Primary Myelofibrosis (PMF), Post–Polycythemia Vera MF (Post–PV-MF), Or Post–Essential Thrombocythemia MF(Post–ET-MF) MedDRA version: 20.0 Level: PT Classification code 10077161 Term: Primary myelofibrosis System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) MedDRA version: 21.0 Level: LLT Classification code 10074689 Term: Post polycythemia vera myelofibrosis System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts an
Conditions
Sponsors
Kartos Therapeutics, Inc.
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Adults >18 years of age 2. Palpable spleen measuring = 5 cm below the left lower costal margin or spleen volume of = 450 cm3 by MRI or CT scan assessment 3. Confirmed diagnosis of PMF, post–PV-MF, or post–ET-MF according to the World Health Organization (WHO) criteria 4. High-risk, intermediate-2 risk, or intermediate-1 risk, defined by Dynamic International Prognostic System (DIPSS) 5. ECOG performance status of 0 to 2 6. Adequate hematological, hepatic, and renal organ function (as per protocol definition and within 28 days prior to the first dose of KRT-232) 7.Female subjects of childbearing potential and their male partners, or male subjects who have female partners of childbearing potential must both use an effective contraception method during the study. In addition, male subjects must continue to use contraception for 3 months and 1 week after the last dose of study drug and female subjects must continue to use contraception for 1 month and 1 week after the last dose of study drug. Effective birth control for males includes either vasectomy or use of condoms. Effective birth control for females includes (a) combined, estrogen and progestogen containing, hormonal contraception (oral, intravaginal, transdermal); (b) progestogen-only hormonal contraception (oral, injectable, implantable); (c) intrauterine device; (d) intrauterine hormone-releasing system; (e) bilateral tubal occlusion; and (f) sexual abstinence, when this is in line with the preferred and usual lifestyle of the subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception. Subjects in Part A must meet the following JAK inhibitor treatment failure criteria in order to be eligible for the study: JAK Inhibitor treatment failure in Part A must meet either criterion (a) or (b) below: a) Either a lack of spleen response defined as receiving at least 12 weeks of JAK inhibitor treatment and having both of the following: • Persistent splenomegaly, by physical exam, that is palpable = 5 cm below the lower costal margin (LCM) • and TSS of >10 on the MPN-SAF TSS v2.0 or patients with a single symptom score of >5 or two symptoms of >3, including only the symptoms of left upper quadrant pain, bone pain, itching, or night sweats b) Or progressive disease any time while on JAK inhibitor treatment as defined by any one of the following: • Spleen volume increase by = 25% from the nadir as assessed by MRI or CT • Appearance of new splenomegaly that is palpable at least 5 cm below the LCM • A = 100% increase in palpable distance, below the LCM, for baseline splenomegaly of 5 to 10 cm • A = 50% increase in palpable distance, below the LCM, for baseline splenomegaly of > 10 cm Subjects in Part B must meet the following ruxolitinib treatment failure criteria in order to be eligible for the study. Ruxolitinib treatment failure in Part B must meet either criterion (a) or (b) below: a) Either a lack of spleen response defined as receiving at least 12 weeks of ruxolitinib treatment and having at least one of the following: • For subjects that have a MRI or CT to assess ruxolitinib treatment, failure to have a least = 35% reduction in spleen volume • A Baseline splenomegaly prior to ruxolitinib treatment that is palpable at 5 to 10 cm, below the LCM, but remains palpable • A Baseline splenomegaly prior to ruxolitinib treatment that is palpable > 10 cm, below the LCM, but does not decrease by at lea
Exclusion criteria
