The primary objective is to compare the efficacy of two dose-schedule arms(s) of pacritinib (pooled once daily [QD] and twice-daily [BID] dosing arms) with that of best available therapy (BAT) in patients with thrombocytopenia and primary…
ID
Source
Brief title
Condition
- Haematological disorders NEC
- Haematopoietic neoplasms (excl leukaemias and lymphomas)
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The efficacy co-endpoints for this analysis are the proportion of patients
achieving a * 35% reduction in spleen volume from baseline to Week 24, as
measured by magnetic resonance imaging (MRI) or computed tomography (CT) scan
and the proportion of patients achieving a * 50% reduction in total symptom
score (TSS) from baseline to Week 24 as measured by the Myeloproliferative
Neoplasm Symptom Assessment Form 2.0 (MPN-SAF TSS 2.0).
Secondary outcome
The secondary objectives are:
1 To compare the efficacy of QD pacritinib with that of BAT, as assessed by the
proportion of patients
achieving a * 35% reduction in spleen volume from baseline to Week 24 by MRI or
CT and the
proportion of patients achieving a * 50% reduction in the TSS from baseline to
Week 24 on the
MPN-SAF TSS 2.0.
2 To compare the efficacy of BID pacritinib with that of BAT, as assessed by
the proportion of patients
achieving a * 35% reduction in spleen volume from baseline to Week 24 by MRI or
CT and the
proportion of patients achieving a * 50% reduction in the TSS from baseline to
Week 24 on the
MPN-SAF TSS 2.0.
Background summary
For a subgroup of patients with myelofibrosis (MF) with low platelet counts,
the approved JAK2 inhibitor requires significant dose reduction and is less
effective than in patients with normal platelet counts.
Data from two phase 2 trials show that pacritinib can be safely administered to
patients with MF, including those who also have thrombocytopenia. Pacritinib
led to clinically meaningful reduction in spleen size and volume in a
substantial proportion of patients with MF. Pacritinib improved disease-related
symptoms. These effects were observed in patients with thrombocytopenia,
including those with platelet counts < 100,000/ul, as well in those with normal
platelet counts.
This study is a multicenter, randomized, controlled, phase 3 study. It will
compare the efficacy and safety of two dose schedules of pacritinib in pooled
and individual group analyses versus BAT in patients with thrombocytopenia and
PMF, PPV-MF, or PET-MF.
Study objective
The primary objective is to compare the efficacy of two dose-schedule arms(s)
of pacritinib (pooled once daily [QD] and twice-daily [BID] dosing arms) with
that of best available therapy (BAT) in patients with thrombocytopenia and
primary myelofibrosis (PMF), post-polycythemia vera myelofibrosis (PPV-MF), or
post-essential thrombocythemia myelofibrosis (PET-MF). The efficacy
co-endpoints for this analysis
are the proportion of patients achieving a * 35% reduction in spleen volume
from baseline to Week 24, as measured by magnetic resonance imaging (MRI) or
computed tomography (CT) scan and the proportion of patients achieving a * 50%
reduction in total symptom score (TSS) from baseline to Week 24 as measured by
the Myeloproliferative Neoplasm Symptom Assessment Form 2.0 (MPN-SAF TSS 2.0).
The secondary objectives are:
1 To compare the efficacy of QD pacritinib with that of BAT, as assessed by the
proportion of patients achieving a * 35% reduction in spleen volume from
baseline to Week 24 by MRI or CT and the proportion of patients achieving a *
50% reduction in the TSS from baseline to Week 24 on the
MPN-SAF TSS 2.0.
2 To compare the efficacy of BID pacritinib with that of BAT, as assessed by
the proportion of patients achieving a * 35% reduction in spleen volume from
baseline to Week 24 by MRI or CT and the proportion of patients achieving a *
50% reduction in the TSS from baseline to Week 24 on the MPN-SAF TSS 2.0.
