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    Summary
    EudraCT Number:2020-002392-35
    Sponsor's Protocol Code Number:KRT-232-113
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2021-06-08
    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 ConcernedItaly - Italian Medicines Agency
    A.2EudraCT number2020-002392-35
    A.3Full title of the trial
    An Open-Label, Multicenter, Phase 1b/2 Study of the Safety and Efficacy of KRT-232 with TL-895 in Subjects with Relapsed/Refractory Myelofibrosis and of KRT-232 in Janus-associated Kinase Inhibitor-Intolerant Myelofibrosis
    Studio multicentrico in aperto di fase 1b/2 su sicurezza ed efficacia di KRT-232 con TL 895 in soggetti affetti da mielofibrosi recidivante/refrattaria e di KRT 232 nella mielofibrosi intollerante agli JAK inibitori
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    An Open-Label, Multicenter Study of the Safety and Efficacy in Subjects with Relapsed/Refractory Myelofibrosis and in Janus-associated Kinase Inhibitor-Intolerant Myelofibrosis
    Studio multicentrico in aperto su sicurezza ed efficacia in soggetti affetti da mielofibrosi recidivante/refrattaria e nella mielofibrosi intollerante agli JAK inibitori
    A.3.2Name or abbreviated title of the trial where available
    KRT-232-113
    KRT-232-113
    A.4.1Sponsor's protocol code numberKRT-232-113
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT04640532
    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 SponsorKartos Therapeutics, 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 supportKartos Therapeutics, Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationKartos Therapeutics, Inc.
    B.5.2Functional name of contact pointClinical Operations Lead
    B.5.3 Address:
    B.5.3.1Street Address275 Shoreline Drive
    B.5.3.2Town/ cityRedwood City, CA
    B.5.3.3Post code94065
    B.5.3.4CountryUnited States
    B.5.4Telephone number+14086914113
    B.5.6E-mailidea@kartosthera.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.3.1Product nameTL-895
    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.3.9.1CAS number 1415823-49-2
    D.3.9.2Current sponsor codeTL-895
    D.3.9.3Other descriptive nameTL-895
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number50
    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 Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    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.IMP: 2
    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 Yes
    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.3.1Product nameLoperamide
    D.3.2Product code [N/A]
    D.3.4Pharmaceutical form 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 INNLOPERAMIDE CLORIDRATO
    D.3.9.1CAS number 53179-11-6
    D.3.9.2Current sponsor codeN/A
    D.3.9.4EV Substance CodeSUB178510
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number2
    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 Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    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.IMP: 3
    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 Yes
    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.3.1Product nameOndansetron
    D.3.2Product code [N/A]
    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 INNONDANSETRON
    D.3.9.1CAS number 99614-02-5
    D.3.9.2Current sponsor codeN/A
    D.3.9.4EV Substance CodeSUB46120
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number8
    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 Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    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.IMP: 4
    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.3.1Product nameTL-895
    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.3.9.1CAS number 1415823-49-2
    D.3.9.2Current sponsor codeTL-895
    D.3.9.3Other descriptive nameTL-895
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number300
    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 Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    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.IMP: 5
    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.3.1Product nameKRT-232
    D.3.2Product code [KRT-232]
    D.3.4Pharmaceutical form 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.3.9.1CAS number 1352066-68-2
    D.3.9.2Current sponsor codeKRT-232
    D.3.9.3Other descriptive nameAMG 232
    D.3.9.4EV Substance CodeSUB123933
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number15
    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 Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    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.IMP: 6
    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.3.1Product nameKRT-232
    D.3.2Product code [KRT-232]
    D.3.4Pharmaceutical form 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.3.9.1CAS number 1352066-68-2
    D.3.9.2Current sponsor codeKRT-232
