<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT04483739</url>
  </required_header>
  <id_info>
    <org_study_id>EMN24</org_study_id>
    <nct_id>NCT04483739</nct_id>
  </id_info>
  <brief_title>Isa-KRd vs KRd in Newly Diagnosed Multiple Myeloma Patients Eligible for Autologous Stem Cell Transplantation (IsKia TRIAL)</brief_title>
  <acronym>IsKia</acronym>
  <official_title>Phase III Study of Isatuximab-Carfilzomib-Lenalidomide-Dexamethasone (Isa-KRd) Versus Carfilzomib-Lenalidomide-Dexamethasone (KRd) in Newly Diagnosed Multiple Myeloma Patients Eligible for Autologous Stem Cell Transplantation (IsKia TRIAL</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>European Myeloma Network</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>EMN Research Italy</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Sanofi</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
    <collaborator>
      <agency>Amgen</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>European Myeloma Network</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      This protocol is a phase III study designed to compare the efficacy and the safety of Isa-KRd&#xD;
      induction, transplant, Isa-KRd post ASCT consolidation and Isa-KRd light consolidation vs KRd&#xD;
      induction, transplant, KRd post ASCT consolidation and KRd light consolidation After&#xD;
      confirmation of eligibility criteria patients will be randomized to one of the 2 treatment&#xD;
      groups in a 1:1 randomization ratio.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This is a open-label randomized phase III study that enrolls newly diagnosed MM patient&#xD;
      eligible for high-dose chemotherapy and ASCT. Patients will be randomized at enrolment (1:1,&#xD;
      stratification according to ISS Stage [3 levels: I vs II vs III] and cytogenetic risk FISH [2&#xD;
      levels: high-risk vs standard risk/missing] based on presence of t(4;14), t(14;16), and/or&#xD;
      del 17p)) into 2 treatment arms: -ARM A: induction with 4 cycles of&#xD;
      Isatuximab-Carfilzomib-Lenalidomide-dexamethasone (Isa-KRd) followed by cyclophophamide and&#xD;
      stem cell collections, chemotherapy with Melphalan 200 mg/m2 followed by ASCT (Mel200-ASCT),&#xD;
      4 cycles of Isa-KRd post ASCT consolidation and 12 cycles of&#xD;
      Isatuximab-Lenalidomide-Carfilzomib-dexamethasone (IsaKRd) light consolidation; ARM B:&#xD;
      induction with 4 cycles of Carfilzomib-Lenalidomide-dexamethasone (KRd) followed by&#xD;
      cyclophophamide and stem cell collections, chemotherapy with Melphalan 200 mg/m2 followed by&#xD;
      ASCT (Mel200-ASCT), 4 cycles of KRd post ASCT consolidation and 12 cycles of&#xD;
      Carfilzomib-Lenalidomide-dexamethasone (KRd) light consolidation. Details of all treatments&#xD;
      (dose and schedule) are given in paragraph 8. After light consolidation patients are allowed&#xD;
      to receive Lenalidomide maintenance as per standard of care.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">September 25, 2020</start_date>
  <completion_date type="Anticipated">December 31, 2032</completion_date>
  <primary_completion_date type="Anticipated">July 31, 2025</primary_completion_date>
  <phase>Phase 3</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Rate of MRD negativity after ASCT consolidation treatment by NGS</measure>
    <time_frame>The end of consolidation, average of 12 months</time_frame>
    <description>The rate of MRD negativity is determined as the proportion of patients with MRD negativity (≥10-5 sensitivity level) after ASCT consolidation treatment using ITT principle. For patients who withdraw from the study or are lost to follow up before four post ASCT consolidation cycles, the best MRD assessment will be considered. Patients will be classified as MRD positive if they have only MRD positive test results or do not undergo MRD assessment.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Post induction MRD negativity rate by NGS</measure>
    <time_frame>The end of induction, average of 4 months</time_frame>
    <description>The rate of MRD negativity after induction is determined as the proportion of patients with MRD negativity (≥10-5 sensitivity level, NGS) after the induction phase using ITT principle. Patients will be classified as MRD positive if they have only MRD positive test results or do not undergo MRD assessment/sample not adequate.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Progression-free survival (PFS) in the 2 arms</measure>
    <time_frame>approximately up to 5 years</time_frame>
