Myelofibrosis, Post-essential Thrombocythemia Myelofibrosis, Post-polycythemia Vera Myelofibrosis
Conditions
Keywords
Myelofibrosis, Anemia, Thrombocytopenia, Pacritinib, Selinexor
Brief summary
This is a phase II, multicenter, open-label trial evaluating the safety and efficacy of pacritinib and selinexor in JAK inhibitor naïve patients with anemia and thrombocytopenia.
Detailed description
This Phase II, multicenter, open-label will evaluate the safety and efficacy of pacritinib and selinexor in JAK inhibitor naïve patients with anemia and thrombocytopenia. Participants will receive pacritinib monotherapy for 1 cycle (4 weeks) and will be assessed for qualification to proceed to combination therapy at Cycle 2 Day 1. Participants who qualify for combination therapy will receiving pacritinib and selinexor for the remaining cycles. Participants who do not qualify at Cycle 2 Day 1 will have weekly assessments and count checks. If they meet criteria for combination therapy at any point, selinexor will be added onto pacritinib. Participants who do not qualify for combination therapy by Cycle 4 Day 1 will complete 6 cycles of pacritinib monotherapy, complete primary endpoint assessments after 24 weeks, and discontinue study participation. Participants receiving combination therapy must demonstrate clinical benefit at Cycle 7 Day 1 (24 weeks) to continue receiving therapy until loss of response, disease progression, unacceptable toxicity, participant/physician withdrawal, or the study is terminated.
Interventions
DRUGPacritinib
Pacritinib 200mg twice a day (BID) by mouth (PO)
DRUGSelinexor
Selinexor 60mg once weekly (QW) by mouth (PO)
Sponsors
John Mascarenhas
Sobi, Inc.
Karyopharm Therapeutics Inc
National Cancer Institute (NCI)
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Adults ≥ 18 years of age capable of providing informed consent * Pathologically confirmed diagnosis of PMF, post-ET MF, or post-PV MF as per the World Health Organization (WHO) diagnostic criteria - Intermediate-1, Intermediate-2, or High-Risk disease by the Dynamic International Prognostic Scoring System (DIPSS) * Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 * Baseline splenomegaly ≥ 5cm palpable below the left costal margin and in the midclavicular line OR ≥ 450cc by imaging (i.e. ultrasound, CT, MRI) * Baseline anemia, defined by hemoglobin \< 10 g/dL within 28 days prior to Cycle 1 Day 1 * Baseline thrombocytopenia, defined by platelet count 50-150 x 109/L without platelet transfusions within 28 days prior to Cycle 1 Day 1 * Adequate organ function as demonstrated by the following within 28 days prior to Cycle 1 Day 1: * ALT (SGPT) and/or AST (SGOT) ≤ 3x the upper limit of normal (ULN), or ≤ 4 x ULN if, upon judgment of the treating physician, it is believed to be due to MF-related extramedullary hematopoiesis (EMH); * Direct bilirubin ≤ 1.5 x ULN; or ≤ 2x ULN if, upon judgment of the treating physician, it is believed to be due to MF-related extramedullary hematopoiesis (EMH) or documented Gilbert's syndrome; * Creatinine clearance ≥ 30 mL/min; * Prothrombin time (PT) and activated partial thromboplastin time (aPTT) ≤ 1.5 × ULN (Exceptions to coagulation parameters may be considered for patients who are taking concomitant anticoagulation medications or have a documented anti-phospholipid antibody, after discussion with Study Chair approval) * Bone marrow and/or peripheral blood blast count \< 5%; and * Absolute neutrophil count (ANC) ≥ 1500 mm3 without need for growth factors within 7 days prior to Cycle 1 Day 1. * Recovery to ≤ Grade 1 or baseline of any toxicities due to prior systemic treatments, excluding alopecia * Life expectancy of at least six months * Patients with active hepatitis B virus are eligible if antiviral therapy for hepatitis B has been given for \>8 weeks and the viral load is \<100 IU/mL. * Patients with history of hepatitis C virus (HCV) are eligible if they have received adequate curative anti-HCV treatment and HCV viral load is below the limit of quantification. * Patients with history of human immunodeficiency virus are eligible if they have cluster of differentiation (CD)4+ T-cell counts ≥350 cells/μL, negative viral load, and no history of acquired immunodeficiency syndrome (AIDS)-defining opportunistic infections in the last year and should be on established antiretroviral therapy for at least 4 weeks. * Women of childbearing potential (WOCBP) and men must agree to use adequate contraception prior to study entry, for the duration of study participation, and for 90 days following completion of therapy. Men must agree to use a condom and not father a child or donate sperm for the duration of the study and for 90 days after the last dose of study therapy * Able to adhere to the study visit schedule and all protocol requirements
Exclusion criteria
* Prior treatment with Janus kinase (JAK) inhibitors * Prior treatment with selinexor or other Exportin 1 (XPO1) inhibitors * Treatment with any MF-directed therapy (including investigational therapies and excluding hydroxyurea) within 2 weeks or 5.5 half-lives, whichever is shorter, of Cycle 1 Day 1 * Completed hematopoietic cell transplant (HCT) * Prior splenectomy, splenic irradiation, or splenic artery embolization within 6 months of Cycle 1 Day 1 * Impairment of gastrointestinal (GI) function or GI disease that could significantly alter the absorption of pacritinib or selinexor, including any unresolved nausea, vomiting, or diarrhea \> National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v6.0 Grade 1 * Uncontrolled or currently progressing ocular toxicities * Moderate or severe cardiovascular disease meeting one or both of the below criteria: * Presence of cardiac disease, including a myocardial infarction within 6 months prior to study entry, unstable angina pectoris, New York Heart Association Class III/IV congestive heart failure, or uncontrolled hypertension * Documented major electrocardiogram (ECG) abnormalities (not responding to medical treatments) * Grade 2 or