Janus associated Kinase Inhibitor (JAKi) Treatment-Naïve Myelofibrosis (MF) Subjects and Subjects with MF who have a Suboptimal Response to Ruxolitinib 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: Phase 1b and Phase 2 Cohort 2 1. Treatment with ruxolitinib for = 12 weeks prior to study entry, and on a stable dose of ruxolitinib in the 8 weeks prior to Sponsor approval of the enrollment form • A stable dose is defined as a ruxolitinib dose that has not required a treatment hold or dose adjustment • Subjects must be taking a stable dose of ruxolitinib of at least 5 mg BID or 10 mg QD Phase 1b and Phase 2 (both cohorts) 2. Subjects = 18 years of age and able to provide informed consent. 3. Confirmed diagnosis of PMF, post-PV MF, or post-ET MF, as assessed by treating physician according to the World Health Organization (WHO) criteria 4. High-risk, intermediate-2 risk, or intermediate-1 risk, defined by Dynamic International Prognostic System (DIPSS) 5. Palpable spleen measuring = 5 cm below the left lower coastal margin (LLCM) or spleen volume of = 450 cm3 by MRI or CT scan assessment 6. MF symptoms as defined by having at least 2 symptoms with a score of at least 1 each on the MFSAF v4.0 7. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2 8. Adequate hematological function within 7 days (Phase 1b) or 28 days (Phase 2) prior to first dose, independent of growth factor support for at least 7 days, with the exception of pegylated Granulocyte Colony-Stimulating Factor (G CSF) which requires at least 14 days, defined as: • Absolute neutrophil count (ANC) = 1.0 × 109/L • Platelet count = 50 × 109/L 9. Adequate hepatic function within 7 days (Phase 1b) or 28 days (Phase 2) prior to first dose of study treatment defined as: • Total serum bilirubin = 2.0 x upper limit of normal (ULN). Subjects with known Gilbert’s syndrome or disease-related hemolysis must have a total bilirubin =3.0 × ULN • Aspartate aminotransferase (AST) = 2.5 × ULN, and alanine aminotransferase (ALT) = 2.5 × ULN. 10. Adequate renal function within 7 days (Phase 1b) or 28 days (Phase 2) defined as an estimated creatinine clearance = 30 mL/min according to Cockcroft Gault. 11. 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 contraception for 1 month and 1 week and male subjects must continue to use contraception for 3 months and 1 week. A woman is considered of childbearing potential (i.e., fertile, following menarche and until becoming postmenopausal) unless permanently sterile (refer to Appendix 2 of the protocol for additional details). Note: Marketed drugs administered concomitantly in this study may have different contraception requirements, including required duration of contraception use. The contraception requirements in the local prescribing guidelines must be followed for all concomitant drugs administered in this study. Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 18 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 52
Exclusion criteria
Exclusion criteria: Phase 2 Cohort 1 1. Prior treatment with any JAKi Phase 1b and Phase 2 Cohort 2 2. Documented disease progression while on ruxolitinib treatment, defined as any of the following: • =100% increase in palpable distance, below the LLCM from nadir for baseline splenomegaly of 5 to 10 cm while on ruxolitinib, or • = 50% increase in palpable distance, below the LLCM from nadir, for baseline splenomegaly of >10 cm while on ruxolitinib, or • =25% increase from nadir in spleen volume by radiographic imaging while on ruxolitinib treatment, or • Regrowth after achieving complete response Phase 1b and Phase 2 (both cohorts) 3. Prior splenectomy or splenic irradiation within 24 weeks prior to first dose of study treatment 4. Prior treatment with a BTK or BMX inhibitor 5. Chemotherapy, cytoreductive therapy, immune therapy, cytokine therapy or any investigational therapy within 28 days prior to first dose of study treatment. Subjects on hydroxyurea therapy may continue treatment until 1 day prior to the first dose of study drug. 6. Active participation in other therapeutic clinical trials including supportive care trials 7. Subjects with a history of bleeding diathesis; major hemorrhage or intracranial hemorrhage within 6 months prior to first dose of study treatment 8. Major surgery or planned major surgery within 28 days prior to first dose of study treatment. 9. History of major organ transplant 10. 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 11. 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; ventricular arrhythmia; history of myocardial infarction within 3 months 12. Grade 2 or higher QTc prolongation (> 480 milliseconds [ms] per National Cancer Institute Common Terminology of Adverse Events [v 5.0]) 13. Clinically significant bacterial, mycobacterial, fungal, parasitic, or viral infection. Intravenous (IV) antibiotics within 2 weeks prior to first dose of study treatment. 