KRT-232 in Combination With TL-895 for the Treatment of R/R MF and KRT-232 for the Treatment of JAKi Intolerant MF

Phase 1

Recruiting

• Conditions: Primary Myelofibrosis; Post-ET Myelofibrosis; Myelofibrosis; Post-PV MF
• Interventions: Drug: KRT-232; Drug: TL-895

• 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.

Study Timeline

• Study Start: 2020-11-17
• Study First Submitted: 2020-11-17
• Study First Submitted QC: 2020-11-17
• Study First Posted: 2020-11-23
• Status Verified: 2022-05
• Last Update Submitted: 2022-05-05
• Last Update Posted: 2022-05-09
• Primary Completion: 2022-05-11
• Study Completion: 2025-07-24

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 116

Inclusion Criteria

• 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

Exclusion Criteria

• 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)

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

Memorial Sloan Kettering Cancer Center (MSKCC); 🇺🇸 New York, New York, United States

LKH Hochsteiermark; 🇦🇹 Leoben, Austria

Meduni Wien, Univ. Klinik für Innere Medizin I; 🇦🇹 Wien, Austria

University Multiprofile Hospital for Active Treatment Dr. Georgi Stranski, Pleven; 🇧🇬 Pleven, Bulgaria

University Multiprofile Hospital for Active Treatment Dr. Georgi Plovdiv; 🇧🇬 Plovdiv, Bulgaria

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