Trial Title:
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
NCT ID:
NCT06303193
Condition:
Myelodysplastic Syndromes
Conditions: Official terms:
Neoplasms
Preleukemia
Myelodysplastic Syndromes
Myeloproliferative Disorders
Myelodysplastic-Myeloproliferative Diseases
Syndrome
Conditions: Keywords:
Myelodysplastic Syndrome
bone marrow disorder
Myelodysplasia
myeloproliferative disorders
pediatric bone marrow failure
5q deletion
multi-lineage dysplasia
Clonal Hematopoiesis
Aplastic Anemia
Study type:
Interventional
Study phase:
Phase 1/Phase 2
Overall status:
Not yet recruiting
Study design:
Allocation:
Non-Randomized
Intervention model:
Parallel Assignment
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Drug
Intervention name:
pacritinib
Description:
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.
Arm group label:
1/Phase I - Pediatric
Arm group label:
2/Phase II - Adult
Summary:
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.
Detailed description:
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.
Criteria for eligibility:
Criteria:
- INCLUSION CRITERIA:
- 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
EXCLUSION CRITERIA:
- 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
to enrollment
- 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
- Participants with ANC < 500 cells/mcL AND hospitalization for a fungal infection in
the 12 months prior to enrollment
- History of allergic reactions attributed to compounds of similar chemical or
biologic composition to pacritinib
- Concomitant administration with sensitive substrates/narrow therapeutic index drugs
of CYP3A4, CYP1A2, P-gp BCRP, and OCT1 should be avoided. Concurrent use of strong
inhibitors and inducers of CYP3A4 are not allowed. Prior use is allowed as long as
medication is stopped two weeks prior to study drug initiation. Because the lists of
these agents are constantly changing, it is important to regularly consult a
frequently-updated medical reference. As part of the enrollment/informed consent
procedures, the patient will be
counseled on the risk of interactions with other agents, and what to do if new
medications need to be prescribed or if the patient is considering a new over-the-counter
medicine or herbal product.
- Participants with the following cardiac conditions at screening:
- Symptomatic congestive heart failure
- Unstable angina pectoris
- Uncontrolled cardiac dysrhythmias
- QTc(F) prolongation >450 ms, or other factors that increase the risk for QT
prolongation (i.e., heart failure, or a history of long QT interval syndrome)
- Grade >= 3 cardiac complication in the 6 months prior to enrollment
- Left ventricular ejection fraction <= 50% by transthoracic echocardiogram (TTE) at
screening
- Participants with any active, uncontrolled viral, bacterial, or fungal infection,
including active HIV-1, Hepatitis B (HBV) and/or Hepatitis C (HCV) infection
(positive HBV or HCV viral load in the setting of positive HBV core antibody or
surface antibody or HCV antibody); history of HIV, HBV, or HCV is allowed if there
is no uncontrolled viral infection
- Pregnancy
- Presence of another known cause of cytopenia or dysplastic marrow that is untreated
and may limit interpretation of results
- Uncontrolled intercurrent illness or any significant disease, evaluated by history,
physical exam and chemistries or social situations that may limit interpretation of
results, limit compliance with study requirements, or that could increase risk to
the participant
Gender:
All
Minimum age:
12 Years
Maximum age:
120 Years
Healthy volunteers:
No
Locations:
Facility:
Name:
National Institutes of Health Clinical Center
Address:
City:
Bethesda
Zip:
20892
Country:
United States
Contact:
Last name:
National Cancer Institute Referral Office
Phone:
888-624-1937
Email:
NCIMO_Referrals@mail.nih.gov
Start date:
November 17, 2024
Completion date:
January 1, 2035
Lead sponsor:
Agency:
National Cancer Institute (NCI)
Agency class:
NIH
Source:
National Institutes of Health Clinical Center (CC)
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT06303193
https://clinicalstudies.info.nih.gov/cgi/detail.cgi?B_001554-C.html