    D.3.9.3Other descriptive nameAMG 232
    D.3.9.4EV Substance CodeSUB123933
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number60
    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 Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    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 and Janus-associated Kinase Inhibitor-Intolerant Myelofibrosis
    Mielofibrosi recidivante/refrattaria e mielofibrosi intollerante agli JAK inibitori
    E.1.1.1Medical condition in easily understood language
    A disorder of the bone marrow
    Una malattia del midollo osseo
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    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 No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Phase 1b (Cohort 1 and Cohort 2)
    To determine the MTD/MAD and RP2D of TL-895 in combination with KRT-232 in subjects with R/R MF (Cohort 1 and Cohort 2)

    Phase 2 (Cohort 1, Cohort 2, and Cohort 3)
    To determine the spleen response rate for each cohort
    Fase 1b (Coorte 1 e Coorte 2)
    Stabilire la MTD/MAD e la RP2D di TL-895 in associazione a KRT-232 nei soggetti con MF R/R (coorte 1 e coorte 2)

    Fase 2 (Coorte 1, Coorte 2, Coorte 3)
    Stabilire il tasso di risposta della milza per ciascuna coorte
    E.2.2Secondary objectives of the trial
    Phase 1b (Cohort 1 and Cohort 2)
    To characterize the PK profile of TL-895 and KRT-232 combination therapy (Cohort 1 and Cohort 2)

    Phase 2 (Cohort 1, Cohort 2, and Cohort 3)
    1.To determine the change in TSS for each cohort
    2.To determine the DoR-spleen for each cohort
    3.To determine the rate of conversion from RBC transfusion dependent to RBC transfusion independent at Week 24 for each cohort
    4.To determine the rate of RBC transfusion independence at Week 24
    5.To determine the OS for each cohort
    6.To determine the PFS for each cohort
    7.To determine spleen size reduction as measured by palpation for each cohort
    8.To determine the clinical response rate at Week 24 for each cohort
    9.To determine the safety and tolerability for each cohort
    10.To characterize the PK profile of TL-895 and KRT-232 combination therapy in Cohort 1 and Cohort 2, and the PK profile of KRT-232 monotherapy in Cohort 3
    Phase 1b (Cohort 1 and Cohort 2)
    Caratterizzare il profilo farmacocinetico della terapia di associazione con TL 895 e KRT-232 (coorte 1 e coorte 2)

    Phase 2 (Cohort 1, Cohort 2, and Cohort 3)
    1. Stabilire la variazione in termini di TSS per ciascuna coorte
    2. Stabilire la DoR-milza per ciascuna coorte
    3. Stabilire il tasso di conversione dalla dipendenza dalle trasfusioni di RCB all’indipendenza da tali trasfusioni alla settimana 24 per ciascuna coorte
    4. Stabilire il tasso di indipendenza dalle trasfusioni di RBC alla settimana 24
    5. Stabilire l’OS per ciascuna coorte
    6. Stabilire la PFS per ciascuna coorte
    7. Stabilire la riduzione delle dimensioni della milza tramite palpazione per ciascuna coorte
    8. Stabilire il tasso di risposta clinica alla settimana 24 per ciascuna coorte
    9. Stabilire la sicurezza e tollerabilità per ciascuna coorte
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    For Cohort 1, Cohort 2, and Cohort 3:
    Subjects in all Cohorts must meet the following criteria in order to be eligible for the study:
    1. Adults >=18 years of age
    2. Confirmed diagnosis of primary MF, post-PV MF, or post-ET MF, as assessed by treating physician according to the World Health Organization (WHO) criteria
    3. Subjects with TP53 WT MF, defined as tumors that do not harbor deleterious alteration in TP53
    4. Palpable spleen measuring >=5 cm below the left lower costal margin or spleen volume of >=450 cm3 by MRI or CT scan assessment
    5. MF symptoms as defined by having at least 2 symptoms with a score of at least 1 each on the MFSAF v4.0
    6. High-risk, intermediate-2 risk, or intermediate-1 risk, defined by Dynamic International Prognostic System (DIPSS) and DIPSS-PLUS
    7. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2 according to ECOG performance status criteria
    8. Adequate hematological, hepatic, and renal organ function (as per protocol definition and within 28 days prior to the first dose of study treatment)
    a. Hematologic:
    i. Absolute neutrophil count (ANC) >=1.0×109/L (Note: ANC eligibility is based on values obtained in the absence of growth factors, ie, 7 days for granulocyte colony-stimulating factor (G-CSF) or 14 days for pegfilgrastim)
    ii. Platelet count >=50×109/L
    iii. Peripheral blood blast count <10%
    b. Hepatic:
    i. Total bilirubin within normal limits if total bilirubin is >upper limit of normal (ULN), then subjects are eligible if the direct bilirubin is <= 2.0×ULN
    ii. Aspartate transaminase/serum glutamic oxaloacetic transaminase and alanine transaminase/serum glutamic pyruvic transaminase <= 2.5×ULN
    c. Renal:
    i. Estimated creatinine clearance (eCcr) >=30 mL/min by Cockcroft Gault.
