Background:
Myelodysplastic syndrome (MDS) and myelodysplastic/myeloproliferative neoplasm (MDS/MPN) are blood disorders that can cause serious complications in children and adults. MDS and MDS/MPN can also progress to acute myeloid leukemia. Treatments for these disorders are risky and not always effective. Better treatments are needed.
Objective:
To test a study drug (pacritinib) in adults and children with MDS or MDS/MPN.
Eligibility:
Children (aged 12 to 17 years) and adults (aged 18 years and older) with MDS or MDS/MPN.
Design:
Participants will be screened. They will have a physical exam with blood tests. They will have tests of their heart function. They may have a bone marrow biopsy: An area over the hip will be numbed; a needle will be inserted to remove a sample of soft tissue from inside the hipbone.
Pacritinib is a capsule taken by mouth. All participants will take the study drug 2 times a day, every day, in 28-day cycles. They will write down the date and time they take each capsule. Doctors will assign varying dosages of the drug to different participants.
Participants will have clinic visits each week during cycle 1; every 2 weeks during cycle 2; and gradually increasing to every 3 months after cycle 13. Treatment will continue for up to 8 years.
Bone marrow biopsies, heart tests, and other tests will be repeated at intervals throughout the study. Participants will also fill out questionnaires about their quality of life, the symptoms of their disease, and other topics.
Participants must have histologically or cytologically confirmed MDS or MDS/MPN, including therapy-related MDS or MDS/MPN, and MDS or MDS/MPN with germline predisposition, by the Department of Laboratory Medicine Hematology Laboratory, CC or by the Laboratory of Pathology, NCI as defined according to the 2016 WHO criteria, 2022 WHO criteria, or 2022 International Consensus Classification
Age 12-17 years for phase I and age >= 18 years for phase II
Participants >= 18 years of age with HR-MDS must have resistance to hypomethylating agents as defined as failure to show improvement after at least 4 cycles of treatment (primary resistance) or relapse in participants with initial response to long-term treatment (secondary resistance) OR have intolerance to hypomethylating agents OR have a contraindication to hypomethylating agents
Severe neutropenia defined by absolute neutrophils count <=0.5(SqrRoot) 10^9/L without the use of granulocyte colony-stimulating factors
Participants with platelet transfusion-refractory thrombocytopenia, with inability to keep platelet threshold above 10 K/mcL with transfusions
Participants with evidence of ongoing hemorrhage, active signs/symptoms of bleeding, or history of severe (grade >= 3) unprovoked bleeding complications in the one year prior to enrollment, or any unprovoked grade 2 bleeding complications in the 3 months prior
Use of anti-platelet or anticoagulant medication other than low-dose aspirin (100 mg daily or less) in the 14 days prior to enrollment, or any ongoing requirement for these medications
Participants who are unwilling to accept blood transfusions
Parallel
pacritinib
DrugPacritinib will be administered orally on a continuous basis for 28 day cycles without a rest period between cycles. Dose assigned by dose level/phase.
Recommended phase 2 dose of pacritinib in participants 12-17 years of age
Determined by the number of participants with dose-limiting toxicities (DLTs) reported at each dose level studied
Efficacy as measured by Objective Response Rate (ORR) per each risk-based cohort
Clinical responses evaluated by CBC and bone marrow biopsy/aspirate reported separately by cohort, with a separate 95% confidence interval for each cohort
Pharmacokinetic (PK) properties of pacritinib
AUC, half-life, and steady state concentration of pactritinib evaluated separately by dose level using descriptive statistics
Extended safety of pacritinib
Grades and types of toxicity noted for the agent at each dose level, separately by cohort
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