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    Summary
    EudraCT Number:2020-003109-73
    Sponsor's Protocol Code Number:TL-895-203
    National Competent Authority:Germany - BfArM
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2020-12-04
    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 ConcernedGermany - BfArM
    A.2EudraCT number2020-003109-73
    A.3Full title of the trial
    An Open-Label, Multicenter, Phase 1b/2 Study of the Safety and Efficacy of TL-895 Combined with KRT-232 in Subjects with Relapsed/Refractory (R/R) FLT3+ Acute Myeloid Leukemia (AML)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    TL-895 and KRT-232 Study in Acute Myeloid Leukemia
    A.4.1Sponsor's protocol code numberTL-895-203
    A.5.4Other Identifiers
    Name:INDNumber:152207
    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 pointRegulatory Affairs
    B.5.3 Address:
    B.5.3.1Street Address275 Shoreline Drive, Suite 325
    B.5.3.2Town/ cityRedwood City, CA
    B.5.3.3Post code94065
    B.5.3.4CountryUnited States
    B.5.4Telephone number001215-200-6781
    B.5.6E-mailkvyas@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.3.1Product 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.3.8INN - Proposed INNTL-895
    D.3.9.1CAS number 1415823-49-2
    D.3.9.2Current sponsor codeTL-895
    D.3.9.3Other descriptive nameTL-895
    D.3.9.4EV Substance CodeSUB216480
    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 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.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 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.3.8INN - Proposed INNNavtemadlin
    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 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.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 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.3.8INN - Proposed INNNavtemadlin
    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 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.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 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.3.8INN - Proposed INNNavtemadlin
    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 number30
    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.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.3.8INN - Proposed INNNavtemadlin
    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 number120
    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.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 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.3.8INN - Proposed INNTL-895
    D.3.9.1CAS number 1415823-49-2
    D.3.9.2Current sponsor codeTL-895
    D.3.9.4EV Substance CodeSUB216480
    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 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 (R/R) FLT3+ Acute Myeloid Leukemia
    E.1.1.1Medical condition in easily understood language
    Patients with Acute Myeloid Leukemia
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    E.1.2Level LLT
    E.1.2Classification code 10081514
    E.1.2Term Acute myeloid leukemia refractory
    E.1.2System Organ Class 100000004864
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Phase 1b:
    Primary:
    To determine the MTD/MAD and RP2D of TL-895 in combination with KRT-232
    To determine the safety and tolerability of TL-895 in combination with KRT-232

    Phase II:
    Primary: To determine the rates of complete remission and complete remission with partial hematologic recovery
    E.2.2Secondary objectives of the trial
    Phase Ib:
    Secondary: To characterize the PK profile of TL 895 and KRT-232
    Exploratory: To evaluate the effect of TL-895 in combination with KRT-232 relative to select PD, PK, or disease markers and markers of resistance
    Phase II:
    Secondary:
    To determine the overall response rate
    To determine the duration of Complete Remission/Complete Remission with partial hematologic recovery response (Duration of Response)
    To determine progression-free survival
    To determine Overall Survival
    To determine the proportion of subjects who transition to allogeneic stem cell transplant
    To determine the safety and tolerability of TL-895 in combination with KRT-232
    To monitor the PK of TL-895 and KRT-232
    Exploratory: To evaluate the efficacy and safety of TL-895 in combination with KRT 232 relative to select PK, PD, or disease markers, and markers of resistance
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Subjects in the Phase 1b and Phase 2 Dose Expansion must meet all the following criteria in order to be eligible for the study:
    1.Adults ≥18 years of age who are able to provide informed consent.
    2.Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2.
    3.Documented primary TP53wt AML or TP53wt AML secondary to myelodysplastic syndrome (MDS), as defined by World Health Organization (WHO) criteria (Arber 2016).
    4.Subject is refractory to and/or relapsed after at least one prior therapy with no alternative therapeutic options likely to produce clinical benefit. Subjects must have received a FLT3 inhibitor (unless contraindicated), if FLT3 inhibitors are approved and available in the country in which the subject is to be treated.
    5.Presence of the FLT3 activating mutation TKD or FLT3-ITD in bone marrow or peripheral blood detected by a test approved by the local health authority or, if not available, by a validated test.
    6.Adequate renal function within 7 days (Phase 1b) or 28 days (Phase 2) prior to the first dose of study treatment defined as an estimated creatinine clearance ≥30 mL/min by Cockcroft-Gault formula.
