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    Summary
    EudraCT Number:2020-002393-27
    Sponsor's Protocol Code Number:TL-895-201
    National Competent Authority:France - ANSM
    Clinical Trial Type:EEA CTA
    Trial Status:Trial now transitioned
    Date on which this record was first entered in the EudraCT database:2020-11-09
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedFrance - ANSM
    A.2EudraCT number2020-002393-27
    A.3Full title of the trial
    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
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Study of TL-895 in Myelofibrosis
    A.4.1Sponsor's protocol code numberTL-895-201
    A.5.4Other Identifiers
    Name:INDNumber:150807
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorTelios Pharma, Inc.
    B.1.3.4CountryUnited States
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportTelios Pharma, Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationTelios Pharma, Inc.
    B.5.2Functional name of contact pointVP, Regulatory Affairs
    B.5.3 Address:
    B.5.3.1Street Address275 Shoreline Drive
    B.5.3.2Town/ cityRedwood City
    B.5.3.3Post codeCA 94065
    B.5.3.4CountryUnited States
    B.5.6E-mailpryan@teliospharma.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.2Product code TL-895
    D.3.4Pharmaceutical form Film-coated tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNTL-895
    D.3.9.1CAS number 1415823-49-2
    D.3.9.2Current sponsor codeTL-895
    D.3.9.3Other descriptive nameM7583
    D.3.9.4EV Substance CodeSUB180031
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typerange
    D.3.10.3Concentration number50 to 300
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Relapsed/Refractory Myelofibrosis, Janus Kinase Inhibitor Intolerant Myelofibrosis, Janus Kinase Inhibitor Treatment Ineligible Myelofibrosis
    E.1.1.1Medical condition in easily understood language
    Myelofibrosis is an uncommon type of bone marrow cancer that disrupts the body's normal production of blood cells.
    E.1.1.2Therapeutic area Diseases [C] - Blood and lymphatic diseases [C15]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10028537
    E.1.2Term Myelofibrosis
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Part A: To determine the recommended phase 2 dose and schedule of TL-895 in each cohort.
    Part B: To determine the spleen volume reduction rate of Cohorts 1, 2 and 3 at Week 24
    E.2.2Secondary objectives of the trial
    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 evaluate the effect of TL-895 on BTK/BMX occupancy in peripheral blood mononuclear cells of subjects in Cohorts 1, 2 and 3
    To characterize the pharmacokinetic profile of TL-895

    Part B:
    Improvement in Total Symptom Score 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 evaluate the effect of TL-895 on BTK/BMX occupancy in peripheral blood mononuclear cells of subjects
    To monitor the pharmacokinetics of TL 895
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    The inclusion criteria mentioned below are applicable to all cohorts unless otherwise specified.
    1. Adults ≥18 years of age
    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) - 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, 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. <10% spleen volume reduction by radiographic imaging
    f. <30% decrease from baseline in spleen size by palpation

    5. Cohort 2 (JAKi intolerant MF) - Must have received JAKi treatment for at least 28 days complicated by one of the following criteria while receiving treatment:
    a. RBC transfusion requirement (≥2 units per month for 2 months)
    b. Grade ≥ 3 thrombocytopenia, anemia, hematoma, and/or hemorrhage

    6. Cohort 3 (JAKi treatment ineligible MF) - Must be ineligible for JAKi treatment defined by a platelet count of ≤50 x 109/L

    7. Palpable spleen measuring ≥5 cm below the LLCM or spleen volume of ≥450 cm3 by MRI or CT scan assessment
    8. MF symptoms as defined by having at least 2 symptoms with a score of at least 1 each on the MFSAF v4.0
    9. Eastern Cooperative Oncology Group (ECOG) performance status of ≤2
    10. Adequate hematological function independent of growth factor support for at least 7 days with the exception of pegylated granulocyte colony-stimulating factor (G-CSF) and darbepoetin which require at least 21 days, defined as:
    a. Absolute neutrophil count (ANC) ≥1.0 × 109/L
    b. Platelet count ≥75 × 109/L for Cohorts 1 and 2, and ≥25 × 109/L for Cohort 3
    11. Adequate hepatic function defined by:
    a. Total bilirubin level within normal limits (WNL); if total bilirubin is > 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 an effective contraception method during the study and continue to use contraception for 60 days after the last dose of study drug. Effective birth control for males is the use of condoms. Effective birth control for females includes (a) combined, estrogen- and progestogen-containing hormonal contraception (oral, intravaginal, transdermal); (b) intrauterine device combined with a barrier method; (c) intrauterine hormone-releasing system combined with a barrier method; (d) bilateral tubal occlusion/ligation; (e) vasectomized partner; (f) sexual abstinence when this is in line with the preferred and usual lifestyle of the subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception.
    E.4Principal exclusion criteria
    1. Prior treatment with any BTK, BMX, BCR-ABL, phosphoinositide 3-kinase (PI3K), mammalian target of rapamycin (mTOR), bromodomain and extraterminal domain (BET) or spleen tyrosine kinase (Syk) inhibitors
    2. 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
    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 (except for JAKi [see exclusion #2]). Hydroxyurea may be taken within 1 day of the first dose of study treatment.
    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
    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. 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
    8. 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
    9. Grade 2 or higher QTc prolongation (> 480 milliseconds per National Cancer Institute Common Terminology of Adverse Events [v 5.0])
    10. Subjects with uncontrolled bacterial, fungal, parasitic, 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.
    11. Subjects with active hepatitis B virus (HBV) or hepatitis C virus (HCV)
    12. Subjects with known history of human immunodeficiency virus (HIV)
    13. 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
    14. 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.
    15. Women who are pregnant or breastfeeding.
    E.5 End points
    E.5.1Primary 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)
    E.5.1.1Timepoint(s) of evaluation of this end point
    Part A: End of Cohort
    Part B: Week 24
    E.5.2Secondary 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
    BTK/BMX occupancy in peripheral blood mononuclear cells
    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 ≥50% reduction in Total Symptom Score at Week 24 by Myelofibrosis Symptom Assessment Form
    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 include the following measurements or assessments - Incidence, nature, the severity of treatment-emergent adverse events and deaths, including the cause of death, from Screening up to the End of Treatment visit. Clinical laboratory measurements, electrocardiogram measures, vital signs, Eastern Cooperative Oncology Group performance status from Screening up to the End of Treatment visit.
    BTK/BMX occupancy in peripheral blood mononuclear cells
    TL-895 pharmacokinetics will be monitored with sparse samples collected on Cycle 1 Day 1 and Cycle 2 Day 1 at pre-dose and 2 hours post-dose
    E.5.2.1Timepoint(s) of evaluation of this end point
    Week 24 or End of Treatment visit
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised No
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA40
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Australia
    Belgium
    Brazil
    Bulgaria
    France
    Germany
    Hungary
    Italy
    Korea, Republic of
    Poland
    Romania
    Spain
    United Kingdom
    United States
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months1
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months4
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 40
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 88
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 65
    F.4.2.2In the whole clinical trial 128
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    Subjects will be treated until disease progression, unacceptable toxicity, death or withdrawal of consent. For disease progression, unacceptable toxicity, or withdrawal of consent, subject would move on to standard care based on local practices.
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2020-12-31
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2021-02-23
    P. End of Trial
    P.End of Trial StatusTrial now transitioned
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