C945 Acute myelofibrosis Acute myelofibrosis
Conditions
Interventions
KRT-232 will be administered orally as 240 mg once daily on Days 1–7, off treatment on
Days 8–28, in 28-day treatment cycles. Tablets should not be crushed, chewed, or dissolved in
water. KRT-232 will
Sponsors
KARTOS THERAPEUTICS, INC
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 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 3. Palpable spleen measuring =5 cm below the left lower costal margin or spleen volume of =450 cm3 by magnetic resonance imaging (MRI) or computed tomography (CT) scan assessment. 4. Two symptoms with a score of at least 3 for each symptom, according to Myelofibrosis Symptom Assessment Form (MFSAF) v4.0. 5. High-risk, or intermediate-1 and 2 risk, defined by Dynamic International Prognostic System (DIPSS) 6. ECOG performance status of 0 to 1. 7. Adequate hematological, hepatic, and renal organ function (as per protocol definition and within 28 days prior to the first dose of study treatment). a. Hematologic: • ANC =1.0 × 109/L (Note: ANC eligibility is based on counts obtained in the absence of growth factors: ie, 7 days for G-CSF or 14 days for pegfilgrastim). • Platelet count =50 × 109/L. b. Peripheral blood blast count upper limit of normal (ULN) then patients are eligible if the direct bilirubin is =2.0 x ULN. • Aspartate transaminase/serum glutamic oxaloacetic transaminase (AST/SGOT) and alanine transaminase/serum glutamic pyruvic transaminase (ALT/SGPT) =2.5 ULN. d. Renal: estimated creatinine clearance =30 mL/min by Cockcroft Gault 8. 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 use of condoms. Effective birth control for females includes (a) combined estrogen- and progestogen- containing hormonal contraception (oral, intravaginal, transdermal); (b) intrauterine device combined with a barrier method; (c) intrauterine hormone-releasing system combined with a barrier method; (d) bilateral tubal occlusion/ligation; (e) vasectomized partner; (f) sexual abstinence, when this is in line with the preferred and usual lifestyle of the subject. Per
Exclusion criteria
Exclusion criteria: 16. 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. 17. Grade 2 or higher QTc prolongation (>480 milliseconds per National Cancer Institute Common Terminology of Adverse Events [NCI-CTCAE] criteria, version 5.0). 18. Major hemorrhage or intracranial hemorrhage within 24 weeks prior to the first dose of study treatment. 19. Having history of difficulty swallowing, gastric or small bowel surgery with history of malabsorption or other chronic gastrointestinal disease or conditions that may hamper compliance and/or absorption of the study treatment. 9. Prior allogeneic stem-cell transplantation or eligible for allogeneic stem cell transplantation. Subjects who are eligible for hematopoietic stem cell transplantation per the opinion of the investigator, but who refuse transplant, are eligible for the study. 10. Women who are pregnant or breastfeeding. 11. History of major organ transplant. 12. Uncontrolled intercurrent illness including, but not limited to clinically significant cardiac disease (New York Heart Association Class III or IV); symptomatic congestive heart failure; unstable angina pectoris; unstable ventricular arrhythmia; or psychiatric illness/ social situations that would limit compliance with study requirements. 13. Subjects with known active hepatitis B virus (HBV) or hepatitis C virus (HCV). 14. Subjects with known history of HIV. 15. Subjects with clinically significant bacterial, mycobacterial, fungal, parasitic, or viral infection, including but not limited to hepatitis A, herpes zoster, and progressive multifocal leukoencephalopathy (PML). Subjects must have completed IV antibiotics at least 2 weeks prior to the first dose of study treatment. Subjects who meet any of the following criteria will not be eligible for the study: 1. Arm 1 (KRT-232) a. Subjects who are positive for p53 mutations. b. Prior MDM2 inhibitor therapy or p53-directed therapy.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| The proportion of subjects achieving =35% SVR at Week 24 by MRI/CT (central review). NAME OF THE RESULT: Spleen response rate of each arm at Week 24 PERIOD OF TIME WHERE TE MEASUREMENT WILL BE CONDUCTED AND WHICH WILL ALLOW OBTAINING THE PRIMARY RESULT: 24 weeks | — |
Secondary
| Measure | Time frame |
|---|---|
| The proportion of subjects achieving =35% SVR at Week 24 by MRI/CT (central review). NAME OF THE RESULT: Spleen response rate of each arm at Week 24 PERIOD OF TIME WHERE TE MEASUREMENT WILL BE CONDUCTED AND WHICH WILL ALLOW OBTAINING THE PRIMARY RESULT: 24 weeks ;The proportion of subjects achieving TSS =50% at Week 24 by Myelofibrosis Symptom Assessment Form (MFSAF) v4.0. NAME OF THE RESULT: To assess the change in total symptom score (TSS) for each arm: PERIOD OF TIME WHERE TE MEASUREMENT WILL BE CONDUCTED AND WHICH WILL ALLOW OBTAINING THE PRIMARY RESULT: 24 weeks ;Time from initial SVR of =35% by MRI/CT (central review) until progression, defined as 25% increase from baseline in spleen volume, or leukemic transformation (bone marrow blast count of =20% or a peripheral blood blast content of =20% associated with an absolute blast count of =1x109/L that lasts for at least 2 weeks) NAME OF THE RESULT: Spleen response duration PERIOD OF TIME WHERE TE MEASUREMENT WILL BE CONDUCTED AND WHICH WILL ALLOW OBTAINING THE PRIMARY RESULT: 24 weeks ;The rate of conversion is defined as the proportion of subjects who convert from transfusion dependent to transfusion independent at Week 24. NAME OF THE RESULT: To determine the rate of conversion from RBC transfusion dependent to RBC transfusion independent at Week 24 for each arm PERIOD OF TIME WHERE TE MEASUREMENT WILL BE CONDUCTED AND WHICH WILL ALLOW OBTAINING THE PRIMARY RESULT: 24 weeks ;Time from first dose to death from any cause. Progression free survival (PFS): Time from first dose to progression (25% increase in spleen volume, or leukemic transformation [bone marrow blast count o | — |
Countries
Belarus, Brazil, Bulgaria, Georgia, Mexico, Peru, Poland, Russian Federation, South Africa, Ukraine, United States
Contacts
Public ContactYANINA ELVIRA ARCHENTI
GOTUZZO ASOCIADOS S.A.C.
Outcome results
None listed