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    Summary
    EudraCT Number:2022-001186-12
    Sponsor's Protocol Code Number:GMMG-HD10/DSMM-XX/64007957MMY2003
    National Competent Authority:Germany - PEI
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2022-07-08
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedGermany - PEI
    A.2EudraCT number2022-001186-12
    A.3Full title of the trial
    A Phase 2 Study to Evaluate Safety and Efficacy of Teclistamab- and Talquetamab-based Combination Regimens in Participants with Newly Diagnosed Transplant Eligible Multiple Myeloma
    Phase-2-Studie zur Bewertung der Sicherheit und Wirksamkeit von Teclistamab- und Talequetamab-basierten Kombinationstherapien bei Teilnehmern mit neu diagnostiziertem multiplem Myelom, die für eine Transplantation geeignet sind.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Clinical Trial to Evaluate Safety and Efficacy of Teclistamab- and Talquetamab-based Combination Regimens in Participants with Newly Diagnosed Transplant Eligible Multiple Myeloma
    Klinische Studie für Patienten mit neu diagnostiziertem multiplem Myelom, die zur Transplantation geeignet sind, zur Untersuchung der Sicherheit und Wirksamkeit von Teclistamab- und Talquetamab-basierten Behandlungskombinationen.
    A.3.2Name or abbreviated title of the trial where available
    GMMG-HD10/DSMM XX
    A.4.1Sponsor's protocol code numberGMMG-HD10/DSMM-XX/64007957MMY2003
    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 SponsorRuprecht-Karls-University Heidelberg, Medical Faculity, represented by University Hospital Heidelberg
    B.1.3.4CountryGermany
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportJanssen Research & Development, LLC
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationGMMG Study Office
    B.5.2Functional name of contact pointGMMG Studiensekretariat
    B.5.3 Address:
    B.5.3.1Street AddressIm Neuenheimer Feld 130.3
    B.5.3.2Town/ cityHeidelberg
    B.5.3.3Post code69120
    B.5.3.4CountryGermany
    B.5.4Telephone number+496221568198
    B.5.5Fax number+496221561957
    B.5.6E-mailstudiensekretariat.gmmg@med.uni-heidelberg.de
    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 Yes
    D.2.1.1.1Trade name TECVAYLI
    D.2.1.1.2Name of the Marketing Authorisation holderJanssen-Cilag International N.V.
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    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 nameTeclistamab
    D.3.2Product code JNJ-64007957
    D.3.4Pharmaceutical form Solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPSubcutaneous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNTeclistamab
    D.3.9.2Current sponsor codeJNJ-64007957
    D.3.9.3Other descriptive nameJNJ-64007957-AAA
    D.3.9.4EV Substance CodeSUB201809
    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 Yes
    D.3.11.13.1Other medicinal product typeHuman IgG4 bispecific antibody against BCMA and CD3
    D.IMP: 2
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name TECVAYLI
    D.2.1.1.2Name of the Marketing Authorisation holderJanssen-Cilag International N.V.
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    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 nameTeclistamab
    D.3.2Product code JNJ-64007957
    D.3.4Pharmaceutical form Solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPSubcutaneous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNTeclistamab
    D.3.9.2Current sponsor codeJNJ-64007957
    D.3.9.3Other descriptive nameJNJ-64007957-AAA
    D.3.9.4EV Substance CodeSUB201809
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number90
    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 Yes
    D.3.11.13.1Other medicinal product typeHuman IgG4 bispecific antibody against BCMA and CD3
    D.IMP: 3
