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    Summary
    EudraCT Number:2019-004839-23
    Sponsor's Protocol Code Number:CA-4948-102
    National Competent Authority:Poland - Office for Medicinal Products
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2022-11-21
    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 ConcernedPoland - Office for Medicinal Products
    A.2EudraCT number2019-004839-23
    A.3Full title of the trial
    A Phase 1/2a, Open-Label Dose Escalation and Cohort Expansion Study of Orally Administered CA-4948(IRAK4i) as a Monotherapy in patients with Acute Myelogenous Leukemia or Myelodysplastic Syndrome
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Study of Orally Administered CA-4948(IRAK4i) as a Monotherapy in patients with Acute Myelogenous Leukemia or Myelodysplastic Syndrome
    A.4.1Sponsor's protocol code numberCA-4948-102
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT04278768
    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 SponsorCuris, 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 supportCuris, Inc
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationCuris, Inc
    B.5.2Functional name of contact pointCatherine Wang
    B.5.3 Address:
    B.5.3.1Street Address128 Spring St., Building C, Suite 500
    B.5.3.2Town/ cityLexington, MA
    B.5.3.3Post code02421
    B.5.3.4CountryUnited States
    B.5.4Telephone number1781460-7077
    B.5.6E-mailCA-4948-102@curis.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 CA-4948
    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 INNEmavusertib
    D.3.9.2Current sponsor codeCA-4948
    D.3.9.4EV Substance CodeSUB208117
    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.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
    Acute Myelogenous Leukemia (AML) or higher risk Myelodysplastic Syndrome (MDS).
    E.1.1.1Medical condition in easily understood language
    AML: cancer of the blood and bone marrow — the spongy tissue inside bones where blood cells are made
    MDS: group of disorders caused by poorly formed blood cells or ones that don't work properly
    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 LLT
    E.1.2Classification code 10001941
    E.1.2Term AML
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10068361
    E.1.2Term MDS
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Phase 1
    •To evaluate the safety and tolerability of CA-4948 in patients with relapsed / refractory (R/R) acute myelogenous leukemia (AML) and higher-risk myelodysplastic syndrome (hrMDS)
    • To identify maximum tolerated dose (MTD) and recommended Phase 2 Dose (RP2D)


    Phase 2a:
    To assess anti-cancer activity of CA-4948 at RP2D in patients with R/R AML with FMS-like tyrosine kinase-3 (FLT-3) mutations, and patients with R/R hrMDS or R/R AML with spliceosome mutations of SF3B1 or U2AF1
    E.2.2Secondary objectives of the trial
    Phase 1
    • To characterize the pharmacokinetic (PK) parameters of CA-4948 using noncompartmental analysis and appropriate PK
    modelling
    • To assess anti-cancer activity

    Phase 2a:
    - To assess tolerability and long-term safety
    - To further assess anti-cancer activity of CA-4948 at RP2D
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Males and females >= 18 years of age
    2. Life expectancy of at least 3 months
    3. Eastern Cooperative Oncology Group (ECOG) Performance Status of ≤ 1
    4. Cytomorphology based confirmed diagnosis of MDS or AML (as per the World Health Organization 2016 classification) with the following characteristics.

    Phase 1 Dose Escalation
    . AML (primary or secondary, including treatment-related; European Leukemia Net category) after failing at least 1 standard treatment (may include chemotherapy, re induction therapy or SCT), based on the assessment of the Investigator.
    OR
    . Higher-risk R/R MDS (International Prognostic Scoring System-revised score >3.5; Pfeilstocker 2016) that are considered resistant/refractory following at least 2 to 3 cycles of hypomethylating agents, or evidence of early progression

    Patients that meet 1 of the following criteria:
    • R/R AML with FLT3 mutations who have been previously treated with a FLT3 inhibitor
    • R/R AML with spliceosome mutations of SF3B1 or U2AF1
    • R/R hrMDS (IPSS-R score > 3.5) with spliceosome mutations of SF3B1 or U2AF1
    And
    • Have had ≤ 2 lines of prior systemic anti-cancer treatment (see Appendix M for guidelines)

