Relapsed/Refractory Myelofibrosis, Janus Kinase Inhibitor Intolerant Myelofibrosis, Janus Kinase Inhibitor Treatment Ineligible Myelofibrosis MedDRA version: 20.0 Level: PT Classification code 10028537 Term: Myelofibrosis System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Conditions
Sponsors
Telios Pharma, Inc.
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: The inclusion criteria mentioned below are applicable to all cohorts unless otherwise specified. 1. Adults =18 years of age who are able to provide informed consent 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. High-risk, intermediate-2 risk, or intermediate-1 risk, defined by Dynamic International Prognostic System (DIPSS) 4. Cohort 1 (relapsed/refractory MF) (closed for enrolment) - Must have relapsed or refractory MF following JAKi treatment. Relapsed MF is defined as 1 of the following: a. Spleen volume increase by =25% by radiographic imaging from nadir b. A =100% increase in palpable distance below the left lower coastal margin (LLCM), for baseline splenomegaly of 5 to 10 cm c. A =50% increase in palpable distance below the LLCM from nadir, for baseline splenomegaly of >10 cm d. Regrowth after achieving complete response Refractory MF is defined as 1 of the following after receiving =12 weeks of JAKi treatment: e. upper limit of normal (ULN) then subjects are eligible if the direct bilirubin is =2.0 x ULN b. Aspartate aminotransferase (AST) =2.5 × ULN, and alanine aminotransferase (ALT) =2.5 × ULN. 12. Adequate renal function defined by an estimated creatinine clearance = 30 mL/min according Cockcroft Gault 13. Female subjects of childbearing potential and their male partners, or male subjects who have female partners of childbearing potential, must both use a highly effective contraception method during the study. In addition, after the last dose of study drug, female subjects must continue to use a highly effective metho
Exclusion criteria
Exclusion criteria: 1. Prior treatment with any BTK or BMX inhibitors 2. Prior treatment with JAKi within 28 days prior to first study treatment. 3. Prior splenectomy or splenic irradiation within 24 weeks prior to first dose of study treatment 4. Prior therapy with: a. Anticancer treatment with chemotherapy, immunomodulating therapy, biologic therapy, radiation therapy, or with any other anticancer therapy within 28 days prior to first dose of study treatment with the exception of prednisone. Prednisone 5 mg QD may be administered from Day 28 until 1 day prior to Cycle 1 Day 1. Subjects on a stable dose of erythroid growth factor support for at least 3 months prior to Cycle 1 Day 1 are eligible for the study. b. Any investigational agent within 28 days or 5 half-lives, whichever is longer, prior to first dose of study treatment. Participation in observational study is permitted. c. Allogeneic stem cell transplant within the last 6 months, or active graft versus host disease following allogeneic transplant, or autologous stem cell transplant within 3 months prior to first dose of study treatment d. For Cohorts 3 and 4: Requiring or receiving anticoagulation within 7 days of first dose of study treatment. Subjects on anti-platelet therapy can be allowed on study after discussion with and approval by the medical monitor. 5. Subjects with a history of bleeding diathesis or major hemorrhage (unrelated to trauma) within 6 months prior to first dose of study treatment. 6. Received major surgical intervention within 28 days prior to first dose of study treatment, or history of major organ transplant 7. Subjects with indwelling surgical drains (eg, peritoneal, CNS, or pleural) 8. Subjects with active fever (temperature higher than 38.2°C [100.8°F]) within 14 days prior to the first dose of study treatment 9. 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 10. 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 11. Grade 2 or higher QTc prolongation (> 480 milliseconds per National Cancer Institute Common Terminology of Adverse Events [v 5.0]) 12. Subjects with uncontrolled bacterial, fungal, parasitic, tuberculosis (TB), or viral infection. Subjects with acute bacterial infections requiring antibiotic use should not enroll until the infection is stable in the judgement of the treating physician; these subjects may be on antibiotics at time of screening. 13. Subjects with active hepatitis B virus (HBV) or hepatitis C virus (HCV) 14. Subjects with known history of human immunodeficiency virus (HIV) 15. 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 16. Requires treatment with proton-pump inhibitors (e.g., omeprazole, esomeprazole, lansoprazole, dexlansoprazole, rabeprazole, or pantoprazole). Subjects receiv
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: Part A: To determine the recommended phase 2 dose and schedule of TL-895 in each cohort. Part B: Improvement in Total Symptom Score at Week 24;Secondary Objective: Part A: To determine the spleen volume reduction rate of each arm of Cohorts 1, 2 and 3 at Week 24 Improvement in Total Symptom Score in each arm of Cohorts 1, 2 and 3 at Week 24 To characterize the pharmacokinetic profile of TL-895 Part B: To determine the platelet response rate To determine the duration of platelet response To determine the incidence of platelet transfusion To determine the incidence of bleeding events To determine the spleen volume reduction rate at Week 24 To determine the rate of conversion from red blood cell transfusion dependent to independent To determine the rate of red blood cell transfusion independence at Week 24 To determine the duration of response To determine the progression-free survival To determine the overall survival To evaluate safety and tolerability of TL-895 To monitor the pharmacokinetics of TL 895;Primary end point(s): Part A: The safety review committee (SRC) will determine the RP2D and schedule for Cohorts 1, 2 and 3 based on safety and tolerability data obtained from each arm of that cohort Part B: The proportion of subjects achieving =35% spleen volume reduction at Week 24 by MRI or CT scan (central review);Timepoint(s) of evaluation of this end point: Part A: End of Cohort Part B: Week 24 | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Part A: The proportion of subjects achieving =35% spleen volume reduction at Week 24 by magnetic resonance imaging or computed tomography scan (central review) The proportion of subjects achieving =50% reduction in Total Symptom Score at Week 24 by Myelofibrosis Symptom Assessment Form TL-895 pharmacokinetic parameters (including but not limited to, predose concentration, Observed concentration 2 hours post dose, Cmax, Tmax, AUC) Part B: The proportion of subjects achieving a platelet response defined as per modified International Working Group – Myeloproliferative Neoplasms Research and Treatment (IWG-MRT 2006) criteria (= 50% increase in platelet count with an absolute platelet count of = 50 x 109/L, both lasting for at least 8 weeks, independent of any platelet transfusion) The proportion of subjects achieving a platelet response defined as per IWG-MRT 2006 criteria (= 100% increase in platelet count with an absolute platelet count of = 50 x 109/L, both lasting for at least 8 weeks, independent of any platelet transfusion; Tefferi 2006) The duration of platelet response in subjects achieving a platelet response defined as per the IWG-MRT 2006 and modified IWG-MRT 2006 criteria The proportion of subjects receiving platelet transfusions while on study treatment The proportion of subjects with major bleeding events (ie, any hemorrhagic event that was an SAE, grade 3 or higher in severity, or that was a central nervous system hemorrhage of any severity grade) The proportion of subjects achieving =35% SVR at Week 24 by MRI or CT scan (central review) The proportion of RBC dependent subjects achieving red blood cell transfusion independence at Week 24 The proportion of subjects with red blood cell transfusion independence at Week 24 Time from initial response to progression Time from the first dose to progression or death from any cause Time from the first dose to death from any cause Analyses of the safety and tolerability endpoints will in | — |
Countries
Australia, Belgium, Brazil, Bulgaria, Croatia, France, Germany, Hungary, Italy, Korea, Republic of, Poland, Spain, Taiwan, United States
Contacts
Public ContactDirector, Regulatory Affairs
Telios Pharma, Inc.
Outcome results
None listed