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Darzalex
    D.2.1.1.2Name of the Marketing Authorisation holderJanssen-Cilag International N.V.
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community Yes
    D.2.5.1Orphan drug designation numberEU/3/13/1153
    D.3 Description of the IMP
    D.3.1Product nameDaratumumab co-formulated with recombinant human hyaluronidase (rHuPH20)
    D.3.2Product code JNJ-54767414
    D.3.4Pharmaceutical form Solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPSubcutaneous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNDaratumumab
    D.3.9.1CAS number 945721-28-8
    D.3.9.2Current sponsor codeJNJ-54767414
    D.3.9.3Other descriptive nameHUMAX-CD38
    D.3.9.4EV Substance CodeSUB175772
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    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 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.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 Yes
    D.2.1.1.1Trade name TALVEY
    D.2.1.1.2Name of the Marketing Authorisation holderJanssen-Cilag International N.V.
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community Yes
    D.2.5.1Orphan drug designation numberEU / 3/21/2486
    D.3 Description of the IMP
    D.3.1Product nameTalquetamab
    D.3.2Product code JNJ-64407564
    D.3.4Pharmaceutical form Solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPSubcutaneous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNTalquetamab
    D.3.9.1CAS number 2226212-40-2
    D.3.9.2Current sponsor codeJNJ-64407564
    D.3.9.3Other descriptive nameJNJ-64407564-AAA
    D.3.9.4EV Substance CodeSUB204100
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number2
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin 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 Yes
    D.3.11.13.1Other medicinal product typehumanized bispecific antibody
    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 Yes
    D.2.1.1.1Trade name TALVEY
    D.2.1.1.2Name of the Marketing Authorisation holderJanssen-Cilag International N.V.
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community Yes
    D.2.5.1Orphan drug designation number EU/3/21/2486
    D.3 Description of the IMP
    D.3.1Product nameTalquetamab
    D.3.2Product code JNJ-64407564
    D.3.4Pharmaceutical form Solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPSubcutaneous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNTalquetamab
    D.3.9.1CAS number 2226212-40-2
    D.3.9.2Current sponsor codeJNJ-64407564
    D.3.9.3Other descriptive nameJNJ-64407564-AAA
    D.3.9.4EV Substance CodeSUB204100
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number40
    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 Yes
    D.3.11.13.1Other medicinal product typea humanized bispecific antibody
    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
    Newly Diagnosed Multiple Myeloma in patients eligible for stem cell transplantation
    Neu diagnostiziertes multiples Myelom bei Patienten, die für eine Stammzelltransplantation geeignet sind
    E.1.1.1Medical condition in easily understood language
    Newly Diagnosed Multiple Myeloma in patients eligible for stem cell transplantation
    Neu diagnostiziertes multiples Myelom bei Patienten, die für eine Stammzelltransplantation geeignet sind
    E.1.1.2Therapeutic area Diseases [C] - Blood and lymphatic diseases [C15]
    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 Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To evaluate the safety and tolerability of teclistamab- and talquetamab-based combination regimens over the entire treatment phase for each arm, in participants with ND-TEMM.
    E.2.2Secondary objectives of the trial
    -To evaluate MRD negativity rates, conversion, and sustainability

