Study of TL-895 in Subjects With Myelofibrosis

Study Overview
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Brief Summary
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This study evaluates TL-895, a potent, orally-available and highly selective irreversible tyrosine kinase inhibitor for the treatment of Myelofibrosis. Participants must be relapsed/refractory (e.g., having failed prior therapy), intolerant, or ineligible to receive JAKi treatment.

Official Title
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A Phase 2, Open-label, Multicenter Study of TL-895 in Subjects With Relapsed/Refractory Myelofibrosis, Janus Kinase Inhibitor Intolerant Myelofibrosis and Janus Kinase Inhibitor Treatment Ineligible Myelofibrosis

Conditions
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Myelofibrosis

Intervention / Treatment
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* Drug: TL-895


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adults ≥18 years of age Confirmed diagnosis of PMF, post-PV MF, or post-ET MF, as assessed by treating physician according to the World Health Organization (WHO) criteria Palpable spleen measuring ≥5 cm below the LLCM or spleen volume of ≥450 cm³ by MRI or CT scan assessment Eastern Cooperative Oncology Group (ECOG) performance status of ≤2 Adequate hematologic, hepatic, and renal functions Exclusion Criteria: Prior treatment with any BTK or BMX inhibitors Cohorts 1 and 2 - Prior treatment with JAKi within 21 days of the Screening MRI/CT scan. Subjects in Cohort 3 must not have received JAKi Prior splenectomy or splenic irradiation within 24 weeks prior to first dose of study treatment

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1a, Relapsed/Refractory Myelofibrosis<br>150 mg of TL-895 will be administered orally, twice daily (BID) continuously starting on Day 1 in a 28-day cycle. | Drug: TL-895<br>* TL-895 is an experimental tyrosine kinase inhibitor anticancer drug taken by mouth.<br>|
| Experimental: Cohort 1b, Relapsed/Refractory Myelofibrosis<br>300 mg of TL-895 will be administered orally, once daily (QD) continuously starting on Day 1 in a 28-day cycle. | Drug: TL-895<br>* TL-895 is an experimental tyrosine kinase inhibitor anticancer drug taken by mouth.<br>|
| Experimental: Cohort 1c, Relapsed/Refractory Myelofibrosis<br>300 mg of TL-895 will be administered orally, twice daily (BID) continuously starting on Day 1 in a 28-day cycle. | Drug: TL-895<br>* TL-895 is an experimental tyrosine kinase inhibitor anticancer drug taken by mouth.<br>|
| Experimental: Cohort 1d, Relapsed/Refractory Myelofibrosis<br>450 mg of TL-895 will be administered orally, twice daily (BID) continuously starting on Day 1 in a 28-day cycle. | Drug: TL-895<br>* TL-895 is an experimental tyrosine kinase inhibitor anticancer drug taken by mouth.<br>|
| Experimental: Cohort 2a, JAKi Intolerant Myelofibrosis<br>150 mg of TL-895 will be administered orally, twice daily (BID) continuously starting on Day 1 in a 28-day cycle. | Drug: TL-895<br>* TL-895 is an experimental tyrosine kinase inhibitor anticancer drug taken by mouth.<br>|
| Experimental: Cohort 2b, JAKi Intolerant Myelofibrosis<br>300 mg of TL-895 will be administered orally, once daily (QD) continuously starting on Day 1 in a 28-day cycle. | Drug: TL-895<br>* TL-895 is an experimental tyrosine kinase inhibitor anticancer drug taken by mouth.<br>|
| Experimental: Cohort 3a, JAKi Ineligible Myelofibrosis<br>150 mg of TL-895 will be administered orally, twice daily (BID) continuously starting on Day 1 in a 28-day cycle. | Drug: TL-895<br>* TL-895 is an experimental tyrosine kinase inhibitor anticancer drug taken by mouth.<br>|
| Experimental: Cohort 3b, JAKi Ineligible Myelofibrosis<br>300 mg of TL-895 will be administered orally, once daily (QD) continuously starting on Day 1 in a 28-day cycle. | Drug: TL-895<br>* TL-895 is an experimental tyrosine kinase inhibitor anticancer drug taken by mouth.<br>|
| Experimental: Cohort 1 Expansion, Relapsed/Refractory Myelofibrosis<br>TL-895 administered orally at RP2D and schedule | Drug: TL-895<br>* TL-895 is an experimental tyrosine kinase inhibitor anticancer drug taken by mouth.<br>|
| Experimental: Cohort 3 Expansion, JAKi Ineligible Myelofibrosis<br>TL-895 administered orally at RP2D and schedule | Drug: TL-895<br>* TL-895 is an experimental tyrosine kinase inhibitor anticancer drug taken by mouth.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Primary Objective, Part A: To determine the RP2D of TL-895 in each cohort. | The safety review committee (SRC) will determine the RP2D for Cohorts 1, 2 and 3 based on safety and tolerability data obtained from each arm of that cohort. | 9 months | 
| Primary Objective, Part B: To determine the spleen volume reduction (SVR) rate at Week 24. | The proportion of subjects achieving ≥35% SVR at Week 24 by MRI or CT scan (central review). | Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Key Secondary Objective: Improvement in Total Symptom Score at Week 24. | The proportion of subjects achieving ≥50% reduction in Total Symptom Score at Week 24 by MFSAF v4.0. | Week 24 | 
| Key Secondary Objective: To determine the duration of response (DOR). | Time from initial response to progression. | 44 months | 
| Key Secondary Objective: To determine the progression-free survival (PFS). | Time from the first dose to progression or death from any cause. | 44 months | 
| Key Secondary Objective: To determine the duration overall response (OS). | Time from the first dose to death of any cause. | 44 months |