    Phase 2a Dose Expansion
    Patients with:
    • R/R AML with FLT3 mutations who have been previously treated with a FLT3 inhibitor
    • R/R AML with spliceosome mutations of SF3B1 or U2AF1
    • R/R hrMDS (IPSS-R score > 3.5) with spliceosome mutations of SF3B1 or U2AF1
    And
    • Have had ≤ 2 lines of prior systemic anti-cancer treatment (see Appendix M for guidelines)

    5. Acceptable organ function at Screening as described below:
    a. Estimated creatinine clearance (CrCl) of ≥ 35 mL/min (Appendix H).
    b. Aspartate aminotransferase or alanine aminotransferase ≤ 2 × ULN
    c. Total bilirubin ≤ 1.5 × ULN or ≤ 3 × ULN in patients with documented Gilbert’s syndrome
    d. White blood cell count ≤ 25,000/μL (hydroxyurea is allowed during Screening and Cycle 1 for cytoreduction, if needed, for patients with AML per Investigator’s discretion. However, hydroxyurea must stop prior to Cycle 2)
    6. CPK < Grade 2.
    7. For patients on a cholesterol lowering agent that has been associated with CPK elevations, such as statins or fibrates, the agent should be discontinued or replaced with an alternative if medically feasible. Otherwise, it should be reduced to the lowest dose that is biologically
    effective (ie, the lowest dose required to achieve the desired clinical effect).
    8. Ability to swallow and retain oral medications
    9. Negative serum pregnancy test in women of childbearing potential (WOCP)
    10. WOCP and men who partner with a WOCP must agree to use highly effective contraceptive methods for the duration of the study and for 180 days after the last dose of CA-4948
    11. Willing and able to provide written informed consent and comply with the requirements of the trial
    12. Biopsy requirement for AML and MDS: patients must be willing to have serial bone marrow sampling and peripheral blood sampling during the study. The diagnosis and evaluation of AML and MDS will be made by bone marrow aspiration and/or biopsy. If an aspirate is unobtainable (i.e., a “dry tap”), the diagnosis is made from the core biopsy
    E.4Principal exclusion criteria
    1. Diagnosed with acute promyelocytic leukemia (APL, M3)
    2. Known active central nervous system (CNS) leukemia; patients with previously treated CNS disease may participate if asymptomatic as determined by treating physician (without symptomatic active disease for at least 4 weeks prior to the first dose of treatment, and any neurologic symptoms have returned to baseline)
    3. Allogeneic SCT within 60 days of the first dose of CA-4948, or clinically significant graft-versus-host disease (GVHD) requiring ongoing up titration of immunosuppressive medications prior to start of CA-4948
    Note: The use of a stable or tapering dose of immunosuppressive therapy post-SCT and/or topical steroids for ongoing skin GVHD is permitted with Medical Monitor approval
    4. Chronic myelogenous leukemia
    5. Any prior systemic anti-cancer treatment such as chemotherapy, immunomodulatory drug therapy, etc., received within 3 weeks (or 5 half-lives), whichever is shorter, or radiotherapy received 2 weeks prior to the start of CA-4948
    Note: Localized radiation or surgical resection of skin cancers is allowed
    6. Use of any investigational agent within 3 weeks (or 5 half-lives), whichever is shorter, prior to start of CA-4948
    7. Presence of an acute or chronic toxicity resulting from prior anti-cancer therapy, with the exception of alopecia that has not resolved to Grade ≤1, as determined by NCI CTCAE v 4.03 within 7 days prior to start of CA 4948 unless approved by the Medical Monitor
    8. Known allergy or hypersensitivity to any component of the formulation of CA-4948 used in this study
    9. Major surgery, other than diagnostic surgery, <28 days from the start of CA-4948; minor surgery <14 days from the start of CA-4948
    Note: Insertion of a vascular access device is not considered minor surgery
    10. Patients with active advanced malignant solid tumors.
    11. Viral Infections:
    a. Known to be human immunodeficiency virus (HIV) positive or have an acquired immunodeficiency syndrome-related illness. If HIV virus is undetectable and maintained on treatment, enrolment may be allowed after discussion with the Sponsor.
    b. Hepatitis B virus (HBV) DNA positive or hepatitis C virus (HCV) infection < 6 months prior to start of CA-4948 unless viral load is undetectable, or HCV with cirrhosis
    Note: testing only required in patients with history of HBV or history of HCV < 6 months prior to start of CA-4948
    12. Concomitant illnesses that would preclude safe participation in study, identified within approximately 28 days of C1D1, including:
    a. Uncontrolled or severe cardiovascular disease, including myocardial infarction or unstable angina within 6 months prior to CA-4948, New York Heart Association Class II or greater congestive heart failure, or left ventricular ejection fraction < 50% by echocardiogram or multi-gated acquisition scan, serious arrhythmias uncontrolled on treatment, clinically significant pericardial disease, cardiac amyloidosis, congenital long QT syndrome, or QTc with Fridericia’s correction (QTcF) that is unmeasurable or > 450 msec on screening electrocardiogram (ECG)
    Note: for QTcF > 450 sec on the Screening ECG, the ECG may be repeated twice at least 24 hours apart; the mean QTcF from the three screening ECGs must be ≤ 450 msec in order to meet eligibility for trial participation
    b. Gastrointestinal disease or disorder that could interfere with the swallowing, oral absorption, or tolerance of CA-4948. This includes major abdominal surgery and/or significant bowel resection and/or gastrointestinal diseases that could alter the assessment of PK or safety
    c. Any other severe, acute, or chronic medical, psychiatric or social condition, or laboratory abnormality that may increase the risk of study participation or CA-4948 administration, may interfere with the informed consent process and/or with compliance with the requirements of the study, or may interfere with the interpretation of the study results and, in the Investigator's opinion, would make the patient inappropriate for entry into this study
    d. Systemic fungal, bacterial, viral, or other infection that is not controlled (defined as exhibiting ongoing signs/symptoms related to the infection and without improvement, despite appropriate antibiotics or other treatment)
    13. Pregnant or lactating
    14. History of ≥ Grade 3 rhabdomyolysis without complete recovery
    E.5 End points
    E.5.1Primary end point(s)
    Phase 1
    • Safety measured by adverse events (AEs), dose-limiting toxicities (DLTs) electrocardiograms (ECGs), chemistry and hematology laboratory values, vital signs, and physical examinations