    -To evaluate the efficacy of teclistamab- and talquetamab-based combination regimens as induction and post-transplant maintenance
    treatments, and teclistamab in combination with talquetamab as replacement for HDT+ASCT following induction: Post-induction, post-ASCT (Arms A, A1, B, E, E1 and, if applicable, F and F1), postmaintenance (Arms A, A1, B, E, E1 and, if applicable, F and F1), post-Tec-Tal (Arm D), and best overall:
    ORR (at least PR or better)
    CR or better
    VGPR or better
    - DOR
    - PFS
    -To assess feasibility of successful transplantation (all arms except Arm D) (Stem cell yield and days to engraftment)
    -To characterize the PK of teclistamab and talquetamab in participants with multiple myeloma before and after ASCT or during Tec-Tal treatment, and to characterize the PK of daratumumab after ASCT (population PK approach)
    -To assess the immunogenicity of teclistamab, talquetamab and daratumumab (ADA)

    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. 18 to 70 years of age, inclusive
    2. Have an ECOG performance status score of 0 to 2 at screening
    3. Have clinical laboratory values meeting the following criteria during the Screening Phase.

    Hematology:
    Hemoglobin>=7.5 g/dL (>=4.65 mmol/L; without prior RBC transfusion within 7 days before the laboratory test; recombinant human erythropoietin use is permitted)
    Platelets: >=75×10E9/L in participants in whom <50% of bone marrow nucleated
    cells are plasma cells and >=50×10E9/L in participants in whom ≥50% of bone marrow nucleated cells are plasma cells (without transfusion support or thrombopoietin receptor agonist within 7 days before the laboratory test)
    Absolute neutrophil count: >=1.0×109/L (prior growth factor support is permitted but must be without support for 7 days for G-CSF or GM-CSF and for 14 days for pegylated-G-CSF)

    Chemistry
    AST, ALT: ≤2.5×ULN
    eGFR: ≥30 mL/min based on Cockcroft-Gault formula or a 24-hour urine collection
    Total bilirubin: ≤2.0×ULN; (isolated total bilirubin ≥ 1.5 x ULN with conjugated [direct] bilirubin <1.5xULN is allowed for those participants with known congenital nonhemolytic hyperbilirubinemia such as Gilbert’s syndrome).
    Serum calcium corrected for albumin: ≤14 mg/dL (≤3.5 mmol/L) or free ionized calcium ≤6.5 mg/dL (≤1.6 mmol/L)


    4. A female participant of childbearing potential must have a negative highly sensitive serum pregnancy test at screening, and within 24 hours before start of study treatment, and must agree to further pregnancy tests during the study.
    5. A participant must be either
    a. Not of childbearing potential, or
    b. Of childbearing potential and practicing 2 effective methods of contraception from the time of signing ICF until 6 months after the last dose of study treatment.
    Contraception must begin 4 weeks prior to dosing of lenalidomide.
    6. A female participant must agree not to donate eggs (ova, oocytes) or freeze for future use, for the purposes of assisted reproduction during the study and for a period of 6 months after receiving the last dose of study treatment.
    7. A male participant must wear a condom when engaging in any activity that allows for passage of ejaculate to another person during the study and for a minimum of 100 days after receiving the last dose of study treatment.
    8. A male participant must agree not to donate sperm for the purpose of reproduction during the study and for a minimum of 100 days after receiving the last dose of study treatment.
    9. Must be willing and able to adhere to the lifestyle restrictions specified in this protocol, including adherence to the global PPP or local PPP program for lenalidomide.
    10. Must sign an ICF indicating that he or she understands the purpose of, and procedures required for, the study and is willing to participate in the study.

    Participants in Arms A, A1, B, D, E, E1, F, F1 must also satisfy all of the following criteria to be enrolled in the study:
    1A. Documented multiple myeloma as defined by the criteria below:
    a. Multiple myeloma diagnosis according to the IMWG diagnostic criteria
    b. Measurable disease at screening as defined by any of the following:
    1. Serum M-protein level ≥1.0 g/dL or
    2. Urine M-protein level ≥200 mg/24 hours or
    3. Serum immunoglobulin free light chain level ≥10 mg/dL and abnormal serum immunoglobulin kappa lambda free light chain ratio
    2A. Newly diagnosed participants for whom HDT and ASCT is part of the intended treatment plan.

