Study of Oral Dasatinib in Subjects With Myelodysplastic Syndrome (MDS) and Excess Marrow Blasts

Study Overview
=================
Brief Summary
-----------------
The main purpose of this study is to learn how patients with myelodysplastic syndrome (MDS) respond to the study drug dasatinib. The study drug, dasatinib, has been approved by the U.S. Food and Drug Administration (FDA) for treatment of leukemia, but has not been approved for the treatment of other kinds of cancer. The use of dasatinib in this study is considered experimental.

Detailed Description
-----------------
Study Core Period: The first 16 weeks after the initial dose of dasatinib is called the Study Core Period. Patients who are eligible and chose to participate in this study should expect to take 100 mg of dasatinib daily for 8 weeks. If the study doctor believes that they have not achieved a partial response after 8 weeks of treatment, the dose may be increased to 150 mg per day. The study doctor may lower the dosage of dasatinib if the 100 mg treatment is too strong. If the lower dose of dasatinib is still too strong, the study doctor may decide to take the patient off of the study. The patient will continue to receive supportive care as needed during the duration of the trial as well as after completion of the trial. During the Study Core Period, participants will have a study visit every 4 weeks. Complete Blood Counts (CBCs) will be obtained every 2 weeks for study purposes and disease monitoring. Bone marrow aspiration and biopsy will be obtained at screening, and at 8 weeks and 16 weeks of treatment for response assessment. Additional bone marrow aspirations and biopsies may be obtained at any other time, to evaluate the disease process, at the doctor's judgment. A bone marrow aspirate and biopsy must be done at the time of study discontinuation. Study Extension Period: The time after the first 16 weeks of treatment is called the study extension period. If the patient is responding to the treatment, does not experience disease progression or any severe adverse events, the patient may continue dasatinib treatment for up to 48 weeks. If patients continue after 48 weeks, they will be asked to enroll in a separate extension study for future follow up. During the Study Extension Period, participants will have a study visit every 4 weeks. Complete Blood Counts (CBCs) will be obtained every 2 or 4 weeks for study purposes and disease monitoring. Bone marrow aspiration and biopsy will be obtained every 16 weeks. A bone marrow aspirate and biopsy must be done at the time of study discontinuation.

Official Title
-----------------
A Pilot Study of Oral Dasatinib in Subjects With MDS and Excess Marrow Blasts

