KRT-232 in Combination With TL-895 for the Treatment of R/R MF and KRT-232 for the Treatment of JAKi Intolerant MF
- Conditions
- Primary MyelofibrosisPost-ET MyelofibrosisMyelofibrosisPost-PV MF
- Interventions
- Registration Number
- NCT04640532
- Lead Sponsor
- Kartos Therapeutics, Inc.
- Brief Summary
This study evaluates KRT-232 in Combination With TL-895 for the Treatment of Relapsed or Refractory Myelofibrosis and KRT-232 for the Treatment of JAK Inhibitor Intolerant Myelofibrosis.
- Detailed Description
Cohorts 1 and 2 will undergo dose finding and dose expansion. Eligible patients will be randomly assigned to an open cohort, either Cohort 1 or Cohort 2. Cohort 3 will be conducted as a dose expansion, independent of Cohorts 1 and 2.
Cohort 1 will follow a 3+3 dose escalation design to determine the maximum tolerated dose (MTD)/maximum administered dose (MAD) and recommended Phase 2 dose (RP2D) of TL-895 administered QD in combination with KRT-232. A Safety Review Committee (SRC) will review the safety data during the dose escalation to decide on dose escalation and/or exploration of intermediate doses.
Cohort 2 will follow a 3+3 dose escalation design to determine the MTD/MAD and recommended RP2D of TL-895 administered BID in combination with KRT-232. An SRC will review the safety data during the dose escalation to decide on dose escalation and/or exploration of intermediate doses.
Cohort 3 will be conducted a 2-stage design. In stage 1, enrollment will continue until 15 evaluable patients have been enrolled. An SRC will review the data during the study and if there are ≥4 responders based on the futility criteria and safety data from Stage 1, Cohort 3 expansion will commence. If there are ≤3 patients responding to therapy, Cohort 3 will be terminated. Once expansion criteria have been met, Cohort 3 will be expanded to a total of 46 evaluable patients for Stage 2 analyses.
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 116
- Confirmed diagnosis of primary MF, post-PV MF, or post-ET MF, (WHO 2016)
- ECOG ≤ 2
- Cohort 1 and Cohort 2: R/R following JAK inhibitor treatment
- Cohort 3: patients who are intolerant to JAK inhibitor treatment
- Prior treatment with MDM2 inhibitors or p53-directed therapies
- Prior treatment with a BCR-ABL, phosphoinositide 3-kinase (PI3k), mammalian target of rapamycin (mTOR), bromodomain and extraterminal domain (BET), histone deacetylase (HDAC), or spleen tyrosine kinase (Syk) inhibitor
- Prior splenectomy
- Splenic irradiation within 3 months prior to the first dose of study treatment
- Clinically significant thrombosis within 3 months of screening
- Grade 2 or higher QTc prolongation
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description Cohort 3 (JAKi Intolerant MF) KRT-232 KRT-232 at 240mg will be administered orally, once daily (QD), on days 1-7 in a 28-day cycle. Cohort 1 (R/R MF), Dose Level 1 TL-895 TL-895 at 200 mg once a day (QD) continuously starting on Cycle 1 Day 1 in a 28-day cycle. KRT-232 240mg will be administered orally, once daily (QD), on days 1-7 in a 28-day cycle starting on Cycle 2 Day 1. Cohort 2 (R/R MF), Dose Level 1 TL-895 TL-895 at 100 mg twice a day (BID) continuously starting on Cycle 1 Day 1 in a 28-day cycle. KRT-232 at 240mg will be administered orally, once daily (QD), on days 1-7 in a 28-day cycle starting on Cycle 2 Day 1. Cohort 1 (R/R MF), Dose Level 1 KRT-232 TL-895 at 200 mg once a day (QD) continuously starting on Cycle 1 Day 1 in a 28-day cycle. KRT-232 240mg will be administered orally, once daily (QD), on days 1-7 in a 28-day cycle starting on Cycle 2 Day 1. Cohort 2 (R/R MF), Dose Level 2 KRT-232 TL-895 at 150 mg twice a day (BID) continuously starting on Cycle 1 Day 1 in a 28-day cycle. KRT-232 at 240mg will be administered orally, once daily (QD), on days 1-7 in a 28-day cycle starting on Cycle 2 Day 1. Cohort 1 (R/R MF), Dose Level 2 KRT-232 TL-895 at 300 mg once a day (QD) continuously starting on Cycle 1 Day 1 in a 28-day cycle. KRT-232 at 240mg will be administered orally, once daily (QD), on days 1-7 in a 28-day cycle starting on Cycle 2 Day 1. Cohort 1 (R/R MF), Dose Level 2 TL-895 TL-895 at 300 mg once a day (QD) continuously starting on Cycle 1 Day 1 in a 28-day cycle. KRT-232 at 240mg will be administered orally, once daily (QD), on days 1-7 in a 28-day cycle starting on Cycle 2 Day 1. Cohort 2 (R/R MF), Dose Level 2 TL-895 TL-895 at 150 mg twice a day (BID) continuously starting on Cycle 1 Day 1 in a 28-day cycle. KRT-232 at 240mg will be administered orally, once daily (QD), on days 1-7 in a 28-day cycle starting on Cycle 2 Day 1. Cohort 2 (R/R MF), Dose Level 1 KRT-232 TL-895 at 100 mg twice a day (BID) continuously starting on Cycle 1 Day 1 in a 28-day cycle. KRT-232 at 240mg will be administered orally, once daily (QD), on days 1-7 in a 28-day cycle starting on Cycle 2 Day 1.