    7.Adequate hepatic function within 7 days (Phase 1b) or 28 days (Phase 2) prior to the first dose of study treatment defined as:
    a.Total serum bilirubin ≤ 2.0 x ULN. Subjects with known Gilbert’s syndrome or disease-related hemolysis must have a total bilirubin ≤3.0 X ULN
    b.Serum AST and/or ALT ≤2.5×ULN.
    8.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 method of contraception for 1 month and 1 week and male subjects must continue to use a highly effective method of contraception for 3 months and 1 week. A woman is considered of childbearing potential (ie, fertile, following menarche and until becoming post menopausal) unless permanently sterile.
    E.4Principal exclusion criteria
    Subjects in the Phase 1b and Phase 2 Dose Expansion who meet any of the following criteria will not be eligible for the study:
    1.Acute promyelocytic leukemia (AML subtype M3).
    2.Subjects with known active central nervous system involvement with AML.
    3.Prior treatment with MDM2 antagonist therapies.
    4.Prior treatment with a BTK inhibitor.
    5.Chemotherapy, cytoreductive therapy, immune therapy, cytokine therapy or any investigational therapy within 14 days prior to first dose of study treatment. Subjects on FLT3 inhibitor therapy must discontinue treatment at least 2 days prior to first dose of study drug.
    6.Active participation in other therapeutic clinical trials including supportive care trials.
    7.Allogeneic stem cell transplant within 3 months; autologous stem cell transplant within 3 months or active graft-versus-host disease prior to first dose of study treatment.
    8.Subjects who are eligible for an allogeneic hematopoietic stem cell transplantation (HSCT) per the opinion of the investigator and have a donor. Subjects who are HSCT eligible in the opinion of the investigator, but who refuse a transplant, are eligible for the study.
    9.Subjects with a history of bleeding diathesis; major hemorrhage or intracranial hemorrhage within 24 weeks prior to the first dose of study treatment
    10.Known infection with human immunodeficiency virus.
    11.Known active hepatitis B or C infection.
    12.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.
    13.Uncontrolled intercurrent illness including but not limited to clinically significant cardiac disease (New York Heart Class III or IV); symptomatic congestive heart failure, unstable angina pectoris, ventricular arrhythmia, or subjects with psychiatric illness/social situations that would limit compliance with study requirements; or subjects who have been committed to an institution by judicial or administrative authority.
    14.Grade 2 or higher QTc prolongation >480 msec per National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 5.0.
    15.History of myocardial infarction within 3 months of first dose of study treatment
    16.History of major organ transplant
    17.Requires or receiving anticoagulation with warfarin or equivalent vitamin K antagonists (e.g., phenprocoumon) within 7 days of the first dose of study drug.
    18.Requires treatment with proton-pump inhibitors (e.g., omeprazole, esomeprazole, lansoprazole, dexlansoprazole, rabeprazole, or pantoprazole); subjects receiving PPIs 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.Phase 1b only: Subjects receiving medications, herbal supplements, or food known to be strong inhibitors of CYP3A within 7 days prior to the first dose of TL-895
    20.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 KRT-232 or TL-895 treatment.
    21.Major surgery or planned major surgery within 28 days prior to first dose of study treatment.
    22.Subjects with clinically significant active infection requiring parenteral therapy.
    23.Pregnant or breast feeding.
    24.Medical condition, serious intercurrent illness, or other circumstance that, in the Investigator's judgment, could jeopardize the candidate's safety as a study subject, or that could interfere with study objectives, including known hypersensitivity to or contraindications to the study drugs or their excipients, or to required prophylaxis.
    E.5 End points
    E.5.1Primary end point(s)
    Phase Ib:
    Endpoints for primary objectives:
    -Dose Limiting Toxicities will be used to establish the MTD/MAD of TL-895 in combination with KRT-232. The Safety Review Committee (SRC) will determine the RP2D based on safety data of the combination of TL 895 and KRT-232.
    -Analyses of the safety endpoints will include the following measurements or assessments: physical examinations, laboratory tests, AEs, serious AEs (SAEs), ECGs, and vital signs.

    Phase II:
    Endpoints for primary objectives:
    -The proportion of subjects who achieved CR or CRh as their best response based on the Modified 2017 European LeukemiaNet (ELN) Response Criteria.
    CRh is defined as <5% of blasts by morphology in the bone marrow, no evidence of disease (blasts in blood by flow cytometry) and at least partial recovery of peripheral blood counts (platelets >50,000/µl and ANC >500/µl).