    Participants Arms C, C1; C2 must also satisfy all of the following criteria
    1B. diagnosed multiple myeloma according to IMWG criteria, see note
    2B. Must have received 4 to 6 cycles of 3 or 4 drug-induction therapy that includes a proteasome inhibitor and/or an IMiD with or without anti-CD38 monoclonal antibody and a single or tandem ASCT. Post-ASCT consolidation is permitted for up to 2 cycles as long as the total number of induction plus consolidation cycles does not exceed 7.
    3B. Must have received only one line of therapy and achieved at least a PR as per IMWG 2016 response criteria based on the investigator’s assessment. Participants with plasmacytomas at the time of diagnosis must meet IMWG 2016 response criteria for ≥PR based on repeat imaging utilizing the same modality.
    4B. Must have received HDT and ASCT within 12 months of the start of induction therapy and be within 6 months of the last ASCT.
    (7 months for participants who received consolidation at the time of enrollment).
    E.4Principal exclusion criteria
    1.a. Ongoing myelodysplastic syndrome or B-cell malignancy (other than MM)
    b. History of malignancy (other than MM), considered high risk of recurrence requiring systemic therapy.
    c. Active malignancy other than MM. Exceptions (details see protocol):
    - Non-muscle invasive bladder cancer
    - Non- melanoma skin cancer after curative therapy or localized melanoma after curative surgical resection alone
    - Non-invasive cervical cancer
    - Breast cancer: adequately treated lobular carcinoma in situ, or history of localized breast cancer
    - Localized prostate cancer, treated locally only
    2. CNS involvement or clinical signs of meningeal involvement of MM.
    3. Stroke, transient ischemic attack or seizure within 6 months prior C1D1.
    4. History of allogeneic stem cell transplant or organ transplantations requiring immunosuppressive therapy.
    5. Any of the following
    - Positive HIV, Hep B, active Hep C (details see protocol)
    - COPD with a FEV1 <50% of predicted normal.
    - Moderate/severe persistent asthma within the past 2 years or uncontrolled asthma.
    6 Concurrent medical or psychiatric condition or disease that is likely to interfere with study procedures, or that in the investigator’s opinion would constitute a hazard for participants, such as:
    a. Acute diffuse infiltrative pulmonary disease
    b. Evidence of active systemic viral, fungal or bacterial infection, requiring systemic antimicrobial therapy
    c. History of autoimmune disease, exc. vitiligo, type I diabetes, prior autoimmune thyroid disease currently euthyroid
    d. Disabling psychiatric conditions, severe dementia, or altered mental status
    e. History of noncompliance
    7. Following cardiac conditions:
    a. New York Heart Association stage III or IV congestive heart failure
    b. Myocardial infarction, unstable angina, or coronary artery bypass graft ≤6 months prior enrollment
    c. History of clinically significant ventricular arrhythmia or unexplained syncope
    d. Uncontrolled cardiac arrhythmia or clinically significant abnormal ECG.
    8. Contraindications or life-threatening allergies, hypersensitivity, or intolerance to any study drug/excipients.
    9. Pregnant, breastfeeding, or planning pregnancy while enrolled in this study or within 6 months after the last dose of any study treatment.
    10. Plans to father a child while enrolled in this study or within 100 days after the last dose of any study treatment.
    11. significant traumatic injury or major surgery within 2 weeks prior to the start of study treatment, or will not have fully recovered from surgery, or has major surgery planned during the study or within 2 weeks after the last dose of study treatment.
    12. Received an investigational drug, used an invasive investigational medical device within 4 weeks or 5 half-lives of the respective drug/IMP before enrollment or is enrolled in an interventional study.
    13. Have gastrointestinal disease that may significantly alter the absorption of oral drugs
    14. Received a live, attenuated vaccine within 4 weeks before the first dose of study treatment.
    15. Be unable or unwilling to undergo antithrombotic prophylactic treatment.

    Arms A, A1, B. D, E, E1, F and F1
    1. Prior or current systemic therapy or stem cell transplant for plasma cell dyscrasia, with the exc. of emergency use of a short course (equiv. of dexamethasone 40 mg/day for a max. 4 days) of corticosteroids before treatment.
    2. Radiotherapy within 14 days or focal radiation within 7 days of enrollment. Radiotherapy on measurable soft-tissue plasmacytoma(s) is not permitted even in the setting of palliation for symptomatic management.
    3. Plasmapheresis within 28 days of enrollment.
    4. Plasma cell leukemia, smoldering MM, Waldenström’s macroglobulinemia, POEMS syndrome, or primary light chain amyloidosis.
    5. Arms B, F, and F1 only: Peripheral neuropathy or neuropathic pain Grade 2 or higher
    6. Arms B, F, and F1 only: received a strong CYP3A4 inducer within 5 half-lives prior to enrollment