    9. 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. In addition, male subjects must continue to use contraception for 3 months and 1 week after the last dose of study drug and female subjects must continue to use contraception for 1 month and 1 week after the last dose of study drug. Effective birth control for males is the use of condoms.
    Effective birth control for females includes the following:
    a. Combined, estrogen and progestogen containing hormonal contraception (PO, intravaginal, or transdermal)
    b. Intrauterine device combined with a barrier method
    c. Intrauterine hormone-releasing system combined with a barrier method
    d. Bilateral tubal occlusion or ligation
    e. Vasectomized partner
    f. Sexual abstinence, when this is in line with the preferred and usual lifestyle of the subject. Periodic abstinence (eg, calendar, ovulation, symptothermal, and post-ovulation methods) and withdrawal are not acceptable methods of contraception.
    For Cohort 1 and Cohort 2 only:
    Must have R/R MF following JAK inhibitor treatment that meets either criterion (1) or (2) below:
    1. Relapsed defined by one of the following:
    a. Spleen volume increase by >=25% by radiographic imaging from nadir b. >=100% increase in palpable distance below the left lower costal margin (LLCM), for Baseline splenomegaly of 5 to 10 cm
    c. >=50% increase in palpable distance below the LLCM, for Baseline splenomegaly of >10 cm
    d. Regrowth after achieving complete response
    2. Refractory defined by one of the following after receiving >=12 weeks of JAK inhibitor treatment:
    a. <10% spleen volume reduction by radiographic imaging
    b. <30% decrease from Baseline in spleen size by palpation
    For Cohort 3 only:
    JAK inhibitor-intolerant MF subjects must meet the following criteria:
    1. Subjects must have received JAK inhibitor treatment for at least 28 days complicated by development of one of the following while receiving treatment:
    a. RBC transfusion requirement (>=2 units per month for 2 months)
    b. Grade >=3 thrombocytopenia, anemia, hematoma, and/or hemorrhage
    Per la coorte 1, la coorte 2 e la coorte 3:
    1. Adulti di età >=18 anni
    2. Diagnosi confermata di MF, MF post-PV o post-ET, in base alla valutazione del medico curante secondo i criteri dell’Organizzazione Mondiale della Sanità (OMS)
    3. Soggetti con MF TP53 WT, definita come un tumore senza alterazioni deleterie di TP53
    4. Milza palpabile di dimensioni >=5 cm sotto il margine costale inferiore sinistro o volume della milza >=450 cm3 in base alla RM o alla TC
    5. Sintomi di MF definiti dalla presenza di almeno 2 sintomi con un punteggio pari ad almeno 1 ciascuno in base al MFSAF v. 4.0
    6. Alto rischio, rischio intermedio 2 o intermedio 1, in base alla definizione del DIPSS (Dynamic International Prognostic System) e del DIPSS-PLUS
    7. Performance status da 0 a 2 secondo i criteri dell’Eastern Cooperative Oncology Group (ECOG)
    8. Adeguata funzione d’organo ematologica, epatica e renale (in base a quanto definito nel protocollo e nei 28 giorni precedenti la prima dose del trattamento dello studio)
    a. Esami ematologici:
    1. Conta assoluta dei neutrofili (ANC) >=1,0×109/L (Nota: l’eleggibilità ANC è basata sui valori ottenuti in assenza di fattori di crescita, ossia 7 giorni per il fattore stimolante la formazione di colonie di granulociti (G CSF) o 14 giorni per il pegfilgrastim)
    ii. Conta piastrinica >=50×109/L
