Pacritinib for Patients With Lower-Risk Myelodysplastic Syndromes (MDS)

Study Overview
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Brief Summary
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The goal of this clinical research study is to learn if pacritinib, either alone or in combination with azacitidine or decitabine, can help to control MDS. The safety of this drug and drug combination will also be studied.

Detailed Description
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Study Drug Administration: Each cycle is 28 days. If you are found to be eligible to take part in this study, you will take pacritinib by mouth 2 times each day during Cycles 1-4. Each dose should be about 12 hours apart (1 dose in the morning, 1 dose in the evening). After Cycle 4, if the study doctor thinks it is in your best interest, you may be able to continue taking pacritinib in combination with either azacitidine or decitabine. The study doctor will tell you which drug you will receive. The study doctor will tell you which drug you will receive. Decitabine and azacitidine may be administered by local doctor or at MD Anderson. Cycle 1 of Part 2 will be administered at MD Anderson. Commercial supplies of decitabine and azacitidine will be used. You will receive either azacitidine by vein over about 1 hour on Days 1-5 of Cycles 5 and beyond or decitabine by vein over about 1 hour or as an injection under the skin on Days 1-7 of Cycles 5 and beyond. You should return any unused study drug and/or any empty bottles to each study visit. Study Visits: One (1) time each week during Cycle 1 and then on Day 1 of each cycle after that, blood (about 1½ teaspoons) will be drawn for routine tests. You may have this blood drawn at a local lab or clinic closer to your home, if the study doctor thinks this is acceptable. The results from the blood draw will be sent to the study doctor. On Day 28 (+/- 5 days) of Cycles 1 and 4, you will have a bone marrow aspiration/biopsy to check for genetic mutations and cytogenetic testing. If you begin receiving pacritinib in combination with either azacitidine or decitabine, you will also have this test repeated at Cycle 4 of your combination therapy. On Day 1 of Cycle 1, Day 28 of Cycles 1 and 4, and at any time the doctor thinks it is needed, you will have an EKG. Length of Treatment: You may continue taking pacritinib for up to 4 cycles. If the doctor thinks it is in your best interest, you may be eligible to continue taking the study drug in combination with either azacitidine or decitabine for as long as the doctor thinks it is in your best interest. You will no longer be able to take the study drug(s) if the disease gets worse, if intolerable side effects occur, or if you are unable to follow study directions. Your participation on the study will be over after the end-of-treatment visit. After the end of therapy and/or 30 days after your last dose of study drug, the study staff will follow your health status by phone call every 2 months (+/- 2 months) until you receive another cancer treatment. End-of-Treatment Visit: About 28 days after the last dose of study drug(s): Blood (about 1½ teaspoons) will be drawn for routine tests. If the doctor thinks it is needed, you will have a bone marrow aspirate/biopsy to check the status of the disease. This is an investigational study. Pacritinib is not FDA approved or commercially available. It is currently being used for research purposes only. Azacitidine and decitabine are both FDA approved and commercially available for the treatment of MDS. The study doctor can explain how the study drugs are designed to work. Up to 40 participants will take part in this study. All will be enrolled at MD Anderson.

Official Title
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Phase II Study of Pacritinib for Patients With Lower-Risk Myelodysplastic Syndromes

