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    Summary
    EudraCT Number:2020-004699-16
    Sponsor's Protocol Code Number:KRT-232-117
    National Competent Authority:France - ANSM
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2020-12-11
    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 number2020-004699-16
    A.3Full title of the trial
    An Open-Label, Multicenter, Phase 1b/2 Study of the Safety and Efficacy of KRT-232 Combined with a Tyrosine Kinase Inhibitor (TKI) in Patients with Relapsed or Refractory Ph+ Chronic Myeloid Leukemia (CML)
    A.4.1Sponsor's protocol code numberKRT-232-117
    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 pointJohn Mei
    B.5.3 Address:
    B.5.3.1Street Address275 Shoreline Drive, Suite 100
    B.5.3.2Town/ cityRedwood City
    B.5.3.3Post codeCA 94065
    B.5.3.4CountryUnited States
    B.5.4Telephone number1650542 0136128
    B.5.6E-mailjmei@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.3.2Product 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.3.11 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
    Phase 1b and Phase 2 Arms A and B: Adults with tumor protein 53 wild type (TP53wt) Philadelphia chromosome positive (Ph+) CML in chronic phase who are refractory or intolerant to ≥ 2 prior TKIs and meeting European LeukemiaNet (ELN) criteria for treatment failure on their current TKI.
    Phase 2 Arm C: Adults with TP53wt Ph+ CML in accelerated phase who are refractory or intolerant to ≥ 2 prior TKIs and meeting ELN criteria for treatment failure on their current TKI.
    E.1.1.1Medical condition in easily understood language
    - Chronic myeloid leukemia in chronic phase
    - Chronic myeloid leukemia in accelerated phase
    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 10009015
    E.1.2Term Chronic myeloid leukemia
    E.1.2System Organ Class 100000004864
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.0
    E.1.2Level LLT
    E.1.2Classification code 10054352
    E.1.2Term Chronic phase chronic myeloid leukemia
    E.1.2System Organ Class 100000004864
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 22.0
    E.1.2Level LLT
    E.1.2Classification code 10082178
    E.1.2Term Philadelphia positive chronic myeloid leukemia
    E.1.2System Organ Class 100000004864
    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: To determine the KRT 232 maximum tolerated dose/ maximum administered dose (MTD/MAD) and recommended Phase 2 dose (RP2D) in combination with dasatinib or nilotinib.
    - Phase 2: To determine the rate of major cytogenetic response rate (MCyR) at 6 months in Arms A and B (Adults with tumor protein 53 wild type (TP53wt) Philadelphia chromosome positive (Ph+) CML in chronic phase who are refractory or intolerant to ≥ 2 prior TKIs and meeting European LeukemiaNet (ELN) criteria for treatment failure on their current TKI).
    - Phase 2: To determine the rate of major hematologic response (MaHR) in Arm C (Adults with TP53wt Ph+ CML in accelerated phase who are refractory or intolerant to ≥ 2 prior TKIs and meeting ELN criteria for treatment failure on their current TKI).
    E.2.2Secondary objectives of the trial
    - Phase 1b: To determine the pharmacokinetics (PK) of KRT-232
    - Phase 1b: To evaluate the effect of KRT-232 in combination with dasatinib or nilotinib on select PK, pharmacodynamics, disease biomarkers and markers of resistance
    - Phase 2: To determine the rate of MCyR at 12 months in Arms A and B
    - Phase 2: To determine the rate of MCyR in Arm C
    - Phase 2: To determine the duration of response (DOR) in each Arm
    - Phase 2 : To determine the rate of complete hematologic response (CHR) in Arms A and B
    - Phase 2: To determine progression-free survival (PFS) in each Arm
    - Phase 2: To determine overall survival (OS) in each Arm
    - Phase 2: To determine the proportion of subjects who transition to ASCT in each Arm
    - Phase 2: To determine the safety and tolerability of KRT 232 in combination with dasatinib or nilotinib
    - Phase 2: To evaluate the effect of KRT-232 in combination with dasatinib or nilotinib on select PK, PD, disease biomarkers and markers of resistance
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Phase 1b and Phase 2 Arms A and B: Documented TP53wt, Ph+, BCR ABL+ CML-CP according to definitions provided in Appendix 6.
    2. Phase 2 Arm C ONLY: Documented TP53wt, Ph+, BCR-ABL+ CML AP according to definitions provided in Appendix 6 with no alternative therapeutic options likely to produce clinical benefit.