greater bleeding event within the past 6 months * QT corrected by the Fridericia method (QTcF) prolongation \> 480 ms or other factors that increase the risk for QT interval prolongation (eg, hypokalemia \[defined as serum potassium \< 3.0 mEq/L that is persistent and refractory to correction\], or history of long QT interval syndrome) * Recipient of organ transplant * History of major surgery or any planned surgical procedures within 28 days prior to Cycle 1 Day 1 * Other malignancy within the last three years, other than curatively treated basal cell or squamous cell skin cancer, carcinoma in situ of the cervix, organ-confined or treated non-metastatic prostate cancer with normal prostate-specific antigen, in situ breast carcinoma after complete surgical resection, or superficial/non-invasive transitional cell bladder carcinoma. * Presence of active serious infection * Use of any prohibited medications (5.8) within two weeks or five half-lives, whichever is longer, prior to Cycle 1 Day 1 * Women who are pregnant or lactating * Any serious, unstable medical or psychiatric condition that would prevent (as judged by the Investigator) the subject from signing the informed consent form (ICF) or any condition, including the presence of laboratory abnormalities, which places the subject at unacceptable risk if they were to participate in the study or confounds the ability to interpret data from the study * Is or has an immediate family member (e.g., spouse, parent/legal guardian, sibling, or child) who is investigational site or sponsor staff directly involved with this trial, unless prospective IRB approval (by chair or designee) is given allowing exception to this criterion for a specific subject
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in spleen volume | Baseline and 24 weeks | Evaluate clinical efficacy of pacritinib and selinexor in myelofibrosis patients who are JAK inhibitor-naïve and have anemia and thrombocytopenia by assessing spleen volume reduction (SVR) of 35% or greater compared to baseline as measured by imaging (MRI/CT) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Spleen response rate | At 24 weeks and 48 weeks | Spleen response rate (by palpation) after 6 and 12 cycles; spleen response is defined as baseline splenomegaly palpable at 5-10cm that becomes not palpable, or baseline splenomegaly of \>10cm that decreases by ≥ 50%, as measured by palpation |
| Change in the Myelofibrosis-Symptom Assessment Form Total Symptom Score (MF-SAF TSS) | At 24 weeks and 48 weeks | Evaluate change in patient reported outcomes of treatment Change in MF-SAF TSS from baseline after 6 and 12 cycles; symptom response will be determined in participants with baseline MF-SAF TSS ≥ 10. The MF-SAF TSS comprises 7 items measuring MF-related symptoms. Each item is scored on a scale ranging from 0 (absent) to 10 (worst imaginable) and the items are summed for a total score. The Mf-SAF TSS is the summation of all the individual scores (0-70 scale). Symptoms response requires ≥50% reduction in the MPN-SAF TSS and will be evaluable only in patients with a baseline TSS \>= 10. |
| Change in Patient Global Impression of Change (PGIC) | At 24 weeks and 48 weeks | Patient Global Impression of Change (PGIC) response after 6 and 12 cycles; PGIC response is defined as "minimally improved" or better The Patient Global Impression of Change (PGIC) will be used to assess self-reported belief about the efficacy of treatment. PGIC is a 7-point scale depicting a patient's rating of overall improvement. Patients rate their change as "very much improved", "much improved", "minimally improved", "no change", "minimally worse", "much worse", or "very much worse. Total scale from 1-7, with higher score indicating poorer health outcomes. |
| Anemia response | At 24 weeks and 48 weeks | Anemia response after 6 and 12 cycles; anemia response is determined according to revised 2024 International Working Group-European LeukemiaNet (IWG-ELN) criteria and includes major response rate and minor response rate for transfusion-dependent anemia. Major response: No transfusions for 12 weeks alongside a 12-week average hemoglobin increase of 150g/L Minor response: A 50% or more reduction in transfusions and failure to meet major response thresholds. |
| Change in hemoglobin level | Continuously across all cycles of treatment, up to 48 weeks | Hemoglobin is the protein molecule in red blood cells that carries oxygen from the lungs to the body's tissues and returns carbon dioxide from the tissues back to the lungs. |
| Change in platelet count | Continuously across all cycles of treatment, up to 48 weeks | Platelets are part of the blood cells. Platelets are a part of the blood clotting system and help in preventing bleeding. |
| Progression-free survival | At time of disease progression or at 48 weeks, whichever occurs first | Progression-free survival (PFS) is defined as time from first treatment to disease progression by IWG-ELN criteria |
| Overall survival | At time of death or censored at last follow-up, at 48 weeks | Overall survival (OS) is defined as time from first treatment to death due to any cause or censored at last follow-up |
| Number of participants achieving RBC transfusion independence) | at 24 weeks and at 48 weeks | The number of participants achieving transfusion independence will be divided by the number of participants who were transfusion-dependent at baseline |
| Number of participants achieving platelet transfusion independence | at 24 weeks and at 48 weeks | The number of participants achieving transfusion independence will be divided by the number of participants who were transfusion-dependent at baseline |
Countries
United States
Contacts
CONTACTGillian Sanchez
CONTACTShakira Forde
STUDY_CHAIRJohn Mascarenhas, MD
Icahn School of Medicine at Mount Sinai
STUDY_CHAIRAbdulraheem Yacoub, MD
University of Kansas School of Medicine
STUDY_CHAIRRuben Mesa, MD, FACP
Atrium Health Wake Forest Baptist Comprehensive Cancer Center
Outcome results
None listed