    E.5.1.1Timepoint(s) of evaluation of this end point
    Phase Ib=C1D1 to C2D1
    Phase 2=Until progression
    E.5.2Secondary end point(s)
    Phase Ib:
    Endpoints for secondary objectives:
    TL-895, KRT-232, and KRT-232 acyl glucuronide metabolite (M1) PK parameters, including but not limited to:
    •Cmax
    •AUC
    •Time of maximum plasma concentration (Tmax)
    Endpoints for exploratory objectives:
    Biomarkers including but not limited to:
    •TP53 mutation status
    •AML related genes
    •Functional and mechanistic markers of BMX/BTK
    •Characterization of peripheral blood blasts
    •Serum/plasma cytokine/chemokine panel, including but not limited to c-reactive protein (CRP), alpha-1-acid glycoprotein (AAG), IL-1b, IL-2, IL-6, IL-8, IL 10, TNF-α, IFN-γ, IL12p70 and SDF-1
    •p53-related gene expression panel, including: p21 (CDKN1A), MDM2, PUMA (BBC3), MIC-1 (GDF15), PIG3(TP53I3), DR5 (TNFRSF10B), GADD45, PCNA, MDMX (MDM4)
    •MIC-1 protein in serum
    •BTK/BMX target occupancy in peripheral blood leukocytes
    •Functional assays in cultured peripheral blasts (United States [US] sites only)
    •Evaluations of BTK/BMX target engagement in bone marrow aspirates (US sites only)

    Phase II:
    Endpoints for secondary objectives:
    -The proportion of subjects who achieve PR or better
    -Median Duration of Response (Kaplan-Meier estimate) defined as the time from first observation of Complete Remission/Complete Remission with partial hematologic recovery to relapse or death from any cause, whichever occurs first. Subjects with morphologic leukemia-free state by bone marrow aspirate and/or biopsy performed earlier in the course of therapy who convert to Complete Remission or complete remission with partial hematologic recovery do not require a separate bone marrow aspirate and/or biopsy at the time of Complete Remission or complete remission with partial hematologic recovery to document this.
    -Median Progression-free Survival (Kaplan- Meier estimate) defined as the time from the first treatment dose to disease progression, relapse or death from any cause, whichever occurs first.
    -Median Overall Survival (Kaplan-Meier estimate) defined as the time from the first treatment dose to death due to any cause
    -The proportion of subjects who transition to allogeneic transplant
    -Analyses of the safety endpoints will include the following measurements or assessments: physical examinations, laboratory tests, AEs, SAEs, ECGs, and vital signs
    -TL-895, KRT-232, KRT-232 acyl glucuronide metabolite (M1), plasma concentrations monitored using sparse sampling.
    Endpoints for exploratory objectives:
    Biomarkers including but not limited to:
    •TP53 mutation status
    •AML related genes
    •Functional and mechanistic markers of BMX/BTK
    •Characterization of peripheral blood blasts
    •Serum/plasma cytokine/chemokine panel, including but not limited to CRP, AAG, IL-1b, IL-2, IL-6, IL-8, IL-10, TNF-α, IFN-γ, IL12p70 and SDF-1
    •p53-related gene expression panel, including: p21 (CDKN1A), MDM2, PUMA (BBC3), MIC-1 (GDF15), PIG3(TP53I3), DR5 (TNFRSF10B), GADD45, PCNA, MDMX (MDM4)
    •MIC-1 protein in serum
    •BTK/BMX target occupancy in peripheral blood leukocytes
    •Functional assays in cultured peripheral blasts (US sites only)
    •Evaluations of BTK/BMX target engagement in bone marrow aspirates (US sites only)

    E.5.2.1Timepoint(s) of evaluation of this end point
    as per Appendix 1 Schedule of Assessments in the study protocol
    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 No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response Yes
    E.6.10Pharmacogenetic Yes
    E.6.11Pharmacogenomic No
    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
    phase Ib (dose escalation, to determine the MTD/MAD and RP2D)
    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 Yes
    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.8.4.1Number of sites anticipated in Member State concerned5
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA30
    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
    Korea, Republic of
    United States
    Austria
    France
    Spain
    Germany
    Italy
    E.8.7Trial has a data monitoring committee No
    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
    The study will be considered complete 2 years after the last subject is enrolled, at which time subjects will be evaluated for eligibility for a rollover study that allows long-term follow-up
    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 months0
    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: 35
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 35
    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 state6
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 50
    F.4.2.2In the whole clinical trial 70
    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)
    Eligible participants will be allowed to take study medication until further progression of their disease, cessation of clinical benefit,
    unacceptable toxicity, or some other factor that necessitates discontinuation from study treatment. Once the participant has been
    discontinued from the study, the participant's doctor will continue to manage them according to the routine standard of 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 Decision2021-03-05
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2021-01-21
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
    P.Date of the global end of the trial2023-02-19
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