    iii. Conta dei blasti nel sangue periferico <10%
    b. Esami epatici:
    i. Bilirubina totale entro i limiti della norma nei casi in cui la bilirubina totale è maggiore del limite superiore della norma (ULN), quindi i soggetti sono eleggibili se la bilirubina diretta è <=2,0 × ULN
    ii. Aspartato transaminasi/transaminasi glutammico-ossalacetico sierica e alanina transaminasi/transaminasi glutammico-piruvica sierica <=2,5×ULN
    c. Esami renali:
    i. Clearance della creatinina stimata (eCcr) >=30 mL/min secondo Cockcroft Gault:
    9. I soggetti di sesso femminile potenzialmente fertili e i relativi partner di sesso maschile, o i soggetti di sesso maschile con partner di sesso femminile potenzialmente fertili devono usare entrambi un metodo contraccettivo efficace per la durata dello studio. Inoltre, i soggetti di sesso maschile devono continuare a usare un metodo contraccettivo per 3 mesi e 1 settimana dopo l’ultima dose del farmaco in studio, mentre i soggetti di sesso femminile devono continuare a usare un metodo contraccettivo per 1 mese e 1 settimana dopo l’ultima dose del farmaco in studio. Un metodo di contraccezione efficace per i soggetti di sesso maschile è rappresentato dall’uso del preservativo. I metodi di contraccezione efficaci per i soggetti di sesso femminile includono i seguenti:
    a. Metodi ormonali combinati a base di estrogeni e progesterone (PO, intravaginali o transdermici)
    b. Dispositivo intrauterino associato a un metodo di barriera
    c. Sistema ormonale intrauterino associato a un metodo di barriera
    d. Chiusura o legatura bilaterale delle tube
    e. Vasectomia del partner
    f. Astinenza sessuale, quando in linea con lo stile di vita preferito e abituale del paziente. L’astinenza periodica (ad es. metodo del calendario, dell’ovulazione, sintotermico, post ovulazione) e il coito interrotto non sono metodi contraccettivi accettabili.
    Solo per la coorte 1 e la coorte 2:
    Devono avere MF R/R dopo il trattamento con un JAK inibitore che soddisfa il criterio (1) o (2) sotto riportati:
    1. Recidivante, definita da una delle seguenti condizioni:
    a. Volume della milza aumentato di >=25% in base agli esami di imaging radiografico dal nadir
    E.4Principal exclusion criteria
    For Cohort 1, Cohort 2, and Cohort 3:
    Subjects in all cohorts who meet any of the following criteria will not be eligible for the study:
    1. Treatment with a JAK inhibitor within 21 days of the Screening MRI/CT
    2. Prior MDM2 inhibitor therapy or TP53-directed therapy
    3. Prior treatment with a BTK, BMX, BCR-ABL, phosphoinositide 3-kinase (PI3k), mammalian target of rapamycin (mTOR), bromodomain and extraterminal domain (BET), histone deacetylase (HDAC), or spleen tyrosine kinase (Syk) inhibitor
    4. Major surgery, chemotherapy, immunomodulating therapy, biologic therapy, or radiation therapy within 28 days prior to the first dose of study treatment; hydroxyurea may be taken within 1 day prior to the first dose of study treatment
    5. Participation in another interventional clinical study within the past 28 days of the first dose of study treatment (participation in observational studies is permitted)
    6. Prior splenectomy
    7. Splenic irradiation within 12 weeks prior to the first dose of study treatment
    8. Prior allogeneic stem-cell transplantation or eligible for allogeneic stem cell transplantation in the opinion of the Investigator; subjects that refuse a transplant are eligible for enrollment in this study.