Exclusion criteria: 1. Patients who are positive for p53 mutations 2. Participation in another interventional clinical trial within the past 4 weeks of the first dose of KRT-232 (participation in observational studies is permitted) 3. Major surgery within the first 28 days of KRT-232 4. Chemotherapy, immunomodulatory drug therapy within 14 days prior to first dose of KRT-232 5. Prior splenectomy 6. Splenic irradiation within 3 months prior to the first dose of KRT-232 7. Prior allogeneic stem-cell transplantation or eligible for allogeneic stem cell transplantation 8. Previous treatment with histone deacetylase (HDAC) inhibitors or BCL-2 inhibitors 9. Prior MDM2 inhibitor therapy or p53-directed therapy 10. Women who are pregnant or breastfeeding 11. History of major organ transplant 12. Uncontrolled intercurrent illness including, but not limited to, acute hepatitis A; known history of human immunodeficiency virus (HIV)-positive; clinically significant cardiac disease (New York Heart Association Class III or IV); symptomatic congestive heart failure; unstable angina pectoris; ventricular arrhythmia; or psychiatric illness/social situations that would limit compliance with study requirements 13. Subjects with clinically significant bacterial, fungal, parasitic, or viral infection that requires therapy. Subjects with acute bacterial infections requiring antibiotic use should delay screening/enrollment until the course of antibiotic therapy has been completed. 14. 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 normal prostate-specific antigen, in situ breast carcinoma after complete surgical resection, or superficial transitional cell bladder carcinoma 15. Grade 2 or higher QTc prolongation (>480 milliseconds per NCI-CTCAE criteria, version 5.0) 16. Growth factor treatment (e.g., erythropoeitin) within 14 days prior to first dose of KRT-232; no darbepoetin within 28 days prior to first dose of KRT-232 17. Active or chronic bleeding within 4 weeks prior to the first dose of KRT-232
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: The primary objective of this study is to determine how well the spleen size can be reduced by treatment with the study medication.;Secondary Objective: To determine the change in modified MPN-SAF Total Symptom Score (TSS) at Week 24 and Week 48; To determine the duration of spleen response (DoR-spleen); To determine spleen size reduction as measured by palpation; To determine red blood cell (RBC) transfusion usage; To determine the clinical response rate at Week 24; To determine the overall survival (OS) rate; To determine the leukemia free survival rate; To determine the safety and tolerability of KRT-232; To determine the pharmacokinetic/ pharmacodynamic (PK/PD) profile of KRT-232; ;Primary end point(s): The proportion of subjects achieving a =35% spleen volume reduction from Baseline to Week 24, as assessed by magnetic resonance imaging (MRI) or computed tomography (CT) scan;Timepoint(s) of evaluation of this end point: The Primary Endpoint will be assessed 24 weeks after each subject is enrolled. | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Proportion of subjects who have at least 50% reduction from baseline to Week 24 and Week 48 in the total symptom score as measured by the modified MPN-SAF v2.0. Duration of a =35% or more reduction from Baseline in spleen volume as measured by MRI (or by CT for applicable subjects) Reduction in spleen size from Baseline to each visit at which spleen is palpated, including the proportion of subjects who have a =50% decrease • RBC transfusions (average number of RBC units per patient-month) • RBC transfusion independence at Week 24 (proportion of patients who were transfusion-independent at Week 24, defined as absence of RBC transfusions and no hemoglobin <8 g/dL in the previous 12 weeks) Complete remission (CR) and partial remission (PR) defined according to International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) and modified European LeukemiaNet (ELN) criteria Overall survival is defined as the interval from randomization to death from any cause Leukemia-free survival is defined as the interval from randomization to the date of first documented leukemia transformation or death from any cause Analyses of the safety endpoints will include the following measurements or assessments: physical examinations, laboratory tests, adverse events (AEs), serious AEs (SAEs), ECGs, vital signs KRT-232 and acyl glucuronide metabolite (M1) PK parameters, including but not limited to, maximum observed concentration (Cmax), minimum observed concentration (Cmin), area under the plasma concentration-time curve (AUC), and terminal elimination half-life (t1/2z);Timepoint(s) of evaluation of this end point: Week 24, Week 48 and duration of study. Please refer to protocol for full details. | — |
Countries
Australia, Bulgaria, Canada, Czechia, Czech Republic, France, Germany, Hungary, Israel, Poland, Spain, United Kingdom, United States
Contacts
Public ContactClinical Operations
Kartos Therapeutics, Inc.
Outcome results
None listed