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Escalating doses of pacritinib (cohort 1)

Low-risk cohort (cohort 2): Initiated on pacritinib 100 mg BID. After three cycles, pacritinib dose escalated to 200 mg BID, the adult phase II recommended dose, if not in complete remission.High-risk cohort (cohort 3): Initiated on pacritnib 200 mg BID, the adult phase II recommended dose.

Pacritinib will be administered orally on a continuous basis for 28 day cycles without a rest period between cycles. Dose assigned by dose level/phase.

pacritinib

Rosandra N Kaplan, M.D.

National Cancer Institute Referral Office

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.

Background:

-Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal hematopoietic disorders characterized by peripheral cytopenia, ineffective and dysplastic hematopoiesis, and increased risk of progression to acute myeloid leukemia (AML).

-The significant genetic heterogeneity of MDS contributes to the challenges in treatment.

* Targeting the bone marrow microenvironment (BMME) may allow for treatments that bypass the genetic complexity of MDS.
* MDS studies support a role for changes within the BMME and support the emerging concept that interdependency between the MDS clone and diverse cell populations in the BMME contributes to disease pathophysiology.
* CSF1R is a receptor tyrosine kinase involved in myeloid-lineage cell survival, proliferation, and differentiation.
* The presence of CSF1R-expressing cells in the AML BMME has been shown with evidence that these cells support leukemic cells through cytokine secretion, and the ligand for CSF1R, CSF1, has been shown to be increased in peripheral blood and bone marrow of some patients with MDS, together supporting CSF1R inhibition as a plausible therapeutic target in myeloid malignancies.
* IRAK1, an immune modulating kinase, is overexpressed and hyperactivated in patients with MDS, supporting IRAK1 inhibition as a plausible therapeutic target in MDS.
* A small percentage of patients with MDS have activating mutations in JAK2 or FLT3, and in these patients, JAK2 or FLT3 inhibition may allow for direct anti-tumor effect.
* Pacritinib is a multi-kinase inhibitor of CSF1R, IRAK1, JAK2, and FLT3, all of which are of therapeutic interest in MDS as discussed above and has been overall well tolerated in clinical trials and has shown efficacy in the treatment of myelofibrosis.

Objectives:

-Phase I:

* To determine the safety and confirm the recommended phase II dose of pacritinib in participants who are 12-17 years of age with MDS or MDS/MPN (myelodysplastic/myeloproliferative neoplasms).

  -Phase II:
* To determine the efficacy of pacritinib in participants who are \>= 18 years of age with MDS or MDS/MPN, as measured by overall response rate, separately by risk-based cohort.

Eligibility:

-Participants with MDS or MDS/MPN, including therapy-related MDS or MDS/MPN, and MDS or MDS/MPN with germline predisposition, 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 higher-risk MDS (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 \<=0.5x10\^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 \<20x10\^9/L or platelets \<50x10\^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 12-17 years of age must weigh \>= 35 kg
* 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

Design:

-This study consists of two phases, which will enroll concurrently:

--Phase I: 3 plus 3 dose-escalation of pacritinib in participants 12-17 years of age with two planned dose levels per group: Group 1 = weight 35 kg to \< 50 kg \[DL1 = 100 mg BID, DL2 = 200 mg BID\], Group 2 = weight \>= 50 kg \[DL1 = alternating days of 100 mg

BID and 200 mg BID, DL2 = 200 mg BID\]

--Phase II: activity evaluation of pacritinib in participants \>= 18 years of age, separated into two cohorts:

* Low risk cohort: Initiate on pacritinib 100 mg BID, after completion of 3 cycles, participants will undergo dose escalation to 200 mg BID, the adult phase II recommended dose, unless they meet criteria for complete remission, in which case lower dose pacritinib will be continued without escalation
* High risk cohort: Initiate on pacritinib 200 mg BID, the adult phase II recommended dose

  * In all participants, pacritinib will be administered orally on a continuous basis for cycles of 28 days.

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

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

.All IPD recorded in the medical record will be shared with intramural investigators upon request. All IPD recorded in the medical record will be shared with intramural investigators upon request. In addition, all large scale genomic sequencing data will be shared with subscribers to dbGaP.

Determined by the number of participants with dose-limiting toxicities (DLTs) reported at each dose level studied

Clinical responses evaluated by CBC and bone marrow biopsy/aspirate reported separately by cohort, with a separate 95% confidence interval for each cohort

AUC, half-life, and steady state concentration of pactritinib evaluated separately by dose level using descriptive statistics

Grades and types of toxicity noted for the agent at each dose level, separately by cohort

Spots Global Cancer Trial Database for pediatric bone marrow failure