    9. Women who are pregnant or breastfeeding
    10. History of major organ transplant
    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; unstable ventricular arrhythmia; or psychiatric illness/social situations that would limit compliance with study requirements
    12. Subjects with active hepatitis B virus or hepatitis C virus
    13. Subjects with known history of human immunodeficiency virus (HIV)
    14. Subjects with clinically significant bacterial, fungal, parasitic, or viral infection that requires therapy. Subjects with acute bacterial infections requiring antibiotic use should delay screening/enrollment until the course of antibiotic therapy has been completed.
    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. Grade 2 or higher QTc prolongation (>480 milliseconds per National Cancer Institute Common Terminology of Adverse Events [NCI-CTCAE] version 5.0 criteria)
    17. Major hemorrhage or intracranial hemorrhage within 6 months prior to the first dose of study treatment
    18. 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 TL-895 or KRT-232
    For Cohort 1 and Cohort 2 only
    1. Requires treatment with proton-pump inhibitors (PPIs; eg, omeprazole, esomeprazole, lansoprazole, dexlansoprazole, rabeprazole, or pantoprazole). Subjects receiving PPIs who switch to H2-receptor antagonists or antacids prior to Cycle 1 Day 1 are eligible for enrollment in this study
    Per la coorte 1, la coorte 2 e la coorte 3:
    Non sono eleggibili per lo studio i soggetti in tutte le coorti che rispondono a uno dei criteri indicati di seguito:
    1. Trattamento con un JAK inibitore nei 21 giorni precedenti la RM/TC di screening
    2. Precedente terapia con un inibitore di MDM2 o terapia mirata a TP53
    3. Precedente trattamento con BTK, BMX, BCR-ABL, fosfoinositide 3-chinasi (Pi3k), bersaglio della rapamicina nei mammiferi (mTOR), proteine contenenti bromodomini e domini extraterminali (BET), istone deacetilasi (HDAC) o inibitore della tirosin-chinasi della milza (Syk)
    4. Intervento di chirurgia maggiore, chemioterapia, terapia immunomodulante, terapia biologica o radioterapia nei 28 giorni precedenti la prima dose del trattamento in studio; l’idrossiurea può essere assunta fino al giorno prima della prima dose del farmaco in studio.
    5. Partecipazione a un altro studio clinico interventistico negli ultimi 28 giorni dalla prima dose del trattamento in studio (la partecipazione a studi osservazionali è consentita)
    6. Precedente splenectomia
    7. Irradiazione splenica nelle 12 settimane precedenti la prima dose del trattamento in studio
    8. Precedente trapianto di cellule staminali allogenico o idoneità a tale trapianto secondo il parere dello sperimentatore; i soggetti che rifiutano un trapianto sono idonei all’arruolamento in questo studio.
    9. Donne in gravidanza o allattamento
    10. Anamnesi positiva per trapianto d’organo maggiore.
    11. Malattia intercorrente non controllata, tra cui a titolo di esempio: malattia cardiaca clinicamente significativa (classe III o IV secondo la New York Heart Association); insufficienza cardiaca congestizia sintomatica, angina pectoris instabile, aritmia ventricolare instabile o patologie psichiatriche/situazioni sociali che limiterebbero l’aderenza ai requisiti dello studio
    12. Soggetti con virus dell’epatite B o dell’epatite C in atto
    13. Soggetti con anamnesi nota di virus dell’immunodeficienza umana (HIV)
    14. Soggetti con infezione batterica, micotica, parassitaria o virale clinicamente significativa che richiede una terapia. I soggetti con infezioni batteriche acute che richiedano l’utilizzo di antibiotici devono rimandare lo screening/arruolamento fino al completamento del ciclo della terapia antibiotica.