    <description>PFS will be measured from the date of randomization to the date of first observation of PD, or death from any cause as an event. Subjects who have not progressed or who withdraw from the study will be censored at the time of the last complete disease assessment. All subjects who were lost to FU will also be censored at the time of last complete disease assessment</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Post light-consolidation MRD negativity rate by NGS</measure>
    <time_frame>At the end of light-consolidation, average of 24 months</time_frame>
    <description>The rate of MRD negativity after light consolidation is determined as the proportion of patients with MRD negativity (≥10-5 sensitivity level, NGS) after light consolidation phase using ITT principle. Patients will be classified as MRD positive if they have only MRD positive test results or do not undergo MRD assessment/sample not adequate. Patients who withdraw from the study or are lost to follow up before MRD evaluation, the best MRD assessment will be considered</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall Response Rate (ORR) post-induction</measure>
    <time_frame>Approx 4 months</time_frame>
    <description>Response rate (sCR, CR, VGPR, PR, ORR) will be evaluated according to IMWG Response criteria after induction.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall Response Rate (ORR) post-transplant</measure>
    <time_frame>Approximately 8 months</time_frame>
    <description>Response rate (sCR, CR, VGPR, PR, ORR) will be evaluated according to IMWG Response criteria after ASCT.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall Response Rate (ORR) post-consolidation</measure>
    <time_frame>Approximately 12 months</time_frame>
    <description>Response rate (sCR, CR, VGPR, PR, ORR) will be evaluated according to IMWG Response criteria after consolidation.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall Response Rate (ORR) post light-consolidation</measure>
    <time_frame>Approximately 24 months</time_frame>
    <description>Response rate (sCR, CR, VGPR, PR, ORR) will be evaluated according to IMWG Response criteria after light consolidation.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Post ASCT MRD negativity rate by NGS</measure>
    <time_frame>After ASCT, approximately 8 months.</time_frame>
    <description>The rate of MRD negativity after ASCT is determined as the proportion of patients with MRD negativity (≥10-5 sensitivity level), NGS using ITT principle. For patients who withdraw from the study or are lost to follow up before ASCT, the best MRD assessment will be considered. Patients will be classified as MRD positive if they have only MRD positive test results or do not undergo MRD assessment.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>MRD negativity rate by NGF post induction</measure>
    <time_frame>Approximately 4 months</time_frame>
    <description>The rate of MRD negativity (by NGF) after induction is determined as the proportion of patients with MRD negativity (≥10-5 sensitivity level) after the specific phase using ITT principle. Patients will be classified as MRD positive if they have only MRD positive test results or do not undergo MRD assessment. Patients who withdraw from the study or are lost to follow up before MRD evaluation phase, the best MRD assessment will be considered.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>MRD negativity rate by NGF post induction</measure>
    <time_frame>Approximately 8 months</time_frame>
    <description>The rate of MRD negativity (by NGF) after ASCT is determined as the proportion of patients with MRD negativity (≥10-5 sensitivity level) after the specific phase using ITT principle. Patients will be classified as MRD positive if they have only MRD positive test results or do not undergo MRD assessment. Patients who withdraw from the study or are lost to follow up before MRD evaluation phase, the best MRD assessment will be considered.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>MRD negativity rate by NGF post consolidation</measure>
    <time_frame>Approximately 8 months</time_frame>
    <description>The rate of MRD negativity (by NGF) after consolidation is determined as the proportion of patients with MRD negativity (≥10-5 sensitivity level) after the specific phase using ITT principle. Patients will be classified as MRD positive if they have only MRD positive test results or do not undergo MRD assessment. Patients who withdraw from the study or are lost to follow up before MRD evaluation phase, the best MRD assessment will be considered.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>MRD negativity rate by NGF post light consolidation</measure>
    <time_frame>Approximately 24 months</time_frame>
