An Open-Label, Phase I/II Study of Two Different Schedules of Dasatinib (Sprycel) and Decitabine (Dacogen) Used in Combination for Patients With Accelerated or Blastic Phase Chronic Myelogenous Leukemia (Protocol CA180357)

Study Overview
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Brief Summary
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The goal of this clinical research study is to learn if combining Sprycel (dasatinib) and Dacogen (decitabine) can help to control Chronic Myeloid Leukemia (CML). The dose level of decitabine will also be studied. Dasatinib is designed to block the protein that is responsible for chronic myeloid leukemia. Decitabine is designed to affect the mechanism that cells use to control the expression of certain genes, some of which are important in the progression of CML. This is an investigational study. Dasatinib is FDA approved and commercially available for the treatment of patients with certain types of CML. Decitabine is FDA approved for the treatment of patients with myelodysplastic syndrome. The combination of these drugs to treat CML is investigational. Up to 84 patients will take part in this study. All will be enrolled at MD Anderson.

Detailed Description
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Study Groups: If you are found to be eligible to take part in this study, you will be assigned to a study group and dose level based on when you join this study and the side effects that are seen. Your doctor will discuss this with you in more detail. There will be up to 5 doses of dasatinib tested in Phase 1. The first 3 participants will receive a lower dose of therapy. If no major side effects are seen in these participants, the next participants will receive a higher dose. Once a dose is identified that is well-tolerated for most participants, that dose will be used for all new participants. If you are in Phase 2, you will receive a dose level tested in Phase 1. You will receive one of 2 doses of decitabine. What dose you receive is determined by chance (like a coin toss). Study Administration: Each cycle is 28 days. You will take dasatinib by mouth 1 time a day. You will receive decitabine by vein for 10 days of each cycle. If the doctor thinks it is in your best interest, you may receive decitabine for fewer days each cycle (5 days instead of 10 days). Your doctor will decide how many doses you will take based on side effects you may have and the status of the disease. If you have severe side effects from the study drug, the study doctor may decide to stop drug dosing until your side effects improve. You will be asked to keep a study diary that will be reviewed at scheduled study visits. In the diary, you will record when you take the study drug. Study Visits: At every visit, you will be asked about any side effects you may have had and to list any drugs you may be taking. Every week for the first 3 cycles and then every 2-4 weeks after that, blood (about 1 tablespoon) will be drawn to check your blood cell counts. About 1 week after your first dose, you will have an ECG. Every 1-2 weeks for the first 3 cycles and then every 4-8 weeks after that, blood (about 1 tablespoon) will be drawn to test your kidney and liver function. Every 1-3 months, blood (about 1 tablespoon) will be drawn for genetic testing. Before the start of Cycle 2, every 2-4 cycles after that for the first year, and then every 6 cycles after that, you will have a complete physical exam. Before the start of Cycle 2, every 3 cycles after that during the first year, then every 4-6 cycles (as needed) you will have a bone marrow aspirate to check the status of the disease. After Cycle 6, the number of blood draws and bone marrow collections may be changed. Length of Study: You may continue taking the study drugs for as long as the doctor thinks it is in your best interest. You will no longer be able to take the study drug if the disease gets worse, if intolerable side effects occur, or if you are unable to follow study directions.

Official Title
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An Open-Label, Phase I/II Study of Two Different Schedules of Dasatinib (Sprycel) and Decitabine (Dacogen) Used in Combination for Patients With Accelerated or Blastic Phase Chronic Myelogenous Leukemia (Protocol CA180357)

