromboembolism (pulmonary embolism or deep vein thrombosis DVT) within 6 months prior to inclusion (patients with recent history of DVT treated by anticoagulant (except therapeutic warfarin)during at least 6 weeks are eligibles), prolonged QTc interval (QTc > 480 msec with Bazett), bradycardia (heart rate < 45bpm), electrolytic troubles (hyponatremia<120mmol/l, kalemia≥6mmol/l) or uncontrolled hypertension while receiving appropriate medication (≥ 160 mm Hg systolic and/or ≥ 90 mm Hg diastolic). Less than 6 weeks between prior neoplastic treatment by tyrosine kinase inhibitor and inclusion and less than 4 weeks for other neoplastic treatments Major surgical procedure, open biopsy, or serious non healing wound within 28 days prior to first day of treatment Concurrent participation in another clinical trial Other disease or illness within the past 6 months prior to study drug administration, including the following: Psychiatric illness or social situation that would preclude study compliance Known human immunodeficiency virus (HIV)- or acquired immunodeficiency syndrome (AIDS)-related illness or other active infection Known brain metastases, spinal cord compression, or carcinomatous meningitis, or evidence of symptomatic brain or leptomeningeal disease peritoneal carcinosis number of metastatic sites > 2 Restriction of freedom by judicial or administrative decision Pregnant or lactating women

Ages Eligible for Study
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Minimum Age: 18 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: association sunitinib radiotherapy<br> | Drug: sunitinib<br>* All patients will be treated with sunitinib (2 dose levels) once a day (in the morning) for 6 weeks in association with radiotherapy.Radiotherapy will be realised 1-4h after taking sunitinib. Dose level 1 : 25 mg once daily Dose level 2 : 37.5 mg once daily Authorization to include a patient in the upper step will be given only if the deadline of 14 weeks after the start of treatment of last patient included were strictly respected and depending of number of DLT occuring.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| the number of DLT occurring at each dose level of sunitinib within 14 weeks after the start of treatment |  | within 14 weeks after the start of treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| the number of early toxicities (within 14 weeks after the beginning of treatment) and late toxicities (after 14 weeks and until 12 months after the start of treatment) using NCI-CTC v3.0 and RTOG-EORTC |  | within 12 months after the start of treatment | 
| response rate at 6 months using MRI (magnetic resonance imaging) |  | 6 months after the start of treatment | 
| progression free survival measured from the date of inclusion to the date of first evidence of progression or date of death of any cause, or to the date of last follow up |  | within 12 months after the start of treatment | 
| evolution of neo-angiogenesis during treatment measured by DCE-US |  | within 6 weeks after the start of treatment | 
| correlation between clinical response and change of tumor perfusion measured by DCE-US |  | within 12 months after the start of treatment | 
| proportion of patients operable after treatment |  | at week 6 after the start of treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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non GIST sarcomas, sunitinib, radiotherapy, dose escalation