- Primary Outcome Measures
Name Time Method Phase 1b - The MTD/MAD and RP2D of TL-895 in combination with KRT-232 in patients with R/R MF (Cohort 1 and Cohort 2) 56 Days DLTs will be used to establish the MTD. RP2D will be determined by the SRC based on safety data from the combination of TL-895 and KRT-232.
Phase 2 - Spleen response rate for each cohort 24 Weeks A reduction in spleen volume as assessed by MRI (or CT) ≥ 35% from baseline at Week 24
- Secondary Outcome Measures
Name Time Method Total Symptom Score (TSS) 24 Weeks The change in TSS based Myelofibrosis Symptom Assessment Form version 4.0 (MFSAF v4.0)
Trial Locations
- Locations (37)
CHU Nantes - Hôtel Dieu
🇫🇷Nantes, France
Medical Center of the University of Pecs, 1st Department of Internal Medicine, Division of Hematology
🇭🇺Pécs, Hungary
Nasz Lekarz Medical Outpatient Clinics Slawomir Jeka
🇵🇱Toruń, Poland
Clinical Center of Serbia
🇷🇸Belgrade, Serbia
University Multiprofile Hospital for Active Treatment Dr. Georgi Plovdiv
🇧🇬Plovdiv, Bulgaria
Szabolcs-Szatmar-Bereg County Hospitals and University Teaching Hospital, Department of Hematology
🇭🇺Nyíregyháza, Hungary
Pratia Onkologia Katowice
🇵🇱Katowice, Poland
Slupsk Provincial Specialist Hospital n.a. Janusz Korczak, Department of Hematology
🇵🇱Słupsk, Poland
University of Alabama at Birmingham School of Medicine, Division of Hematology and Oncology
🇺🇸Birmingham, Alabama, United States
The Oncology Institute of Hope
🇺🇸Whittier, California, United States
Lake City Cancer Center
🇺🇸Lake City, Florida, United States
Carle Cancer Center
🇺🇸Urbana, Illinois, United States
Columbia University Medical Center
🇺🇸Fort Lee, New Jersey, United States
LKH Hochsteiermark
🇦🇹Leoben, Austria
Memorial Sloan Kettering Cancer Center (MSKCC)
🇺🇸New York, New York, United States
Meduni Wien, Univ. Klinik für Innere Medizin I
🇦🇹Wien, Austria
University Multiprofile Hospital for Active Treatment Dr. Georgi Stranski, Pleven
🇧🇬Pleven, Bulgaria
Hematology Clinic Specialized Hospital for Active Treatment of Hematological Diseases, Sofia
🇧🇬Sofia, Bulgaria
Chu Amiens Picardie Site Sud
🇫🇷Amiens, France
CHU de Nice Hospital
🇫🇷Nice, France
CHU de Limoges Service Hématologie Clinique et Thérapie Cellulaire
🇫🇷Limoges, France
Centre Hospitalier Lyon Sud
🇫🇷Pierre-Bénite, France
University Hospital Halle (Saale), Department of Internal Medicine IV - Hematology and Oncology
🇩🇪Halle, Germany
Hôpital Saint Louis
🇫🇷Paris, France
University Hospital Marburg, Department of Hematology, Oncology and Immunology
🇩🇪Marburg, Germany
Moritz Kaposi General Hospital, Department of Hematology
🇭🇺Kaposvár, Hungary
Polyclinic S. Orsola-Malpighi
🇮🇹Bologna, Italy
Fejer County St. Gyorgy University Teaching Hospital, Department of Internal Medicine III, Hematology
🇭🇺Székesfehérvár, Hungary
Careggi University Hospital
🇮🇹Florence, Italy
ASST Spedali Civili di Brescia
🇮🇹Brescia, Italy
Hospital of Ravenna, Operative Unit of Hematology
🇮🇹Ravenna, Italy
Hospital Casa Sollievo della Sofferenza, Department of Oncology and Hematology, Division of Hematology
🇮🇹Foggia, Italy
Jan Biziel University Hospital #2 in Bydgoszcz, Department of Hematology
🇵🇱Bydgoszcz, Poland
Frederic Chopin Provincial Teaching Hospital No. 1 in Rzeszow, Department of Hematology
🇵🇱Rzeszów, Poland
Clinical Center of Vojvodina
🇷🇸Novi Sad, Serbia
Hematologia Clínica
🇪🇸Barcelona, Spain
University Clinical Hospital of Salamanca, Department of Hematology
🇪🇸Salamanca, Spain