Sorafenib in Myelodysplastic Syndrome

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the efficacy of sorafenib in patients with Myelodysplastic Syndrome (MDS). Eligible subjects will receive Sorafenib administered at 400mg orally twice a day, given on days 1-28 of a 28-day cycle. Patients will be evaluated for hematological response after 2 cycles and then every 3 cycles thereafter for a maximum of 5 years from study entry. If a patient achieves a complete response they may receive an additional 6 cycles of therapy beyond documentation of complete response unless unacceptable toxicity occurs. For patients with partial response, hematological improvement or stable disease they will continue treatment until relapse, progression of disease, or unacceptable toxicity occurs.

Official Title
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Phase II Trial of Sorafenib in Patients With Myelodysplastic Syndrome

Conditions
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Myelodysplastic Syndromes, Leukemia, Myelomonocytic, Chronic

Intervention / Treatment
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* Drug: Sorafenib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must have a diagnosis of primary or therapy-related myelodysplastic syndrome or myelodysplastic/ myeloproliferative disorders as defined by the WHO Refractory anemia with excess blasts - 1 or 2 Chronic myelomonocytic leukemia type 2 Refractory anemia, refractory anemia with ringed sideroblasts, refractory cytopenia with multilineage dysplasia, refractory cytopenia with multilineage dysplasia with ringed sideroblasts, 5q- syndrome, myelodysplastic syndrome unclassified or chronic myelomonocytic leukemia type 1 if at least one of the following criteria is met: HgB < 10 g/dl, Platelets < 50,000/ul,ANC < 1,000 ul, Transfusion dependent defined as 2 transfusions within an 8 week period. Patients may have low, intermediate-1, intermediate-2 or high risk MDS or CMML. Patients are eligible without regard to prior treatment status except for allogenic bone marrow transplant. Patients must be 18 years of age or older. Patient has an estimated or measured creatinine clearance ≥30 ml/min at study enrollment. AST, ALT, total bilirubin ≤ than 2.5 times the upper limit of normal. ECOG performance status of 0-2. Voluntary written informed consent before performance of any study-related procedure not part of normal medical care. Female subject is either post-menopausal or surgically sterilized or willing to use an acceptable method of birth control. Male subject agrees to use an acceptable method for contraception for the duration of the study therapy and for 2 weeks after study completion. Exclusion Criteria: Female subject is pregnant or lactating. Confirmation that the subject is not pregnant must be established by a negative serum B-human chorionic gonadotropin (B-hCG) pregnancy test result within 2 weeks of enrollment. Pregnancy testing is not required for post-menopausal or surgically sterilized women. Patient has received other investigational drugs for this disease within 14 days of enrollment No growth factor support with erythropoietin, GCSF, or GMCSF within 28 days of enrolling in the study. Serious medical or psychiatric illness likely to interfere with participation in this clinical study. Patients with another malignancy within the last one year (from documentation of remission) other than basal or squamous cell skin cancer or CIS of the cervix. Patients who underwent allogeneic stem cell transplant will be excluded. History of leukemia (having more than 20% blasts in blood or marrow) Current treatment with coumadin, heparin and its derivatives. Major surgery (including needle biopsy of visceral organs) for 1-month prior to study and fully recovered. In addition, no placement of a subcutaneous or tunneled venous access device for 3 days prior to study and adequately healed. Significant cardiac or vascular events within 6 months: acute MI, unstable angina, severe peripheral vascular disease (ischemic pain at rest class 3 or worse, non-healing ulcers/wounds, congestive heart failure (NHYA class ≥ 2), uncontrolled cardiac arrhythmias, and disseminated intravascular coagulation. No use of hematopoetic growth factors within 4 weeks of starting sorafenib. Known severe hypersensitivity to Sorafenib or any component of the formulation. Caution should be exercised with the concomitant use of other CYP3A4 inducers, such as rifampin, St. John's Wort, phenytoin, phenobarbital and dexamethasone. Uncontrolled hypertension with a systolic blood pressure greater than 160 or a diastolic blood pressure greater than 100 despite treatment.

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: all patients<br>sorafenib | Drug: Sorafenib<br>* 400 mg twice a day until progression or unacceptable toxicity develops.<br>* Other names: Nexavar;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Subjects Achieving Hematological Response | Hematological response is defined as the number of subjects who achieve either a complete response (CR), Partial response (PR) or Hematologic improvement.(HI). HI is defined as peripheral blood counts with hemoglobin ≥11 g/dL, absolute neutrophil count ≥1x10(9)/L and platelet count ≥100x10(9)/L, and normal bone marrow morphology with no evidence of dysplasia or blasts. CR is defined as the disappearance of all signs and symptoms related to disease, along with HI. PR is defined as fulfilling the criteria for CR in the peripheral blood but blasts decreasing by 50% or more in the bone marrow or to a less advanced WHO classification pretreatment. | During treatment - up to a maximum of 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Subjects Requiring Dose Reductions | The number of subjects who took study drug for more than 1 cycle and required a dose reduction down to the next dose level. | While on study drug, a maximum of 5 years | 
| Time to Progression | Time to progression will be defined as the number of months between on-study and the date of progression or death, whichever comes first, in subjects who took study drug for at least cycle 1. | 5 years | 
| Overall Survival | Overall Survival is defined as the number of months from enrollment onto the study until death from any cause in subjects who took study drug for at least cycle 1. | 1 year from the last dose of study drug | 
| Change in Microvessel Density | Microvessel density will be measured before and after treatment, and the distribution of change across time will be summarized with descriptive statistics. | Measured before and after treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Sorafenib, Myelodysplastic Syndromes, MDS