    <description>The rate of MRD negativity (by NGF) after light consolidation are determined as the proportion of patients with MRD negativity (≥10-5 sensitivity level) after the specific phase using ITT principle. Patients will be classified as MRD positive if they have only MRD positive test results or do not undergo MRD assessment. Patients who withdraw from the study or are lost to follow up before MRD evaluation phase, the best MRD assessment will be considered.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Duration of response</measure>
    <time_frame>approximately up to 9 years</time_frame>
    <description>Duration of response is defined as the time between first documentation of response (achievement of at least a PR) and PD with deaths owning to causes other than progression not counted, but censored. Responders without disease progression at the cut-off date of final analysis will be censored either at the time of lost to FU, at the time of death due to other cause than PD, or at the at the time of last contact</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Duration of MRD negativity (by NGS and NGF)</measure>
    <time_frame>approximately up to 9 years</time_frame>
    <description>The duration of MRD Negativity (by NGS and NGF) is defined as time between first MRD Negativity and first MRD positivity. Patients without MRD positivity will be censored at last complete assessment</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Determine the rate of sustained for 1-year MRD negativity (by NGF and NGS) from post ASCT consolidation to post light consolidation</measure>
    <time_frame>approximately up to 9 years</time_frame>
    <description>Rate of 1 year sustained MRD negativity by NGS (from post ASCT consolidation to post light consolidation) will be also evaluated.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Determine the time to progression (TTP)</measure>
    <time_frame>approximately up to 9 years</time_frame>
    <description>From the date of randomization to the date of first disease progression or death per PD, whichever occurs first</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall Survival (OS)</measure>
    <time_frame>approximately up to 9 years</time_frame>
    <description>Overall Survival (OS), measured from the date of from randomization to the date the subject's death</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Time to next therapy (TNT)</measure>
    <time_frame>approximately up to 9 years</time_frame>
    <description>TNT will be measured from the date of randomization to the date of next anti-myeloma therapy. Death due to any cause before starting therapy will be considered an event. Subjects who have not progressed or who withdraw from the study will be censored at the time of the last complete disease assessment. Subjects lost to FU will also be censored at the time of last contact.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Progression-free survival on the next line of therapy (PFS2)</measure>
    <time_frame>approximately up to 9 years</time_frame>
    <description>Progression-free survival on the next line of therapy (PFS2) is defined as the time from randomization to progression on the next line of treatment or death, whichever comes first.</description>
  </secondary_outcome>
  <number_of_arms>6</number_of_arms>
  <enrollment type="Actual">302</enrollment>
  <condition>Multiple Myeloma</condition>
  <arm_group>
    <arm_group_label>Krd Induction</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>4 28 day cycles of Carfilzomib = 20 mg/m2 IV on day 1 cycle 1 only, followed by 56 mg/m2 IV on days 8, 15 cycle 1 and on days 1, 8, 15 for cycles 2-4 Lenalidomide= 25 mg orally daily on days 1-21 Dexamethasone = 40 mg orally/IV on days 1, 8, 15, 22</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Isa-KRd induction</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Isatuximab= 10 mg/kg IV on day 1, 8, 15, and 22 during Cycle 1, followed by 10 mg/kg IV on days 1 and 15 during Cycles 2 to 4.&#xD;
Carfilzomib = 20 mg/m2 IV on day 1 cycle 1 only, followed by 56 mg/m2 IV on days 8, 15 cycle 1 and on days 1, 8, 15 for cycles 2-4 Lenalidomide= 25 mg orally daily on days 1-21 Dexamethasone = 40 mg orally/IV on days 1, 8, 15, 22</description>
  </arm_group>
  <arm_group>
    <arm_group_label>KRd post ASCT consolidation</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>4 28 day cycles of Carfilzomib = 56 mg/m2 IV on days 1, 8, 15 cycle 5-8 Lenalidomide= 25 mg orally daily on days 1-21 Dexamethasone = 40 mg orally/IV on days 1, 8, 15, 22</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Isa-KRd post ASCT consolidation:</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>4 28 day cycles of Isatuximab= 10 mg/kg IV on days 1 and 15 on cycles 5-8 Carfilzomib = 56 mg/m2 IV on days 1, 8, 15 cycle 5-8 Lenalidomide= 25 mg orally daily on days 1-21 Dexamethasone = 40 mg orally/IV on days 1, 8, 15, 22</description>