    15. Altra neoplasia maligna negli ultimi 3 anni, fatta eccezione per carcinoma squamocellulare o basocellulare della cute trattato con intento curativo, carcinoma in situ della cervice, carcinoma prostatico non metastatico trattato o confinato all’organo con antigene prostatico specifico nella norma, carcinoma mammario in situ dopo completa resezione chirurgica o carcinoma della vescica a cellule transizionali superficiale
    16. Prolungamento del Qtc di grado 2 o maggiore (>480 millisecondi secondo i criteri del National Cancer Institute Common Terminology of Adverse Events [NCI-CTCAE] versione 5.0)
    17. Emorragia maggiore o intracranica nei 6 mesi precedenti la prima dose del trattamento in studio
    18. Anamnesi positiva per difficoltà di deglutizione, interventi chirurgici allo stomaco o all’intestino tenue con storia di malassorbimento o altre patologie gastrointestinali croniche o condizioni che potrebbero compromettere l’aderenza alla terapia e/o l’assorbimento di TL-895 o KRT-232
    Solo per la coorte 1 e la coorte 2
    1. Necessità di un trattamento con gli inibitori della pompa protonica (PPI; ad es. omeprazolo, esomeprazolo, lansoprazolo, dexlasoprazolo, rabeprazolo o pantoprazolo). I soggetti che assumono i PPI e che passano agli antagonisti di recettori H2 o agli antiacidi prima del ciclo 1 giorno 1 possono partecipare a questo studio
    E.5 End points
    E.5.1Primary end point(s)
    Phase 1b (Cohort 1 and Cohort 2)
    DLTs will be used to establish the MTD. The SRC will determine the RP2D based on safety data from the combination of TL-895 and KRT-232.
    Phase 2 (Cohort 1, Cohort 2, and Cohort 3)
    The proportion of subjects achieving a >=35% spleen volume reduction from Baseline to Week 24, as assessed by MRI or CT scan by central review.
    Fase 1b (Coorte 1 e Coorte 2)
    Le DLT saranno utilizzate per stabilire la MTD. L’SRC stabilirà la RP2D sulla base dei dati di sicurezza derivanti dall’associazione di TL-895 e KRT-232.
    Fase 2 (Coorte 1, Coorte 2, Coorte 3)
    La proporzione di soggetti che raggiungono una riduzione del volume della milza >=35% dal basale alla settimana 24, valutato tramite RM o TC mediante revisione centrale.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Phase 1b (Cohort 1 and Cohort 2)
    The DLT evaluation period for Cohort 1 and Cohort 2 is 28 days starting from Cycle 2 Day 1 until Cycle 3 Day 1.
    Phase 2 (Cohort 1, Cohort 2, and Cohort 3)
    week 24
    Fase 1b (Coorte 1 e Coorte 2)
    28 giorni dall'inizio del D1C2 fino al C3D1
    Fase 2 (Coorte 1, Coorte 2, Coorte 3)
    W24
    E.5.2Secondary end point(s)
    Phase 1b (Cohort 1 and Cohort 2)
    TL-895, KRT-232, and acyl glucuronide metabolite (M1) PK parameters, including but not limited to the following:
    • Cmax
    • tmax
    • AUC
    Phase 2 (Cohort 1, Cohort 2, and Cohort 3)
    1.Proportion of subjects who have >=50% reduction in the TSS from Baseline to Week 24, as measured by MFSAF v4.0.
    2.Duration of a >=35% or more reduction from Baseline in spleen volume as measured by MRI (or by CT for applicable subjects).
    3.The rate of conversion is defined as the proportion of subjects who convert from transfusion dependent to transfusion independent at Week 24.
    4.The proportion of subjects with RBC transfusion independence at Week 24.
    5.Median time to death (Kaplan-Meier estimate in months) and landmark OS rates (%) (OS defined as the interval from the first dose to death from any cause).
