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    Summary
    EudraCT Number:2018-003188-78
    Sponsor's Protocol Code Number:R5458-ONC-1826
    National Competent Authority:Belgium - FPS Health-DGM
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2019-10-21
    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 ConcernedBelgium - FPS Health-DGM
    A.2EudraCT number2018-003188-78
    A.3Full title of the trial
    PHASE 1/2 FIH STUDY OF REGN5458 (ANTI-BCMA X ANTI-CD3 BISPECIFIC ANTIBODY) IN PATIENTS WITH RELAPSED OR REFRACTORY MULTIPLE MYELOMA
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    First in Human (FIH) Study of REGN5458 in Patients With Relapsed or Refractory Multiple Myeloma
    A.3.2Name or abbreviated title of the trial where available
    LINKER-MM1
    A.4.1Sponsor's protocol code numberR5458-ONC-1826
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT03761108
    A.5.4Other Identifiers
    Name:INDNumber:138791
    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 SponsorRegeneron Pharmaceuticals, 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 supportRegeneron Pharmaceuticals, Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationRegeneron Pharmaceuticals, Inc.
    B.5.2Functional name of contact pointClinical Trial Information
    B.5.3 Address:
    B.5.3.1Street Address777 Old Saw Mill River Road
    B.5.3.2Town/ cityTarrytown, NY
    B.5.3.3Post code10591
    B.5.3.4CountryUnited States
    B.5.4Telephone number+18447346643
    B.5.6E-mailclinicaltrials@regeneron.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 nameREGN5458
    D.3.4Pharmaceutical form Concentrate for solution for injection/infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    Subcutaneous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNREGN5458
    D.3.9.2Current sponsor codeREGN5458
    D.3.9.3Other descriptive nameREGN5458
    D.3.9.4EV Substance CodeSUB197034
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number10
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    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 Yes
    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
    Multiple Myeloma
    E.1.1.1Medical condition in easily understood language
    Multiple Myeloma
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.0
    E.1.2Level LLT
    E.1.2Classification code 10028228
    E.1.2Term Multiple myeloma
    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 1
    Part 1 (Intravenous Dose Escalation)
    • To assess the safety, tolerability, and dose-limiting toxicities (DLTs) and to determine one or more recommended phase 2 dose regimens (RP2DRs) of REGN5458 as IV monotherapy in patients with relapsed or refractory multiple myeloma (RRMM)
    Part 2 (Subcutaneous Administration):
    To assess the safety, tolerability, and dose-limiting toxicities (DLTs), and pharmacokinetic (PK) properties, and to determine a dosing regimen of subcutaneous REGN5458 monotherapy in patients with RRMM.

    Phase 2
    • Cohorts 1 and 2:
    To assess the anti-tumor activity of REGN5458 separately in cohorts 1 and 2, as measured by objective response rate (ORR) and as determined by an Independent Review Committee (IRC), in patients who have progressed on or after 3 prior lines of therapy or who are triple-refractory (defined as refractory to a(n) PI, IMiD, and anti-CD38 monoclonal antibody).
    • For Cohort 3 primary objective please see study protocol.
    E.2.2Secondary objectives of the trial
    Phase 1
    Part 1 (IV Dose Escalation):
    • To assess the preliminary anti-tumor activity of REGN5458 as determined by the investigator and measured by ORR, DOR, PFS, rate of minimal residual disease (MRD) negative status, and OS
    • To evaluate the PK properties of REGN5458
    • To characterize the immunogenicity of REGN5458
    • To assess the anti-tumor activity of IV REGN5458 in patients treated in phase 1 dose level 7 (full dose 200 mg) as measured by ORR and as determined by an IRC, in patients who have progressed on or after 3 prior lines of therapy or who are triple-refractory (defined as refractory to a(n) proteasome inhibitor (PI), immunomodulatory imide drug (IMiD), and anti-CD38 monoclonal antibody)

    Part 2 (Subcutaneous Administration):
    • To assess the preliminary anti-tumor activity of REGN5458 as determined by the investigator and measured by ORR, DOR, PFS, rate of MRD negative status, and OS
    • To characterize the immunogenicity of REGN5458

    Please see protocol for Phase 2
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    Future Biomedical Research (Optional)
    Patients who agree to participate in the future biomedical research sub-study will be required to consent to this optional sub-study before samples are banked for future biomedical research. The unused biomarker samples for study-related research, as well as unused PK and ADA samples, will be collected as part of the future biomedical research sub-study. Additional peripheral blood samples will also be collected from patients who agree to participate in this optional sub-study. All samples will be stored for up to 15 years after the final date of the database lock (or for a shorter time period if required per regional laws and regulations). The unused samples may be utilized for future biomedical research that may or may not be directly related to the study, including being used as reference samples and assay development or validation. The results of these future biomedical research analyses will not be presented in the CSR.
    E.3Principal inclusion criteria
    1. Age ≥18 years.