Conditions
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Leukemia

Intervention / Treatment
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* Drug: Dasatinib
* Drug: Decitabine
* Drug: Decitabine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients age 18 years of age or older with CML-AP, CML-BP or Philadelphia chromosome-positive acute myeloid leukemia defined as follows: CML-AP is defined by the presence of 15-29% blasts in peripheral blood (PB) or bone marrow (BM), >/= 20% basophils in PB or BM, >/= 30% blasts plus promyelocytes (with blasts <30%) in PB or BM, <100 x10(9)/L platelets unrelated to therapy, or by clonal cytogenetics evolution (i.e., the presence of cytogenetic abnormalities other than the Philadelphia chromosome); CML-BP is defined by the presence of >/= 30% blasts in the bone marrow and/or peripheral blood or the presence of extramedullary disease. Patients are eligible whether they have received or not prior TKI therapy. For the phase I portion of the study, patients who had received prior therapy with dasatinib should have been able to tolerate the dose equivalent to the starting dose of dasatinib in the dose level at which the patient is being entered. Patients who previously received dasatinib but never at the dose being proposed are eligible provided they tolerated the maximum dose they were prescribed with no grade 3-4 toxicity not responding to optimal management. Eastern Cooperative Oncology Group (ECOG) performance status 0-3. Men and women of childbearing potential should practice 2 methods of contraception; 1 method must be highly effective and a second method must be either highly effective or less effective. Men and women of childbearing potential are defined as: a male that has not been surgically sterilized or a female that has not been amenorrheic for at least 12 consecutive months or that has not been surgically sterilized. Patients must use birth control during the study and for 3 months after the last dose of study drug if they are sexually active. Women of childbearing potential must have a pregnancy test at screening. Signed informed consent. Patients must have been off all prior therapy for CML for 2 weeks prior to start of study therapy and recovered from the toxic effects of that therapy. Exceptions to these are hydroxyurea and Tyrosine kinase inhibitor (TKIs) (including but not limited to imatinib, nilotinib, and bosutinib) which should be discontinued >/= 24 hrs prior to the start of therapy. Patients who are receiving dasatinib prior to enrollment do not have to discontinue this agent prior to start of study therapy. Adequate organ function: Serum creatinine </= 2.0 mg/dl or creatinine clearance >/=60 mL/min; Total bilirubin </= 1.5 x upper limit of normal (ULN) (unless considered due to Gilbert's syndrome or hemolysis); Alanine aminotransferase (ALT) </= 3 x ULN unless considered due to leukemic involvement. Exclusion Criteria: New York Heart Association (NYHA) cardiac class 3-4 heart disease. Cardiac disease including: Uncontrolled angina within 3 months. Diagnosed or suspected congenital long QT syndrome; Any history of clinically significant ventricular arrhythmias (eg, ventricular tachycardia, ventricular fibrillation, or Torsades de pointes); Prolonged QTc interval on pre-entry electrocardiogram (> 470 msec) on the Fridericia's correction; Uncontrolled hypertension (defined for this protocol as sustained systolic BP >/=150 and diastolic >/=100); Patients currently taking drugs that are generally accepted to have a risk of causing Torsades de Pointes. Serious uncontrolled medical disorder or uncontrolled active systemic infection or current unstable or decompensated respiratory or cardiac conditions which makes it undesirable or unsafe for the patient to participate in the study. Patients with known, clinically significant pericardial or pleural effusion. History of significant bleeding disorder unrelated to cancer, including diagnosed congenital bleeding disorders (e.g., von Willebrand's disease), or diagnosed acquired bleeding disorders within one year (e.g., acquired anti-factor VIII antibodies). Subject is receiving potent inhibitors of CYP3A4; for such medications, a wash-out period of >/= 7 days is required prior to starting dasatinib unless discontinuation or substitution of such an inhibitor is not in the best interest of the patient as determined by the investigator. These include the following medications: itraconazole, ketoconazole, miconazole, voriconazole; amprenavir, atazanavir, fosamprenavir, indinavir, nelfinavir, ritonavir; ciprofloxacin, clarithromycin, diclofenac, doxycycline, enoxacin, isoniazid, ketamine, nefazodone, nicardipine, propofol, quinidine, telithromycin. In instances where use of these agents is felt to be required for the best management of the patients, inclusion of such a patients should be discussed with PI and the rationale documented. Females who are pregnant or are currently breastfeeding. Patients that are eligible (including having available donor) and willing to receive an allogeneic stem cell transplant within 4 weeks.

