Study of TL-895 Combined With Ruxolitinib in JAKi Treatment-Naïve MF Subjects and Subjects With MF Who Have a Suboptimal Response to Ruxolitinib

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 have MF (PMF, Post PV MF, or Post ET MF) who are JAKi treatment-naïve or those who have a suboptimal response to ruxolitinib.

Official Title
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An Open-Label, Multicenter, Phase 1b/2 Study of the Safety and Efficacy of TL-895 Combined With Ruxolitinib in Janus-associated Kinase Inhibitor (JAKi) Treatment-Naïve Myelofibrosis (MF) Subjects and Subjects With MF Who Have a Suboptimal Response to Ruxolitinib

Conditions
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Myelofibrosis, Primary Myelofibrosis, Post-PV MF, Post-ET Myelofibrosis

Intervention / Treatment
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* Drug: TL-895
* Drug: Ruxolitinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects with suboptimal response to ruxolitinib: Treatment with at a stable dose of ruxolitinib prior to study entry Subjects ≥ 18 years of age and able to provide informed consent. Confirmed diagnosis of PMF, post-PV MF, or post-ET MF, as assessed by treating physician according to the World Health Organization (WHO) criteria High-risk, intermediate-2 risk, or intermediate-1 risk, defined by Dynamic International Prognostic System (DIPSS) Palpable spleen measuring ≥ 5 cm below the left lower coastal margin (LLCM) or spleen volume of ≥ 450 cm3 by MRI or CT scan assessment Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2 Adequate hematological, hepatic, & renal function. Exclusion Criteria: Treatment-naive subjects: Prior treatment with any JAKi Subjects with suboptimal response to ruxolitinib: Documented disease progression while on ruxolitinib treatment All subjects: Prior splenectomy or splenic irradiation within 24 weeks prior to first dose of study treatment Prior treatment with a BTK or BMX inhibitor

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: Non-Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Phase 1b - Dose Escalation Design Phase 2 - Dose Expansion
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase 1b - Dose Level 1<br>150 mg of TL-895 will be administered orally, twice daily (BID) continuously starting on Day 1 in a 28-day cycle combined with the subject's pre-study stable dose of ruxolitinib. | Drug: TL-895<br>* TL-895 is an experimental tyrosine kinase inhibitor anticancer drug taken by mouth.<br>Drug: Ruxolitinib<br>* Ruxolitinib is an FDA-approved janus kinase inhibitor anticancer drug taken by mouth.<br>* Other names: Jakavi;|
| Experimental: Phase 1b - Dose Level 2<br>300 mg of TL-895 will be administered orally, twice daily (BID) continuously starting on Day 1 in a 28-day cycle combined with the subject's pre-study stable dose of ruxolitinib. | Drug: TL-895<br>* TL-895 is an experimental tyrosine kinase inhibitor anticancer drug taken by mouth.<br>Drug: Ruxolitinib<br>* Ruxolitinib is an FDA-approved janus kinase inhibitor anticancer drug taken by mouth.<br>* Other names: Jakavi;|
| Experimental: Phase 1b - Dose Level 3<br>450 mg of TL-895 will be administered orally, twice daily (BID) continuously starting on Day 1 in a 28-day cycle combined with the subject's pre-study stable dose of ruxolitinib. | Drug: TL-895<br>* TL-895 is an experimental tyrosine kinase inhibitor anticancer drug taken by mouth.<br>Drug: Ruxolitinib<br>* Ruxolitinib is an FDA-approved janus kinase inhibitor anticancer drug taken by mouth.<br>* Other names: Jakavi;|
| Experimental: Phase 2 - Cohort 1 JAKi treatment-naïve MF<br>The RP2D of TL-895 as determined in Phase 1b will be administered orally, twice daily (BID) continuously starting on Day 1 in a 28-day cycle. The dose of ruxolitinib will be based on the subject's baseline platelet count. | Drug: TL-895<br>* TL-895 is an experimental tyrosine kinase inhibitor anticancer drug taken by mouth.<br>Drug: Ruxolitinib<br>* Ruxolitinib is an FDA-approved janus kinase inhibitor anticancer drug taken by mouth.<br>* Other names: Jakavi;|
| Experimental: Phase 2 - Cohort 2 suboptimal response to Ruxolitinib<br>The RP2D of TL-895 as determined in Phase 1b will be administered orally, twice daily (BID) continuously starting on Day 1 in a 28-day cycle. The dose schedule will be the stable ruxolitinib dose schedule as the subject is currently taking prior to entry into the study. | Drug: TL-895<br>* TL-895 is an experimental tyrosine kinase inhibitor anticancer drug taken by mouth.<br>Drug: Ruxolitinib<br>* Ruxolitinib is an FDA-approved janus kinase inhibitor anticancer drug taken by mouth.<br>* Other names: Jakavi;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1b - Recommended Phase 2 dose of TL-895 in combination with ruxolitinib | Dose-limiting toxicities (DLTs) will be used to establish the maximum-tolerated dose (MTD) of TL-895 in combination with ruxolitinib. The safety review committee (SRC) will determine the RP2D based on safety and efficacy data of the combination of TL-895 and ruxolitinib. | 28 days | 
| Phase 2 - Spleen Volume Reduction (SVR) at Week 24 | The proportion of subjects achieving SVR of ≥35% at Week 24 by magnetic resonance imaging (MRI) or computed tomography (CT) scan. | 24 Weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1b - Spleen Volume Reduction (SVR) at Week 24 | The proportion of subjects achieving ≥35% SVR at Week 24 by MRI or CT scan. | 24 Weeks | 
| Phase 1b - TSS reduction at Week 24 | The proportion of subjects achieving ≥50% reduction in TSS at Week 24 by Myelofibrosis Symptom Assessment Form (MFSAF) v4.0. | 24 Weeks | 
| Phase 2 - TSS reduction at Week 24 | The proportion of subjects achieving ≥50% reduction in TSS at Week 24 by MFSAF v4.0. | 24 Weeks | 
| DOR Spleen | Time from initial SVR of ≥ 35% by MRI/CT until the first occurrence of disease progression or death | 48 Months | 
| Progression Free Survival | Time from first dose to progression or death from any cause. | 48 Month | 
| Overall Survival | Time from first dose to death from any cause | 48 Months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Myelofibrosis