14. Subjects with active hepatitis B virus (HBV) or hepatitis C virus (HCV) 15. Known infection with HIV 16. Known hypersensitivity or contraindications to the study drugs or any of their excipients. 17. History of another 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 non-metastatic prostate cancer with normal prostate-specific antigen, in situ breast carcinoma after complete surgical resection or superficial transitional cell bladder carcinoma 18. Requires treatment with proton-pump inhibitors (e.g., omeprazole, esomeprazole, lansoprazole, dexlansoprazole, rabeprazole, or pantoprazole). Subjects receiving proton-pump inhibitors who switch to H2-receptor antagonists or antacids are eligible for enrollment in this study provided the proton pump inhibitor is discontinued at least 3 days prior to first dose of study drug. 19. Women who are pregnant or breastfeeding. 20. Medical condition, serious intercurrent illness, psychiatric condition, or other circumstance (i.e., committed to an institution by judicial or administrative authority) that, in the Investigator's judgment, could jeopardize the subject's safety
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: Phase 1b: To determine the recommended Phase 2 dose (RP2D) of TL-895 in combination with ruxolitinib. Phase 2: To determine the spleen reduction volume (SVR) rate at Week 24.;Secondary Objective: Phase 1b: To determine: the spleen volume reduction (SVR) rate at Week 24 the improvement in Total Symptom Score (TSS) at Week 24 spleen response the duration of spleen response (DoR-spleen) the rate of conversion from Red Blood Cell (RBC) transfusion dependent to independent the clinical response rate: complete response (CR) and partial response (PR) the overall survival (OS) rate progression-free survival (PFS) To characterize the pharmacokinetic (PK) profile of TL-895 and ruxolitinib To determine the safety and tolerability of TL 895 Phase 2: To determine the improvement in TSS at Week 24 To determine spleen response To determine the DoR-spleen To determine the rate of conversion from RBC transfusion dependent to independent To determine the clinical response rate: CR and PR To determine the OS rate To determine PFS To monitor the PK of TL 895 and ruxolitinib To determine the safety and tolerability of TL 895 ;Primary end point(s): Phase 1b: 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. Phase 2: The proportion of subjects achieving SVR of =35% at Week 24 by MRI or CT scan (central review) ;Timepoint(s) of evaluation of this end point: Phase 1b: End of Phase Phase 2: Week 24 | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Phase 1b: The proportion of subjects achieving =35% SVR at Week 24 by magnetic resonance imaging (MRI) or computed tomography (CT) scan (central review) The proportion of subjects achieving =50% reduction in TSS at Week 24 by Myelofibrosis Symptom Assessment Form (MFSAF) v4.0 The proportion of subjects achieving =35% SVR at any time point from Baseline while on study, as assessed by MRI (or by CT scan for applicable subjects) Time from initial SVR of = 35% by MRI/CT (central review) until the first occurrence of disease progression or death The proportion of RBC dependent subjects achieving RBC transfusion independence at Week 24 The proportion of subjects with CR and PR at any time point, from Baseline while on study, defined according to International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) and modified European LeukemiaNet (ELN) criteria OS is defined as the time from first dose to death from any cause PFS is the time from first dose date to: • Disease progression (=25% increase in spleen volume) or • Leukemic transformation (bone marrow blasts =20% or peripheral blood blasts =20% associated with an absolute blast count of at least 1 x 10^9/L that lasts for at least 2 weeks) or • Death from any cause TL-895 and ruxolitinib PK parameters, including but not limited to: • Maximum observed concentration (Cmax) • Area under the plasma concentration-time curve (AUC) • Time of maximum plasma concentration (Tmax) Analyses of the safety endpoints will include the following measurements or assessments: physical examinations, laboratory tests, adverse events (AEs), serious AEs (SAEs), electrocardiograms (ECGs), and vital signs Phase 2: The proportion of subjects achieving =50% reduction in TSS at Week 24 by MFSAF v4.0 The proportion of subjects achieving =35% SVR at any time point from Baseline while on study, as assessed by MRI (or by CT scan for applicable subjects) Time from initial SVR of = 35% by MRI/CT (ce | — |
Countries
France, Germany, Hungary, Israel, Italy, Poland, Spain, United Kingdom, United States
Contacts
Public ContactVP, Regulatory Affairs
Telios Pharma, Inc.
Outcome results
None listed