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
Allocation: Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase I - Dasatinib 100 mg + Decitabine 10 mg/m2<br>Less Intensive, Schedule A1 Dasatinib 100 mg daily by mouth ; Decitabine 10 mg/m^2 by vein over 1 hour daily for 10 days; 28 day cycle. | Drug: Dasatinib<br>* Starting Dose: 100 mg by mouth once daily of a 28 day cycle.<br>* Other names: Sprycel;Drug: Decitabine<br>* Starting Dose (less intensive group) Schedule A: 10 mg/m2 by vein daily for 10 days of a 28 day cycle.<br>* Other names: Dacogen;|
| Experimental: Phase I - Dasatinib 100 mg + Decitabine 20 mg/m2<br>More Intensive, Schedule A2: Dasatinib 100 mg daily by mouth ; Decitabine ose 20 mg/m^2 by vein over 1 hour daily for 10 days; 28 day cycle. | Drug: Dasatinib<br>* Starting Dose: 100 mg by mouth once daily of a 28 day cycle.<br>* Other names: Sprycel;Drug: Decitabine<br>* Starting Dose (more intensive group) Schedule B: 20 mg/m2 by vein daily for 10 days of a 28 day cycle.<br>* Other names: Dacogen;|
| Experimental: Phase I - Dasatinib 140 mg + Decitabine 10 mg/m2<br>Less Intensive, Schedule B1 Dasatinib 140 mg daily by mouth ; Decitabine 10 mg/m^2 by vein over 1 hour daily for 10 days; 28 day cycle. | Drug: Dasatinib<br>* Starting Dose: 100 mg by mouth once daily of a 28 day cycle.<br>* Other names: Sprycel;Drug: Decitabine<br>* Starting Dose (less intensive group) Schedule A: 10 mg/m2 by vein daily for 10 days of a 28 day cycle.<br>* Other names: Dacogen;|
| Experimental: Phase I - Dasatinib 140 mg + Decitabine 20 mg/m2<br>More Intensive, Schedule B2 Dasatinib 140 mg daily by mouth ; Decitabine 20 mg/m^2 by vein over 1 hour daily for 10 days; 28 day cycle. | Drug: Dasatinib<br>* Starting Dose: 100 mg by mouth once daily of a 28 day cycle.<br>* Other names: Sprycel;Drug: Decitabine<br>* Starting Dose (more intensive group) Schedule B: 20 mg/m2 by vein daily for 10 days of a 28 day cycle.<br>* Other names: Dacogen;|
| Experimental: Phase II - Dasatinib 140 mg + Decitabine 10 mg/m2<br>Less Intensive, Schedule B1 Dasatinib 140 mg daily by mouth; Decitabine e 10 mg/m^2 by vein over 1 hour daily for 10 days; 28 day cycle. | Drug: Dasatinib<br>* Starting Dose: 100 mg by mouth once daily of a 28 day cycle.<br>* Other names: Sprycel;Drug: Decitabine<br>* Starting Dose (less intensive group) Schedule A: 10 mg/m2 by vein daily for 10 days of a 28 day cycle.<br>* Other names: Dacogen;|
| Experimental: Phase II - Dasatinib 140 mg + Decitabine 20 mg/m2<br>More Intensive, Schedule B2 Dasatinib140 mg daily by mouth; Decitabine 20 mg/m^2 by vein over 1 hour daily for 10 days; 28 day cycle. | Drug: Dasatinib<br>* Starting Dose: 100 mg by mouth once daily of a 28 day cycle.<br>* Other names: Sprycel;Drug: Decitabine<br>* Starting Dose (more intensive group) Schedule B: 20 mg/m2 by vein daily for 10 days of a 28 day cycle.<br>* Other names: Dacogen;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Ph I Study: Maximum Tolerated Dose (MTD) Dasatinib | Maximum tolerated dose (MTD) defined as highest dose at which 0 of 3 or </= 1/6 participant experience a first cycle dose limiting toxicity (DLT). | End of first 28-day cycle | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Hematologic Responses During First 3 Months of Treatment | Number of participants with hematologic response (HR) to therapy during first 3 months of combination dasatinib and decitabine therapy, where HR defined as any hematologic response observed during the first 3 months of treatment. Overall Hematologic Response (OHR) is defined as complete hematologic response (CHR), no evidence of leukemia (NEL) or minor hematologic response (MiHR) | 3 months | 
| Overall Survival | Overall Survival will be measured from the date treatment is started to the date of death or last follow-up. | Up to seven years | 
| Duration of Response | Duration of Response will be measured from the date the given response is achieved to the date the response is first known to be lost | up to seven years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Dasatinib, CML, Leukemia, Chronic myelogenous leukemia, Chronic myeloid leukemia, Accelerated phase, Blastic phase, BMS-354825, Sprycel, Decitabine, Dacogen