Phase I/II Trial of Pacritinib, a Kinase Inhibitor of CSF1R, IRAK1, JAK2, and FLT3, in Adults and Pediatric Participants 12 Years of Age or Older With Myelodysplastic Syndromes or Myelodysplastic/Myeloproliferative Neoplasms
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
• Participants \>= 18 years of age with LR-MDS must be refractory to or ineligible to receive standard of care therapies, i.e. erythropoietin-stimulating agents, lenalidomide, luspatercept, and present with one of the following characteristics:
‣ Severe neutropenia defined by absolute neutrophils count \<=0.5(SqrRoot) 10\^9/L without the use of granulocyte colony-stimulating factors
⁃ Symptomatic anemia defined by hemoglobin 16-week average \<10 g/dL and symptoms that may include fatigue, weakness, reduced exercise tolerance, dyspnea on exertion, palpitations, (orthostatic) hypotension, near syncope and restless legs
⁃ Thrombocytopenia defined as platelets \<20(SqrRoot) 10\^9/L or platelets \<50(SqrRoot) 10\^9/L and a history of clinically relevant non-major or major bleeding according to the ISTH classification
• Participants 12-17 years of age with MDS must be relapsed/refractory OR ineligible to receive immunosuppressive therapy and hematopoietic stem cell transplantation
⁃ -Ineligibility to receive hematopoietic stem cell transplantation will include participants who are not anticipated to be candidates to receive transplantation within the next 3 months due to medical comorbidities, lack of appropriate donor, or logistical barriers to transplant
• Participants with MDS/MPN must be relapsed/refractory (failed a minimum of 1 standard of care therapy) OR ineligible to receive standard of care OR without known life-prolonging therapy options OR have a diagnosis for which no known standard of care exists
• Participants 12-17 years of age must weigh \>= 35 kg
• If any of the prior therapies noted below were given to the participant, they must have been completed within the following timeframes:
‣ 7 days from last dose of short-acting myeloid growth factors (i.e., filgrastim) and \>= 14 days for long-acting (i.e., pegfilgrastim)
⁃ 14 days from last dose of short-acting thrombopoietic growth factors (i.e.,eltrombopag) and \>= 28 days for long-acting (i.e., romiplostim)
⁃ 14 days or 5 pharmacokinetic half-lives from biological therapy agent
⁃ 21 days from myelosuppressive chemotherapy
⁃ 28 days from last dose of immunosuppressive therapy (e.g., ATG, cyclosporine, steroids greater than physiologic replacement)
⁃ 28 days from last dose of lenalidomide
⁃ 28 days from last dose of venetoclax
⁃ 28 days from any other investigational agent
⁃ 42 days from last dose of erythropoiesis stimulating agents
⁃ 56 days from last dose of luspatercept
⁃ 100 days from stem cell transplant with no evidence of active graft vs. host disease in participants who relapsed following transplant
⁃ 150 days from total body irradiation
• Performance status:
‣ For participants \>= 16 years of age, ECOG performance status \< 2 (Karnofsky \>= 60%)
⁃ For participants \< 16 years of age, Lansky \>= 60%
• Participants must have adequate organ function as defined below:
‣ Total bilirubin: \<= 1.5 X institutional upper limit of normal OR \<= 3 x institutional upper limit of normal in participants with Gilbert s syndrome
⁃ AST(SGOT)/ALT(SGPT): \<= 2.5 X institutional upper limit of normal
⁃ Creatinine clearance: \>= 50 mL/min/1.73 m\^2 for participants with creatinine levels above institutional normal
⁃ PT and PTT: \<= 1.5 X institutional upper limit of normal, except in the setting of PTT elevation due to lupus anticoagulant, in which case these participants would be exempt from meeting this inclusion criterion
• Individuals of child-bearing potential (IOCBP) and individuals able to father a child with a partner able to become pregnant must agree to use one (1) highly effective form of contraception (e.g., intrauterine device \[IUD\], surgical) or two (2) effective forms of contraception (e.g., barrier method) while on study drug and for 30 days after the last dose of study drug
• Nursing participants must discontinue breastfeeding and/or not begin breastfeeding until 2 weeks after the last dose of study drug
• Ability of participant or parent/guardian (for participants 12-17 only) to understand and the willingness to sign a written informed consent document