Primary Or Secondary (Post-PV MF or Post-ET-MF) Myelofibrosis (MF) With Intermediate Or High-Risk TP53 Wild-Type (TP53 WT) Who Are Relapsed Or Refractory to Janus Kinase (JAK) - Inhibitor Treatment. 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 O
Conditions
Interventions
Product Name: KRT-232
Pharmaceutical Form: Tablet
INN or Proposed INN: navtemadlin
Current Sponsor code: KRT-232
Other descriptive name: AMG-232
Concentration unit: mg milligram(s)
Concentration type:
Sponsors
Kartos Therapeutics, Inc.
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: Part A: 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 LLCM • and TSS of >10 on the MPN-SAF TSS v.2.0 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 Part B: 1. Adults >18 years of age 2. Confirmed diagnosis of PMF, post PV MF, or post ET MF, as assessed by treating physician according to the World Health Organization (WHO) criteria (Appendix 3) 3. High-risk, intermediate-2 risk, or intermediate-1 risk, defined by Dynamic International Prognostic System (DIPSS) (Appendix 4) 4. Subjects with p53WT MF by central laboratory testing 5. Relapsed or refractory to prior treatment with an approved JAK inhibitor defined as: Relapsed subjects are those with progressive disease after JAK inhibitor treatment, defined by one of the following: • Increase in spleen volume by =25% by radiographic imaging from nadir • =100% increase in palpable distance below LLCM for baseline splenomegaly
Exclusion criteria
Exclusion criteria: Part A: 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 NCICTCAE 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 Part B: 1. Prior MDM2 inhibitor therapy or p53-directed therapy 2. Participation in an interventional clinical trial within 28 days before randomization (participation in observational studies is permitted) 3. Major surgery or radiotherapy within 21 days prior to randomization, or anticipation of needing such procedures while receiving study treatment 4. JAK-, PI3k-, SYK-, BTK-, BET- or MTOR inhibitor treatment within 28 days prior to the Screening MRI/CT scan 5. Treatment with any other anticancer agent including chemotherapy, immunotherapy or biologic therapy within 28 days prior to randomization. Hydroxyurea may be taken within 1 day prior to Cycle 1 Day 1 6. Prior splenectomy 7. Splenic irradiation within 12 weeks of randomization. 8. Prior allogeneic stem-cell transplantation or plans for allogeneic stem cell transplantation 9. Women who are pregnant, lactating, breastfeeding or intending to become pregnant during the study. 10. History of major organ transplant 11. Active serious viral, mycobacterial, parasitic, fungal, and bacterial infections, including acute hepatitis A, herpes zoster, and progressive multifocal leukoencephalopathy (PML). Active serious infections must be resolved before randomization. Patients with acute infections requiring systemic antibiotic use should complete antibiotic therapy at
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: Part A: to determine spleen response. Part B: To compare the spleen volume reduction (SVR) at Week 24 between Arm 1 and Arm 2;Secondary Objective: Part A: 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 RBC transfusion usage; To determine the clinical response rate at Week 24; To determine the overall survival (OS) rate; To determine the safety and tolerability of KRT-232; To determine the PK/PD profile of KRT-232 Part B: To compare the improvement of TSS at Week 24 between Arm 1 and Arm 2; To compare the OS between Arm 1 and Arm 2; To compare the progression free survival (PFS) between Arm 1 and Arm 2; To compare the overall SVR at any time in each study arm; To evaluate the spleen response duration between Arm 1 and Arm2; To compare the rate of conversion from RBC transfusion dependent to independent at Week 24 between Arm 1 and Arm 2; To evaluate the safety between Arm 1 and Arm 2; To monitor the PK of KRT-232 (Arm 1 only);Primary end point(s): Part A: 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 Part B: The proportion of subjects in each arm achieving SVR of = 35% at Week 24 by MRI/CT scan (central review) ;Timepoint(s) of evaluation of this end point: Part A: The Primary Endpoint will be assessed 24 weeks after each subject is enrolled. Part B: Week 24 | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Part A: Proportion of subjects who have at least a 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 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 concentrationtime curve (AUC), and terminal elimination half-life (t1/2z) Part B: The proportion of subjects in each arm with = 50% reduction in TSS (MFSAF v4.0) at Week 24 Time from randomization to death from any cause in each arm PFS is defined as the time from randomization to either the first occurrence of disease progression or death due to any cause. Disease progression is defined as any occurrence of the following: • Spleen progression (=25% increase in spleen volume from baseline) • Leukemic transformation (bone marrow blast count of =20% or a peripheral blood blast content | — |
Countries
Argentina, Australia, Brazil, Bulgaria, Canada, Croatia, Czechia, Czech Republic, France, Germany, Greece, Hong Kong, Hungary, Israel, Italy, Lithuania, Mexico, Philippines, Poland, Portugal, Romania, Spain, Taiwan, Thailand, Turkey, United Kingdom, United States
Contacts
Public ContactRegulatory Affairs
Kartos Therapeutics, Inc.
Outcome results
None listed