    2. Eastern Cooperative Oncology Group (ECOG) performance status ≤1.

    3. Confirmed diagnosis of active MM by IMWG diagnostic criteria.

    4. Patients must have myeloma that is response-evaluable according to the 2016 IMWG response criteria.

    5. Phase 1 Part 1 (Dose Escalation): Patients with MM who have exhausted all therapeutic options that are expected to provide meaningful clinical benefit, either through disease relapse, treatment refractory disease, or intolerance of the therapy, and including either:
    a. Progression on or after at least 3 lines of therapy, or intolerance of therapy, including a proteasome inhibitor (PI), an IMiD, and an anti-CD38 antibody, OR
    b. Progression on or after an anti-CD38 antibody and have disease that is “double refractory” to a PI and an IMiD, or intolerance of therapy. The anti-CD38 antibody may have been administered alone or in combination with another agent such as a PI. Refractory disease is defined as lack of response or relapse within 60 days of last treatment.

    6. Phase 1 Part 2 (SC Administration): Patients with MM whose disease meets the following criteria:
    a. Progression on or after at least 3 prior lines of therapy including a(n) PI, IMiD, and anti-CD38 antibody, OR
    b. Patients must be triple- refractory, defined as being refractory* to prior treatment with at least 1 PI, 1 IMiD, and an anti-CD38 antibody.
    *Refractory disease is defined as progression during treatment or within 60 days after completion of therapy, or <25% response to therapy.

    Phase 2 (Cohorts 1 and 2): Patients with MM whose disease meets the following criteria:
    a. Progression on or after at least 3 prior lines of therapy including a(n) PI, IMiD, and anti-CD38 antibody, OR
    b. Patients must be triple- refractory, defined as being refractory* to prior treatment with at least 1 PI, 1 IMiD, and an anti-CD38 antibody. *Refractory disease is defined as progression during treatment or within 60 days after completion of therapy, or <25% response to therapy.

    Phase 2 (Cohort 3): Patients with MM whose disease meets the following criteria:
    a. Progression on or after at least 3 prior lines of therapy including a(n) PI, IMiD, and anti-CD38 antibody, OR
    b. Patients must be triple- refractory, defined as being refractory* to prior treatment with at least 1 PI, 1 IMiD, and an anti-CD38 antibody. *Refractory disease is defined as progression during treatment or within 60 days after completion of therapy, or <25% response to therapy.
    AND if they have relapsed after a BCMA-directed CAR-T cellular therapy then:
    • Treatment with a CAR-T must have been associated with a response of PR or better, and
    • If CAR-T cellular therapy was the most recent prior therapy, excluding corticosteroids, then treatment must have been a minimum of 60 days prior to treatment with REGN5458.

    NOTE: Other protocol-defined Inclusion Criteria apply.
    E.4Principal exclusion criteria
    1. Diagnosis of plasma cell leukemia, primary systemic light-chain amyloidosis (excluding myeloma-associated amyloidosis), Waldenström macroglobulinemia (lymphoplasmacytic lymphoma), or POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes).

    2. Patients with known MM brain lesions or meningeal involvement.

    3. Prior treatment with BCMA-directed immunotherapies, including BCMA bispecific antibodies and BiTEs, and BCMA CAR T cells. Note: BCMA antibody-drug conjugates are not excluded.

    4. History of allogeneic stem cell transplantation at any time, or autologous stem cell transplantation within 12 weeks of the start of study treatment.