Study design
This study is a multicenter, randomized, controlled, phase 3 study. It will
compare the efficacy and safety of two dose schedules of pacritinib in pooled
and individual group analyses versus BAT in patients with thrombocytopenia and
PMF, PPV-MF, or PET-MF. A total of 300 eligible patients will be randomized in
a 1:1:1 allocation to pacritinib 400 mg dosed QD, pacritinib 200 mg dosed BID,
or BAT:
- Pacritinib 400 mg taken orally, QD
- Pacritinib 200 mg taken orally, BID
- BAT
BAT includes any physician-selected treatment for PMF, PPV-MF, or PET-MF, such
as approved JAK2 inhibitors (administered according to package insert for
patients with thrombocytopenia), and may include any treatment received before
study entry. For example, BAT may include ruxolitinib, other approved JAK2
inhibitors, hydroxyurea, glucocorticoids, erythropoietic agents,
immunomodulatory agents, mercaptopurine, danazol, interferons, cytarabine,
melphalan, or other agents. BAT also includes *no treatment* and
symptom-directed treatment without MF-specific treatment.
During the study, patients taking pacritinib may not receive chemotherapy,
immunotherapy, corticosteroids, erythropoietic agents, or other treatment for
PMF, PPV-MF, or PET-MF.
Patients may not receive splenic irradiation or a splenectomy while receiving
study treatment.
Spleen volume will be measured by MRI or CT at baseline and every 12 weeks
thereafter. The analysis of the primary outcome of spleen response will be
performed when all randomized patients have completed the Week 24 MRI or CT
evaluation, met progressive disease criteria, or discontinued study treatment,
whichever occurs first. An independent radiology facility (IRF), blind to
treatment assignments, will measure spleen volumes.
Patients will also be followed for safety, LFS, OS, frequency of RBC and
platelet transfusions, and other exploratory endpoints. Bone marrow slides
obtained at or prior to baseline, as required for study eligibility, and those
obtained at Week 24 may be evaluated by a central pathology laboratory, in
addition to local pathology review.
An Independent Data Monitoring Committee (IDMC) will evaluate the safety of
pacritinib. No interim efficacy analysis is planned.
Intervention
Patients taking pacritinib will be supplied with 100-mg capsules of the drug.
If assigned to the QD dosing arm, patients will take 400 mg (4 capsules) of
pacritinib orally once a day at the same time of day, with or without food.
Patients assigned to BID dosing will take 200 mg (2 capsules) of pacritinib
orally twice each day at the same times of day, with or without food.
BAT includes any physician-selected treatment for PMF, PPV-MF, or PET-MF, such
as approved JAK2 inhibitors (administered according to package insert for
patients with thrombocytopenia), and may include any treatment received before
study entry. For example, BAT may include ruxolitinib, other approved JAK2
inhibitors, hydroxyurea, glucocorticoids, erythropoietic agents,
immunomodulatory agents, mercaptopurine, danazol, interferons, cytarabine,
melphalan, or other agents. BAT also includes *no treatment* and
symptom-directed treatment without MF-specific treatment.
Study burden and risks
Pacritinib has been investigated in 130 patients with myelofibrosis, including
PMF and Post PV/ET MF. The most common adverse events (in at least 10% of the
patients) that do or do not have a relationship with the study medication are
low platelet counts (thrombocytopenia), low red blood cell count (anemia),
diarrhea, nausea, vomiting and fatigue. Many of these adverse events are also
symptoms of the disease.
Possible side effects of biopsy and bone marrow tests are pain, fatigue,
bruising, soreness and sensitivity. In rare cases an infection can occur at
the puncture site.
Possible adverse events of the tape that is put on the skin when making an ECG
are rash or mild irritation of the skin.
During a CT-scan of the abdomen patients are exposed to radiation. The dose of
the radiation is approximately 10 mSv (millisievert), which is comparable with
the exposure to natural background radiation during approximately 3 years. This
exposure can slighly increase the risk of getting cancer. If the patient cannot
have a MRI scan, the research physician can choose for a CT-scan instead of a
MRI. In that case the research physician will be available to explain why a CT
scan is more suitable than an MRI-scan and to answer potential questions
regarding the difference in risk between the two procedures.
Patients will be asked to come to the hospital at Screening, Baseline, Week 2,
4, 8, 12, 16, 20, 24 every 12 weeks thereafter until progression of the
disease. The normal visits will take approxmately 30 minutes. The visits with a
CT or MRI (at Baseline and then every 12 weeks until progression) will take
approximately 1 hour.