    3. Subject is resistant (relapsed or refractory) and/or intolerant to at least 2 prior TKIs.
    a. Resistance is defined as meeting at least one of the following criteria:
    i. No cytogenetic response (> 95% Ph+) or failure to achieve CHR 3 months after the initiation of therapy;
    ii. Less than a minor cytogenetic response (> 65% Ph+) 6 months after the initiation of therapy;
    iii. Less than a PCyR (> 35% Ph+) 12 months after the initiation of therapy;
    iv. The development of new BCR-ABL kinase domain mutations in the absence of CCyR at any time after the initiation of therapy;
    v. The development of new clonal evolution in the absence of CCyR at any time after the initiation of therapy; OR
    vi. The loss of cytogenetic response (from complete [0%], partial [1 to 35%], minor [36 to 65%], or minimal [66 to 95%] to a response at least 1 grade worse), confirmed in at least 2 consecutive analyses, separated by at least 4 weeks, at any time after the initiation of therapy.
    b. Intolerant is defined as either:
    i. Non-hematologic intolerance: subjects with Grade 3 or 4 toxicity while on therapy, or with persistent Grade 2 toxicity, unresponsive to optimal management, including dose adjustments (unless dose reduction is not considered in the best interest of the subject if response is already suboptimal) in the absence of CCyR; OR
    ii. Hematologic intolerance: subjects with Grade 3 or 4 absolute neutrophil count (ANC) or platelets while on therapy that is recurrent after dose reduction to the lowest recommended doses by the manufacturer in the absence of CCyR.
    4. Treatment failure on current TKI therapy (as per ELN criteria) defined as either:
    a. No CHR or > 95% Ph+ metaphases 3 months after initiation of therapy, OR
    b. BCR-ABL1 ratio > 10% International Standards (IS) and/or > 65% Ph+ metaphases 6 months after initiation of therapy, OR
    c. BCR-ABL1 ratio > 10% IS and/or > 35% Ph+ metaphases 12 months after initiation of therapy.
    5. On a stable dose for at least 4 weeks on the current TKI therapy prior to the first dose of study treatment. This TKI will be continued on the study.
    6. Adults ≥ 18 years of age.
    7. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2.
    8. Adequate hematologic function independent of growth factor support for at least 7 days with the exception of pegylated granulocyte-colony stimulating factor and darbepoetin which require at least 14 days, defined as:
    a. ANC ≥ 1.0 x 10(9)/L.
    b. Platelet count ≥ 100 x 10(9)/L for subjects with CML-CP; platelet count ≥ 75 x 109/L for subjects with CML-AP.
    9. Adequate hepatic function within 28 days prior to the first dose of study treatment defined as:
    a. Total serum bilirubin within normal limits; if total bilirubin > upper limit of normal (ULN) then subjects are eligible if the direct bilirubin is ≤ 1.5 x ULN.
    b. Serum aspartate transaminase (AST) and/or alanine transaminase (ALT) ≤ 2.5×ULN.
    10. Adequate renal function defined by an estimated creatinine clearance ≥ 30 mL/min by Cockcroft-Gault formula.
    11. Female subjects of childbearing potential and their male partners, or male subjects who have female partners of childbearing potential must both use a highly effective contraception method during the study. A woman is considered of childbearing potential (ie, fertile, following menarche and until becoming postmenopausal) unless permanently sterile (Appendix 2).
    E.4Principal exclusion criteria
    1. Phase 1b and Phase 2 Arms A and B: Documented Ph+, BCR-ABL+ CML-AP according to definitions provided in Appendix 6.
    2. Documented Ph+, BCR-ABL+ CML-BC according to definitions provided in Appendix 6.
    3. Known history of T315I mutation.
    4. Known history of central nervous system (CNS) leukemia involvement.
    5. Prior treatment with MDM2 antagonist therapies.
    6. Concurrent anticancer treatment such as chemotherapy, cytoreductive therapy, immune therapy, investigational new drug, or cytokine therapy within 28 days of the first dose of study treatment. Current TKI dosing is permitted.
    7. Intolerance to current TKI therapy
    8. Active participation in any other therapeutic clinical trials including supportive care trials.
    9. History of major hemorrhage or intracranial hemorrhage within 6 months prior to the first dose of study drug.
    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, unstable ventricular arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
    14. Grade 2 or higher corrected QT interval (QTc) prolongation > 480 msec per National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0.