    NOTE: Other protocol-defined Exclusion criteria apply
    E.5 End points
    E.5.1Primary end point(s)
    Phase 1
    Part 1 (Intravenous Dose Escalation):
    1. Incidence of DLTs from the first dose through the end of the DLT observation period
    2. Incidence and severity of treatment-emergent adverse events (TEAEs)

    Part 2 (Subcutaneous Administration):
    3. The incidence of DLTs from the first dose through the end of the DLT observation period
    4. The incidence and severity of TEAEs and AESIs with REGN5458
    5. Assessment of the PK of REGN5458 administered via SC injection

    Phase 2
    Cohorts 1 and 2:
    6. To assess the anti-tumor activity of IV REGN5458 separately in cohorts 1 and 2, as measured by objective response rate (ORR) and as determined by an Independent Review Committee (IRC), in patients who have progressed on or after 3 prior lines of therapy or who are triple-refractory (defined as refractory to a(n) proteasome inhibitor (PI), immunomodulatory imide drug (IMiD), and anti-CD38 monoclonal antibody).

    Cohort 3:
    7. To assess the incidence and severity of CRS with REGN5458 administered after anti-IL-6R pre-treatment in patients who have progressed on or after 3 prior lines of therapy or who are triple-refractory (defined as refractory to a(n) PI, IMiD, and anti-CD38 monoclonal antibody), and in patients who have relapsed after receiving BCMA directed chimeric antigen receptor (CAR)-T cellular therapy.
    8. To assess the anti-tumor activity of IV REGN5458 administered after anti-IL-6R pre-treatment, as measured by investigator assessed ORR in patients who have progressed on or after 3 prior lines of therapy or who are triple-refractory (defined as refractory to a(n) PI, IMiD, and anti-CD38 monoclonal antibody), and in patients who have relapsed after receiving BCMA directed chimeric antigen receptor (CAR)-T cellular therapy.
    E.5.1.1Timepoint(s) of evaluation of this end point
    As specified in the protocol.
    E.5.2Secondary end point(s)
    PHASE 1
    Part 1 (Intravenous Dose Escalation):
    • Concentrations of REGN5458 in the serum over time
    • Incidence and titer of anti-drug antibodies (ADAs) and incidence of (neutralizing antibody) NAb to REGN5458 over time
    • DOR using the IMWG criteria
    • PFS as measured using the IMWG criteria
    • Rate of MRD negative status using the IMWG criteria
    • OS
    • ORR as measured using the IMWG criteria
    • For patients enrolled in DL7 (200 mg full dose): ORR as determined by blinded IRC, as measured using the IMWG criteria
    Part 2 (Subcutaneous Administration):
    • Incidence and titer of ADAs and incidence of NAb to REGN5458 over time
    • DOR using the IMWG criteria
    • PFS as measured using the IMWG criteria
    • Rate of MRD negative status using the IMWG criteria
    • OS
    • ORR as measured using the IMWG criteria

    PHASE 2
    • ORR according to IMWG criteria as determined by the investigator (cohorts 1 and 2 only)
    • DOR and PFS according to IMWG criteria and as determined by an IRC (cohorts 1 and 2 only) and the investigator
    • Rate of MRD negative status
    • OS
    • Evaluation of the effects of REGN5458 on HRQoL and patient-reported symptoms and functioning (per European Organization for Research and Treatment of Cancer Quality of Life Questionnaire [EORTC QLQ]-C30, Quality of Life Questionnaire-Multiple Myeloma module 20 [QLQ-MY20]), and per EuroQoL-5 Dimension-3 Level Scale [EQ-5D-3L])
    • Change from baseline in patient-reported global health status/QoL per EORTC QLQC30
    • Time to definitive deterioration in patient-reported global health status/QoL per EORTC QLQ-C30
    • Evaluation of the effects of REGN5458 on general health status (per EQ-5D-3L), patient-reported functions and symptoms (per EORTC QLQ-C30 and QLQ-MY20)
    • The incidence and severity of TEAEs and AESI with REGN5458
    • Concentrations of REGN5458 in the serum over time
    • Incidence and titer of ADAs and incidence of NAb to REGN5458 over time
    E.5.2.1Timepoint(s) of evaluation of this end point
    As specified in the 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 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 No
    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 Yes
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised No
    E.8.1.2Open 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 EEA13
    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
    Korea, Republic of
    United Kingdom
    United States
    Belgium
    Germany
    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
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months1
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years4
    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: 387
    F.1.3Elderly (>=65 years) No
    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 state20
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 100
    F.4.2.2In the whole clinical trial 387
    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 Decision2019-12-04
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2020-02-07
    P. End of Trial
    P.End of Trial StatusOngoing
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