3101 Western Avenue Suite 600
Seattle WA 98121
US
3101 Western Avenue Suite 600
Seattle WA 98121
US
Listed location countries
Age
Inclusion criteria
1. Intermediate-1, intermediate -2, or high risk PMF, PPV-MF, or PET-MF
2. Thrombocytopenia (platelet count * 100,000/µL) at any time after signing informed consent
3. Informed consent may be signed up to 35 days prior to randomization
4. Palpable splenomegaly *5 cm below the lower costal margin (LCM) in midclavicular line by physical examination
5. Total Symptom Score (TSS) *13 on the MPN-SAF TSS 2.0, not including the inactivity question
6. Age *18 years
7. Eastern Cooperative Oncology Group (ECOG) performance status 0 to 3
8. Peripheral blast count <10%
9. Absolute neutrophil count (ANC) >500/*L
10. Patients who are platelet or RBC transfusion dependent are eligible
11. Adequate liver and renal function, defined by liver transaminases (AST/SGOT and ALT/SGPT)
*3 × ULN (AST/ALT *5 × ULN if transaminase elevation is related to MF), direct bilirubin
*4 × ULN, and creatinine *2.5 mg/dL
12. At least 6 months from prior splenic irradiation
13. At least 12 months from prior 32P therapy
14. At least 1 week since prior treatment (most recent dose) with a potent cytochrome P450 3A4
(CYP3A4) inhibitor
15. At least 2 weeks since receiving any treatment for PMF, PPV-MF, or PET-MF
16. If fertile, males and females must agree to use effective birth control methods during the study
17. Willing to undergo and able to tolerate frequent MRI or CT assessments during the study
18. Able to understand and willing to complete symptom assessments using a patient-reported outcome instrument
19. Able to understand and willing to sign the Informed Consent Form
Exclusion criteria
1. Any gastrointestinal (GI) or metabolic condition that could interfere with absorption of oral
medication
2. Life expectancy less than 6 months
3. Prior treatment with more than 2 JAK2 inhibitors or with pacritinib
4. There is no maximum of cumulative prior JAK2 inhibitor treatment (approved or investigational)
5. Completed allogeneic stem cell transplant (ASCT), or are eligible for and willing to complete ASCT
6. History of splenectomy or planning to undergo splenectomy
7. Uncontrolled intercurrent illness, including but not limited to ongoing active infection, psychiatric
illness, or social situation that, in the judgment of the treating physician, would limit compliance with study requirements
8. Active bleeding requiring hospitalization during the screening period
9. Other malignancy within the last 3 years, other than curatively treated basal cell or squamous cell skin cancer, carcinoma in situ of the cervix, organ-confined or treated nonmetastatic prostate cancer with negative prostate-specific antigen, in situ breast carcinoma after complete surgical resection, or superficial transitional cell bladder carcinoma
10. Inflammatory or chronic functional bowel disorder, such as Crohn disease, inflammatory bowel disease, chronic diarrhea, or constipation
11. Clinically symptomatic and uncontrolled cardiovascular disease
12. History of any of the following within 6 months prior to randomization: myocardial infarction,
severe/unstable angina, or symptomatic congestive heart failure
13. New York Heart Association Class III or IV congestive heart failure
14. Patients with National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events
(CTCAE) grade 2 cardiac arrhythmias may be considered for inclusion, with the approval of the
medical monitor, if the arrhythmias are stable, asymptomatic, and unlikely to affect patient safety.
Patients will be excluded if they have ongoing cardiac dysrhythmias of CTCAE grade *3, corrected
QT interval (QTc) prolongation >450ms, or other factors that increase the risk for QT interval
prolongation (eg, heart failure, hypokalemia [defined as serum potassium <3.0mEq/L that is
persistent and refractory to correction], or family history of long QT interval syndrome).
15. Erythropoietic agent within 28 days prior to randomization
16. Thrombopoietic agent within 14 days prior to randomization
17. Known seropositivity for human immunodeficiency virus (HIV)
18. Known active hepatitis A, B, or C virus infection
19. Women who are pregnant or lactating
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2013-004000-19-NL |
| ClinicalTrials.gov | NCT02055781 |
| CCMO | NL48480.078.14 |