Conditions
-----------------
Myelodysplastic Syndromes

Intervention / Treatment
-----------------
* Drug: Dasatinib


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Documented diagnosis of MDS or Myeloproliferative Disorders (MPS/MPD) with blast percentage > 10% in bone marrow, MDS/AML with <30% blasts: MDS [all World Health Organization (WHO) types] with blast percentage > 10% in bone marrow Chronic myelomonocytic leukemia (CMML) with blast percentage > 10% in bone marrow Myelodysplastic / Myeloproliferative (MDS/MPD) syndromes with blast percentage > 10% in bone marrow Acute myeloid leukemia with Multilineage Dysplasia (MDS/AML) with <30% blasts and declined standard induction chemotherapy or deemed unfit for standard induction chemotherapy Eastern Cooperative Oncology Group (ECOG) Performance Status 0 to 2 Previous therapy with Azacitidine or Decitabine with last dose at least 2 months prior to first dose of dasatinib okay. Must be at least 4 weeks out from any previous investigational therapy. Adequate Organ Function Total bilirubin < 2.0 times institutional Upper Limit of Normal (ULN) Hepatic enzymes (AST, ALT) ≤ 2.5 times institutional ULN Serum Na, K+, Mg2+, Phosphate and Ca2+≥ Lower Limit of Normal (LLN) [low electrolyte levels must be repleted to all for entry] Serum Creatinine < 1.5 times ULN Prothrombin time (PT), partial thromboplastin time (PTT) Grade 0-1 Able to take oral medication (Dasatinib must be swallowed whole. Tablets can be dissolved in juice and then put down an NG/G tube or drank as a solution) Women of childbearing potential (WOCBP) must have Negative serum or urine pregnancy test within 72 hours prior to start of study drug Persons of reproductive potential must agree to use adequate birth control throughout treatment and at least 4 weeks after study drug is stopped Signed written informed consent Exclusion Criteria: White blood count (WBC) >50,000 off hydroxyurea for >72 hours Malignancy [other than the one treated in this study] requiring radiotherapy or systemic treatment within past 3 years Chemotherapy or any agent with activity in MDS or AML concurrent with the study. Chemotherapy for MDS or AML prior to enrollment not allowed other than Azacitidine or Decitabine >2 months prior to first dose Concurrent medical condition which may increase the risk of toxicity, including: Pleural or pericardial effusion Serious medical condition, unstable medical co-morbidity, psychiatric illness that will prevent subject from signing informed consent form or place them at unacceptable risk if they participate Cardiac Symptoms, including: Uncontrolled angina, congestive heart failure or myocardial infarction (MI) within 6 months Diagnosed congenital long QT syndrome History of clinically significant ventricular arrhythmias (such as ventricular tachycardia, ventricular fibrillation, or Torsades de Pointes) Prolonged QTc interval on pre-entry electrocardiogram (> 450 msec) Hypokalemia or hypomagnesemia if cannot be corrected History of significant bleeding disorder unrelated to cancer, including: Congenital bleeding disorders Acquired bleeding disorder within 1 year Ongoing or recent (≤ 3 months) significant gastrointestinal bleeding Concomitant Medications, consider the following prohibitions: Drugs generally accepted to have risk of causing Torsades de Pointes(Must discontinue drug 7 days prior to starting dasatinib) Concomitant use of H2 blockers or proton pump inhibitors with dasatinib not recommended. Use of antacids should be considered in place of H2 blockers or proton pump inhibitors in patients receiving dasatinib therapy. On-going requirement for treatment with platelet function inhibitor or anti-coagulation. Must discontinue St. Johns Wort while receiving dasatinib therapy Must agree that intravenous (IV) bisphosphonates be withheld for first 8 weeks of Dasatinib therapy due to risk of hypocalcemia. May not be receiving any prohibited CYP3A4 inhibitors Women: Positive pregnancy test at baseline Pregnant or breastfeeding Prisoners or patients who are compulsorily detained for treatment of either psychiatric or physical (e.g., infectious) illness

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dasatinib Dose Escalation<br>Patients will be started on dasatinib at a continuous oral daily dose of 100 mg per day. At 8 weeks, if the initial dose is well tolerated and patient has not achieved a partial response, the dose may be increased to 150 mg per day. All patients will be followed per protocol for a total core period of 16 weeks from the first dose. Responding patients will continue dasatinib treatment for up to 48 weeks in the absence of treatment failure, disease progression, limiting toxicity or death. Patients continuing after 48 weeks will be enrolled in a separate extension study for future follow up. | Drug: Dasatinib<br>* DOSE ESCALATION OF DASATINIB AFTER 8 WEEKS IF ELIGIBLE Dose Level and Dose of dasatinib: Starting dose (1-8 weeks)= 100 mg orally (po) daily +1 (<8 weeks if no PR and well tolerated) = 150 mg po daily DOSE MODIFICATION OF DASATINIB Dose Level and Dose of dasatinib: Starting dose = 100 mg po daily -1 = 70 mg po daily -2 = 50 mg po daily OR Dose Level and Dose of dasatinib: Starting dose = 150 mg po daily -1 = 120 mg po daily -2 = 90 mg po daily -3 = 50 mg po daily<br>* Other names: SPRYCEL®;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Marrow Complete Remission (CR) | Complete remission (modified IWG); IWG = International MDS Working Group. Bone Marrow Response must last ≥4 weeks. Bone marrow evaluation: Bone marrow showing ≤5% myeloblasts with normal maturation of all cell lines. | 1 Year 4 Months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Hematologic Improvement | Hematologic improvement in platelets, red blood cell (RBC), neutrophils according to modified IWG Criteria; Cytogenetic response (modified IWG); Change in percentage of blasts in bone marrow and peripheral blood; Src-Tyr416 phosphorylation in medullary myeloblasts. Hematologic improvements must last ≥ 8 weeks. | 1 Year 4 Months | 
| Number of Participants With Partial Remission (PR) | Partial remission (PR) (modified IWG); IWG = International MDS Working Group. All of the CR criteria (if abnormal prior to treatment), except: Bone marrow evaluation: Blasts decreased by ≥ 50% over pretreatment but still >5%. Cellularity and morphology are not relevant. | 1 Year 4 Months | 
| Number of Participants With Stable Disease (SD) |  | 1 Year 4 Months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
MDS, MDS/MPD, MDS/AML, CMML, Excess Marrow Blasts