Conditions
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Leukemia

Intervention / Treatment
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* Drug: Pacritinib
* Drug: 5-azacitidine
* Drug: Decitabine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed informed consent indicating that patients are aware of the investigational nature of this study, in keeping with the policies of MD Anderson Cancer Center (MDACC), must be obtained prior to any study specific procedures. Patients with a histologically confirmed diagnosis of MDS by World Health Organization (WHO) classification, and lower-risk MDS as defined by the IPSS classification (Low or Int-1 disease) or R-IPSS classification (Very Low or Low) are eligible. Patients with MDS/MPD overlap syndromes including CMML are also eligible if they have Low or Int-1 disease per IPSS. Patients may have received MDS-directed therapy (i.e. lenalidomide), although patients with prior exposure to hypomethylating agents (e.g. 5-azacitidine or decitabine) are not eligible. The interval from prior treatment to time of study drug administration is at least 1 week (except for hydroxyurea or steroid therapy) with recovery from all prior therapy-related toxicities Age >/= 18 years old. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2. Adequate liver function, as evidence by serum bilirubin </= 2x the laboratory normal range (except for patients with Gilbert's Disease) or an aspartate aminotransferase (AST) or alanine aminotransferase (ALT) of </= 2.5x the upper limit of normal (ULN) or </= 5x ULN if hepatic disease involvement is present as determined by the investigator. Serum creatinine (Cr) </= 2x ULN or 24-hour creatinine clearance >/=50 ml/min Subjects of reproductive potential must agree to the use of acceptable contraceptive methods for the duration of the time on study and a further 6 months after completion of treatment. Women of childbearing potential must have a negative blood or urine pregnancy test within 72 hours of start of treatment. Exclusion Criteria: Subjects with any prior exposure to the hypomethylating agents (5-azacitidine or decitabine) are excluded. Subjects with any prior exposure to JAK2 inhibitor therapy (i.e. ruxolitinib or prior pacritinib therapy) are excluded. Any prior or coexisting medical condition that in the investigator's judgment will substantially increase the risk associated with the subject's participation in the study. Psychiatric disorders or altered mental status precluding understanding of the informed consent process and/or completion of the necessary study procedures. Active uncontrolled serious infection or sepsis at study enrollment. Patients receiving antibiotics for infections that are under control may be included in the study. Gastrointestinal disorders that may significantly interfere with absorption of study drug. Subjects have received potent CYP3A inhibitors within 7 days prior to the initiation of study treatment. History of myocardial infarction, severe/unstable angina, or symptomatic congestive heart failure (New York Heart Failure (NYHA) Class III or IV congestive heart failure) within 6 months prior to study enrollment or Left ventricular ejection fraction (LVEF) <50% Impaired cardiac function including ongoing cardiac dysrhythmias of Grade > 2, ejection fraction < 50%, atrial fibrillation of any grade, or QTc prolongation > 450 ms, or other factors that increase the risk of QT prolongation (i.e. family history of long QT interval syndrome, hypokalemia defined as serum potassium < 3.0 mEq/L) Diagnosis of other malignancies within the last 3 years other than curatively treated non-melanoma skin cancer, carcinoma in situ of the cervix, organ-confined or treated non-metastatic prostate cancer, in situ breast carcinoma after complete surgical resection, or superficial transitional cell bladder carcinoma. Known active Hepatitis A, B or C. Known HIV seropositivity. Women who are pregnant or lactating.

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: Pacritinib + Azacitidine or Decitabine<br>Part 1: Pacritinib 200 mg taken by mouth twice daily. Study cycles administered every 28 days. Part 2: After 4 cycles of treatment, Pacritinib combined with 5-azacitidine or Decitabine. Pacritinib decreased to 200 mg in morning and 100 mg in evening for first cycle of combined therapy with Pacritinib increased to 200 mg twice a day on subsequent cycles of combined therapy. Those with disease progression prior to 4 cycles of Pacritinib may initiate Pacritinib + HMA study portion prior to completion of 4 cycles. Starting dose of either 5-azacitidine 75 mg/m2 by vein (IV) or Decitabine 20 mg/m2 IVon Days 1 - 5 of Cycles 5 and beyond. | Drug: Pacritinib<br>* Part 1: Pacritinib 200 mg taken by mouth twice daily. Part 2: Pacritinib dose decreased to 200 mg in the morning and 100 mg in the evening for the first cycle of combined therapy. If no toxicity is observed in first cycle of combined therapy, Pacritinib dose may be increased to 200 mg twice a day on subsequent cycles of combined therapy.<br>Drug: 5-azacitidine<br>* Part 2 Starting Dose of 5-azacitidine: 75 mg/m2 by vein on Days 1 - 5 of Cycles 5 and beyond.<br>* Other names: Azacytidine;Drug: Decitabine<br>* Part 2 Starting Dose of Decitabine: 20 mg/m2 by vein on on Days 1 - 7 of Cycles 5 and beyond.<br>* Other names: Dacogen;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate (ORR) | The primary efficacy outcome of both parts is the overall response rate (ORR) based mainly on hematologic improvement defined by (International Working Group) IWG-2006 criteria, and which also includes complete remission (CR), partial remission (PR) and marrow complete remission. | 28 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Leukemia, Myelodysplastic syndromes, MDS, Lower-risk, Pacritinib, 5-azacitidine, Azacitidine, 5-azacytidine, Vidaza, 5-AZC, AZA-CR, Ladakamycin, NSC-102816, Azacytidine, Decitabine, Dacogen