    6.Median PFS (Kaplan-Meier estimate in months) among subjects who achieve a response (PFS defined as the interval from the first dose to the date of first documented progression of disease by spleen volume, leukemic transformation, or death) and landmark PFS rate (%).
    7.Reduction in spleen size from Baseline to each visit at which spleen is palpated, including the proportion of subjects who have a >=50% decrease in spleen size.
    8.CR and PR defined according to IWG-MRT.
    9.Analyses of the safety endpoints will include the following measurements or assessments: physical examinations, laboratory tests, AEs, SAEs, ECGs, and vital signs.
    10.TL-895, KRT-232, and acyl glucuronide metabolite (M1) PK parameters, including but not limited to the following:
    • Cmax
    • tmax
    • AUC
    Fase 1b (Coorte 1 e Coorte 2)
    Parametri PK di TL-895, KRT-232 e del metabolita acil glucuronide (M1), tra cui, a titolo esemplificativo:
    • Cmax
    • tmax
    • AUC
    Fase 2 (Coorte 1, Coorte 2, Coorte 3)
    1. Percentuale di soggetti con una riduzione >=50% di TSS dal basale alla settimana 24, secondo il MFSAF v. 4.0.
    2. Durata di una riduzione >=35% o superiore dal basale nel volume della milza misurata tramite RM (o TC per i soggetti idonei).
    3. Il tasso di conversione è definito come la proporzione di soggetti che da dipendenti dalla trasfusione diventano indipendenti dalla trasfusione alla settimana 24.
    4. Percentuale di soggetti con indipendenza dalla trasfusione di RBC alla settimana 24
    5. Tempo mediano al decesso (stime di Kaplan-Meier in mesi) e tassi (%) di OS landmark (OS definita come l’intervallo di tempo tra la prima dose e il decesso per qualsiasi causa).
    6. PFS mediana (stime di Kaplan-Meier in mesi) tra i soggetti che raggiungono una risposta (PFS definita come l’intervallo di tempo tra la prima dose e la data della prima progressione documentata della malattia in base a volume della milza, trasformazione leucemica o decesso) e tassi (%) di PFS landmark.
    7. Riduzione delle dimensioni della milza dal basale a ciascuna visita a cui viene palpata la milza, inclusa la percentuale di soggetti con una riduzione >=50% delle dimensioni della milza.
    8. CR e PR definite in base all’IWG-MRT.
    9. Le analisi degli endpoint di sicurezza comprenderanno le seguenti misurazioni o valutazioni: esami obiettivi, test di laboratorio, AE, EA seri, ECG e parametri vitali.
    10. Parametri PK di TL-895, KRT-232 e del metabolita acil glucuronide (M1), tra cui, a titolo esemplificativo:
    • Cmax
    • tmax
    • AUC
    E.5.2.1Timepoint(s) of evaluation of this end point
    Phase 1b (Cohort 1 and Cohort 2)
    Cycle 2
    Phase 2 (Cohort 1, Cohort 2, and Cohort 3)
    Week24
    Fase 1b (Coorte 1 e Coorte 2)
    Ciclo 2
    Fase 2 (Coorte 1, Coorte 2, Coorte 3)
    Settimana 24
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis Yes
    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 Yes
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic Yes
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) Yes
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other Yes
    E.7.1.3.1Other trial type description
    safety and efficacy
    sicurezza ed efficacia
    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 Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group Yes
    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) Yes
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial5
    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.8.4.1Number of sites anticipated in Member State concerned9
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA39
    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 Information not present in EudraCT
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Austria
    Bulgaria
    France
    Germany
    Hungary
    Italy
    Poland
    Serbia
    Spain
    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
    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 months8
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years4
    E.8.9.2In all countries concerned by the trial months10
    E.8.9.2In all countries concerned by the trial days14
    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: 58
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 58
    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 state16
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 72
    F.4.2.2In the whole clinical trial 116
    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)
    Standard care
    Standard care
    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 Decision2021-06-07
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2021-05-25
    P. End of Trial
    P.End of Trial StatusOngoing
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