  </arm_group>
  <arm_group>
    <arm_group_label>KRd light consolidation</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>12 28 day cycles of Carfilzomib = 56 mg/m2 IV on days 1, 15 Lenalidomide = 10 mg orally on days 1-21 Dexamethasone = 20 mg orally/IV on days 1, 15</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Isa-KRd light consolidation</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Isatuximab= 10 mg/kg IV on day 1 Carfilzomib = 56 mg/m2 IV on days 1, 15 Lenalidomide = 10 mg orally on days 1-21 Dexamethasone = 20 mg orally/IV on days 1, 15</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Carfilzomib Lenalidomide Dexamethasone</intervention_name>
    <description>Isatuximab-Carfilzomib-Lenalidomide-Dexamethasone (Isa-KRd) versus Carfilzomib-Lenalidomide-Dexamethasone (KRd) in newly diagnosed multiple myeloma patients eligible for autologous stem cell transplantation</description>
    <arm_group_label>KRd light consolidation</arm_group_label>
    <arm_group_label>KRd post ASCT consolidation</arm_group_label>
    <arm_group_label>Krd Induction</arm_group_label>
    <other_name>KRd</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Isatuximab Carfilzomib Lenalidomide Dexamethasone</intervention_name>
    <description>Isatuximab-Carfilzomib-Lenalidomide-Dexamethasone (Isa-KRd) versus Carfilzomib-Lenalidomide-Dexamethasone (KRd) in newly diagnosed multiple myeloma patients eligible for autologous stem cell transplantation</description>
    <arm_group_label>Isa-KRd induction</arm_group_label>
    <arm_group_label>Isa-KRd light consolidation</arm_group_label>
    <arm_group_label>Isa-KRd post ASCT consolidation:</arm_group_label>
    <other_name>Isa-KRD</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Patient with newly diagnosed multiple myeloma and eligible to ASCT.&#xD;
&#xD;
          -  Patient is, in the investigator's opinion, willing and able to comply with the study&#xD;
             visits and procedures required per protocol.&#xD;
&#xD;
          -  Patient has provided written informed consent in accordance with federal, local, and&#xD;
             institutional guidelines prior to initiation of any study-specific activities or&#xD;
             procedures. Subject does not have kind of condition that, in the opinion of the&#xD;
             Investigator, may compromise the ability of the subject to give written informed&#xD;
             consent and patient is, in the investigator(s) opinion, willing and able to comply&#xD;
             with the protocol requirements.&#xD;
&#xD;
          -  Monoclonal plasma cells in the bone marrow ≥10% or presence of a biopsy proven&#xD;
             plasmacytoma and documented multiple myeloma satisfying at least one of the calcium,&#xD;
             renal, anemia, bone (CRAB) criteria or biomarkers of malignancy criteria:&#xD;
&#xD;
          -  CRAB criteria:&#xD;
&#xD;
               -  Hypercalcemia: serum calcium &gt;0.25 mmol/L (&gt;1 mg/dL) higher than upper limit of&#xD;
                  normal (ULN) or &gt;2.75 mmol/L (&gt;11 mg/dL)&#xD;
&#xD;
               -  Renal insufficiency: creatinine clearance &lt;40mL/min or serum creatinine &gt;177&#xD;
                  μmol/L (&gt;2 mg/dL)&#xD;
&#xD;
               -  Anemia: hemoglobin &gt;2 g/dL below the lower limit of normal or hemoglobin &lt;10 g/dL&#xD;
&#xD;
               -  Bone lesions: one or more osteolytic lesions on skeletal radiography, CT, or&#xD;
                  PET-CT&#xD;
&#xD;
          -  Biomarkers of Malignancy:&#xD;
&#xD;
               -  Clonal bone marrow plasma cell percentage ≥60%&#xD;
&#xD;
               -  Involved: uninvolved serum FLC ratio ≥100&#xD;
&#xD;
               -  &gt;1 focal lesion on magnetic resonance imaging (MRI) studies&#xD;
&#xD;
          -  Patient is 18 - 70 years old and is eligible for autologous stem cell transplantation&#xD;
&#xD;
          -  Patient has measurable disease as defined by any one of the following:&#xD;
&#xD;
               -  Serum monoclonal paraprotein (M-protein) level ≥1.0 g/dL or urine M-protein level&#xD;
                  ≥200 mg/24 hours; or&#xD;
&#xD;
               -  Light chain multiple myeloma without measurable disease in the serum or the&#xD;
                  urine: Serum immunoglobulin FLC ≥10 mg/dL and abnormal serum immunoglobulin kappa&#xD;
                  lambda FLC ratio.&#xD;
&#xD;
          -  Life expectancy ≥ 3 months&#xD;
&#xD;
          -  ECOG status ≤2&#xD;
&#xD;
          -  Clinical laboratory values meeting the following criteria during the Screening Phase:&#xD;
&#xD;