    15. Subjects who have a 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.
    16. History of major organ transplant.
    17. 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 judgment of the treating physician, these subjects may be on antibiotics at the time of enrollment.
    18. Subjects who are pregnant or breast feeding.
    19. Subjects with a 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.
    E.5 End points
    E.5.1Primary end point(s)
    - Phase 1b: Determination of the dose limiting toxicities (DLTs) will be used to establish the MTD/MAD of KRT-232 in combination with dasatinib or nilotinib.
    - Phase 2: The proportion of subjects who achieved complete cytogenetic response (CCyR) or partial cytogenetic response (PCyR) according to modified ELN criteria (Appendix 5).
    - Phase 2: The proportion of subjects who achieved MaHR according to modified ELN criteria (Appendix 5).
    E.5.1.1Timepoint(s) of evaluation of this end point
    - Primary Efficacy Endpoints for Phase 2: For Arms A and B, the MCyR rate at month 6 will be reported including a 90% exact confidence interval (CI).For Arm C, the MaHR rate will be reported including a 90% exact confidence interval (CI).
    - Phases 1b & 2: Throughout the study
    E.5.2Secondary end point(s)
    Phase 1b: KRT-232 and acyl glucuronide metabolite (M1) PK parameters including but not limited to:
    • Maximum observed concentration (Cmax)
    • Minimum observed concentration (Cmin)
    • Area under the plasma concentration-time curve (AUC)
    • Time to maximum plasma concentration (Tmax)
    - Phase 1b: Biomarkers including but not limited to:
    TP53, BCR-ABL1 status, myeloid markers of CML and myeloproliferative neoplasms (MPN)
    • Ex vivo drug sensitivity in bone marrow aspirate (United States [US] sites only)
    • Pharmacodynamic pathway activation/modulation
    • Inflammatory markers (C-reactive protein [CRP] and other serum analytes)
    • Peripheral blood cell phenotyping
    - Phase 2: The proportion of subjects who achieved CCyR or PCyR according to modified ELN criteria (Appendix 5).
    - Phase 2: DOR (Kaplan-Meier estimate) defined as the time from first observation of response to progression/relapse or death, whichever comes first- - - - - Phase 2: The proportion of subjects who achieve a CHR according to modified ELN criteria (Appendix 5).
    - Phase 2: PFS is defined as the time from the first treatment dose date to progression/relapse or death, whichever comes first
    - Phase 2: OS is defined as the time from the first treatment dose date to death from any cause
    - Phase 2: The proportion of subjects who transition to allogeneic transplant
    - Phase 2: Analyses of the safety endpoints will include the following measurements or assessments: physical examinations, laboratory tests, adverse events (AEs), serious adverse events (SAEs), electrocardiograms (ECGs), and vital signs
    - Phase 2: KRT-232 and acyl glucuronide metabolite (M1) PK parameters including but not limited to:
    • Observed concentration 2 hours post dose (C2hr)
    • Cmin
    E.5.2.1Timepoint(s) of evaluation of this end point
    Secondary Efficacy Endpoints
    - The secondary efficacy endpoints (DOR, PFS, and OS) will be summarized by Kaplan Meier analyses with estimated medians, 95% CI, and ranges reported in months. The MCyR rate at month 12 (for Arms A and B) and MCyR rate (Arm C), and the proportion of subjects achieving CHR, will be reported with a 95% CI. The proportion of subjects who have transitioned to ASCT will be summarized. Secondary safety endpoints will be summarized by AE incidence by severity, seriousness, and relationship to the study drug(s).
    Exploratory Endpoints: The rate of CCyR at 6 months and at 12 months for Arms A and B, as well as the rate of MMR for each Arm will be reported with a 95% CI.
    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 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) 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
    Dose determining
    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 Yes
    E.8.1.7.1Other trial design description
    Dose escalation
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other Yes
    E.8.2.4Number of treatment arms in the trial3
    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 EEA18
    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
    Canada
    Czechia
    France
    Germany
    Hungary
    Israel
    Italy
    Poland
    Spain
    United States
    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
    Last Patient Last Visit (LPLV)
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned months2
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months2
    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: 66
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 67
    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 No
    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.4.2.2In the whole clinical trial 133
    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)
    Patients may be given an opportunity to participate in future interventional trials if they complete the study.
    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 Decision2021-02-23
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2021-03-15
    P. End of Trial
    P.End of Trial StatusOngoing
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