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
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 ClassificationAge 12-17 years for phase I and age >= 18 years for phase IIParticipants >= 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 agentsParticipants >= 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 factorsSymptomatic 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 legsThrombocytopenia 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 classificationParticipants 12-17 years of age with MDS: must be relapsed/refractory OR ineligible to receive immunosuppressive therapy and hematopoietic stem cell transplantationIneligibility 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 barriersto transplantParticipants 12-17 years of age must weigh >= 35 kgParticipants 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 existsDesign:-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 mgBID 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 escalationHigh risk cohort: Initiate on pacritinib 200 mg BID, the adult phase II recommended doseIn all participants, pacritinib will be administered orally on a continuous basis for cycles of 28 days..
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Klinische Studie| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
ClinicalTrials.gov - (2024) vom: 02. Apr. Zur Gesamtaufnahme - year:2024 |
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| Sprache: |
Englisch |
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| Links: |
Volltext [kostenfrei] |
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| Anmerkungen: |
Source: Link to the current ClinicalTrials.gov record., First posted: March 12, 2024, Last downloaded: ClinicalTrials.gov processed this data on April 03, 2024, Last updated: April 03, 2024 |
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| Study ID: |
NCT06303193 |
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| Veröffentlichungen zur Studie: |
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| PPN (Katalog-ID): |
CTG000045322 |
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| 245 | 1 | 0 | |a 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 |b 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 |
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| 500 | |a Source: Link to the current ClinicalTrials.gov record., First posted: March 12, 2024, Last downloaded: ClinicalTrials.gov processed this data on April 03, 2024, Last updated: April 03, 2024 | ||
| 520 | |a 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 ClassificationAge 12-17 years for phase I and age >= 18 years for phase IIParticipants >= 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 agentsParticipants >= 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 factorsSymptomatic 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 legsThrombocytopenia 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 classificationParticipants 12-17 years of age with MDS: must be relapsed/refractory OR ineligible to receive immunosuppressive therapy and hematopoietic stem cell transplantationIneligibility 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 barriersto transplantParticipants 12-17 years of age must weigh >= 35 kgParticipants 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 existsDesign:-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 mgBID 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 escalationHigh risk cohort: Initiate on pacritinib 200 mg BID, the adult phase II recommended doseIn all participants, pacritinib will be administered orally on a continuous basis for cycles of 28 days. | ||
| 650 | 2 | |a Neoplasms | |
| 650 | 2 | |a Preleukemia | |
| 650 | 2 | |a Myelodysplastic Syndromes | |
| 650 | 2 | |a Myeloproliferative Disorders | |
| 650 | 2 | |a Myelodysplastic-Myeloproliferative Diseases | |
| 650 | 2 | |a Syndrome | |
| 650 | 4 | |a Study Type: Interventional | |
| 650 | 4 | |a Recruitment Status: Not yet recruiting | |
| 650 | 4 | |a Phase: Phase 1, Phase 2 | |
| 650 | 4 | |a 610 | |
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