    Phase 2a
    Clinical response in AML or hrMDS assessed as follows:
    • AML: Proportion of patients who achieve CR + CRh
    • hrMDS: ORR (CR + PR)
    E.5.1.1Timepoint(s) of evaluation of this end point
    24 months
    E.5.2Secondary end point(s)
    Phase 1
    • PK parameters of CA-4948 measured by maximum plasma concentration (Cmax), trough plasma concentration (Cmin), time to Cmax (Tmax,) area under the concentration-time curve from 0-24 hours (AUC 0-24), area under the concentration-time curve from 0 to infinity (AUC 0-inf), and half-life (T ½)

    Clinical response in AML or hrMDS assessed as follows:
    • AML:
    o Proportion of patients who achieve complete response (CR) + complete response with partial hematological recovery (CRh)
    o Proportion of patients who achieve complete response with incomplete hematological recovery (CRi), or
    CR, or CRh, or partial response (PR), or morphologic leukemia-free state (MLFS)
    o Duration of response (DOR)
    o Time to response
    • hrMDS:
    o Overall response rate (ORR): proportion of patients who achieve CR or PR
    o DOR
    o Time to response
    • Transfusion independence in AML or hrMDS

    Phase 2
    • Safety measured by AEs, ECGs, chemistry and hematology laboratory values, vital signs, and physical examinations
    Clinical response in AML or hrMDS assessed as follows:
    • Proportion of patients with AML who achieve CR or CRh or CRi
    • Proportion of patients with hrMDS who achieve CR, or PR, or mCR, with or without hematological improvement
    • DOR
    • Time to responses
    • Transfusion independence
    •Overall survival (OS)
    E.5.2.1Timepoint(s) of evaluation of this end point
    24 months
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response Yes
    E.6.10Pharmacogenetic Yes
    E.6.11Pharmacogenomic Yes
    E.6.12Pharmacoeconomic No
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    Tolerability
    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 escalation
    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 concerned2
    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
    Israel
    United States
    Czechia
    France
    Germany
    Italy
    Poland
    Spain
    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
    The end of the study is defined as after the last patient has completed the SFU visit and there are no longer any patients will being followed.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months1
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial months60
    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: 73
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 293
    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 state10
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 145
    F.4.2.2In the whole clinical trial 366
    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)
    NONE
    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 Decision2023-03-18
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2022-11-10
    P. End of Trial
    P.End of Trial StatusCompleted
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