    Arms C, C1 and C2
    1. Received any prior BCMA-directed therapy (Arms C and C1 only) or GPRC5D-directed therapy (Arm C2 only).
    2. Any previous therapy with an immune cell redirecting agent or gene modified adoptive cell therapy (eg, CAR T cells, NK cells).
    3. Discontinued treatment due to any AE related to lenalidomide as determined by the investigator.
    4. Radiotherapy within 14-day or focal radiation within 7 days of enrollment.
    5. Progressed on MM therapy any time prior to screening.
    6. Received a cumulative dose of corticosteroids equivalent to ≥40 mg dexamethasone within the 14 day period before the start of study treatment.
    7. Plasma cell leukemia, smoldering MM, Waldenström’s macroglobulinemia, POEMS syndrome, or primary light chain amyloidosis.
    8. Intolerant to starting dose of lenalidomide.
    E.5 End points
    E.5.1Primary end point(s)
    Incidence and severity of AEs and SAEs
    E.5.1.1Timepoint(s) of evaluation of this end point
    any time during the study
    E.5.2Secondary end point(s)
    To evaluate MRD negativity rates, conversion, and sustainability:
    Post-induction, post-ASCT, post-maintenance, and best overall
    - MRD negative CR
    Sustained MRD negative CR (duration ≥12 months) after 18 cycles of maintenance treatment
    MRD negative CR conversion and deepening during maintenance

    To evaluate the efficacy of Teclistamab and Talquetamab based combination regimes as induction and posttransplant maintenance treatments, and teclistamab in combination with talquetamab as replacement for ASCT following induction.
    Post-induction, post-ASCT (Arms A, A1, B, E, E1 and, if applicable, F and F1), postmaintenance (Arms A, A1, B, E, E1 and, ifapplicable, F and F1), post-Tec-Tal (Arm D),
    and best overall:
    - ORR (at least a PR or better)
    - CR or better
    - VGPR or better
    DOR
    PFS

    To assess feasibility of successful transplantation (all arms except ArmD):
    Stem cell yield and days to engraftment (all arms except Arm D)

    To characterize the PK of teclistamab and talquetamab in participants with multiple myeloma before and after an ASCT or during Tec-Tal treatment, and to characterize the PK of daratumumab after an ASCT: PK parameters using population PK approach

    To assess the immunogenicity of teclistamab, talquetamab and daratumumab: Measure presence of ADAs
    E.5.2.1Timepoint(s) of evaluation of this end point
    MRD negativity rates, conversion, and sustainability: Post-induction, post-ASCT, post-maintenance, and best overall

    Sustained MRD negative CR: ≥12 months and after 18 cycles of maintenance treatment. Sustained MRD negative CR

    - ORR (at least a PR or better)
    - CR or better
    - VGPR or better
    Post-induction, post-ASCT, post-maintenance (assessments 3-monthly), and best overall:

    DOR: 3-monthly response assessment
    PFS: 3-monthly response assessment

    PK analysis: over the course of the study
    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 No
    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) No
    E.7.1.1First administration to humans No
    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 Information not present in EudraCT
    E.8.1.3Single blind Information not present in EudraCT
    E.8.1.4Double blind Information not present in EudraCT
    E.8.1.5Parallel group Information not present in EudraCT
    E.8.1.6Cross over Information not present in EudraCT
    E.8.1.7Other Information not present in EudraCT
    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.8.2.4Number of treatment arms in the trial11
    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 concerned11
    E.8.5The trial involves multiple Member States No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    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 end of study is defined as when all participants have completed 18 cycles of maintenance treatment (or optional participants have completed 12 months of MRD negativity during maintenance phase) and have been followed for an additional 6 months or when the sponsor decides to stop the study.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years6
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned 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: 100
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 30
    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 state130
    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)
    According to Multiple Myeloma Standard of Care treatment
    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 Decision2022-10-21
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2022-11-07
    P. End of Trial
    P.End of Trial StatusOngoing
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