               -  Adequate hepatic function, with serum (alanine aminotransferase) ALT ≤ 2.5 times&#xD;
                  the upper limit of normal (ULN), AST (aspartate transaminase) ≤ 2.5 x the ULN&#xD;
&#xD;
               -  Serum direct bilirubin ≤ 1.5 ULN) (except in subjects with congenital&#xD;
                  bilirubinemia, such as Gilbert syndrome, direct bilirubinemia ≤ 1.5 ULN)&#xD;
&#xD;
               -  Absolute neutrophil count (ANC) ≥ 1.0 × 109/L&#xD;
&#xD;
               -  Platelet count ≥ 75× 109/L (≥ 50× 109/L if myeloma involvement in the bone marrow&#xD;
                  is &gt; 50%) and no platelet infusion in the 1 week prior to screening platelet&#xD;
                  count&#xD;
&#xD;
               -  Creatinine clearance (CrCl) ≥ 30 mL/minute. Creatinine clearance should be&#xD;
                  calculated using eGFR (Modified Diet in Renal Disese [MDRD])&#xD;
&#xD;
               -  Corrected serum calcium ≤ 13.5 mg/dL (3.4 mmol/L)&#xD;
&#xD;
               -  LVEF ≥ 40%. 2-D transthoracic echocardiogram (ECHO) is the preferred method of&#xD;
                  evaluation. Multigated Acquisition Scan (MUGA) is acceptable if ECHO is not&#xD;
                  available.&#xD;
&#xD;
          -  Females of childbearing potential (FCBP)* complies with the conditions of the&#xD;
             Pregnancy Prevention Plan, including confirmation that she has an adequate level of&#xD;
             understanding and must agree to ongoing pregnancy testing and to practice&#xD;
             contraception or true abstinence. FCBP must use a highly effective and an additional&#xD;
             barrier contraception method simultaneously for 4 weeks before starting therapy,&#xD;
             during treatment and dose interruptions and for 5 months after the last dose of study&#xD;
             drugs.&#xD;
&#xD;
          -  Male subjects must agree to practice contraception if sexually active with FCBP during&#xD;
             the treatment and for 5 months after the last dose of study drugs. Males must agree to&#xD;
             refrain from donating sperm for at least 90 days after the last dose of carfilzomib&#xD;
             and for at least 5 months after the last dose of isatuximab.&#xD;
&#xD;
          -  *Note 1: a FCBP is a woman who:&#xD;
&#xD;
          -  has achieved menarche at some time point,&#xD;
&#xD;
          -  has not undergone a hysterectomy or bilateral oophorectomy or,&#xD;
&#xD;
          -  has not been naturally postmenopausal (amenorrhea following cancer therapy does not&#xD;
             rule out childbearing potential) for at least 24 consecutive months (ie, has had&#xD;
             menses at any time in the preceding 24 consecutive months).&#xD;
&#xD;
          -  Note 2: true abstinence is acceptable when this is in line with the preferred and&#xD;
             usual lifestyle of the patient. Periodic abstinence (eg, calendar, ovulation,&#xD;
             symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of&#xD;
             contraception.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Previous treatment with anti-myeloma therapy (does not include radiotherapy,&#xD;
             biphosphonates, or a single short course of steroid ≤ to the equivalent of&#xD;
             dexamethasone 40 mg/day for 4 days).&#xD;
&#xD;
          -  Patients with non-secretory MM unless serum free light chains are present and the&#xD;
             ratio is abnormal or a plasmacytoma with minimum largest diameters of &gt; 2 cm.&#xD;
&#xD;
          -  Patients with plasma cell leukemia, amyloidosis, Waldenstrom Disease, POEMS syndrome&#xD;
&#xD;
          -  Meningeal involvement of multiple myeloma&#xD;
&#xD;
          -  Patient ineligible for autologous transplantation&#xD;
&#xD;
          -  Pregnant or lactating females&#xD;
&#xD;
          -  Acute active infection requiring treatment (systemic antibiotics, antivirals, or&#xD;
             antifungals) within 14 days prior to randomization&#xD;
&#xD;
          -  Known human immunodeficiency virus infection (HIV)&#xD;
&#xD;
          -  Active hepatitis A, B or C infection. Hepatitis C infection (subjects with hepatitis C&#xD;
             that achieve a sustained virologic response after antiviral therapy are allowed), or&#xD;
             hepatitis B infection (subjects with hepatitis B surface antigen or core antibody that&#xD;
             achieve sustained virologic response with antiviral therapy are allowed). Tests to be&#xD;
             performed if required per local country regulations. In fact it is not possible to&#xD;
             avoid the risk of virological reactivation with the study treatments.&#xD;
&#xD;
          -  Unstable angina or myocardial infarction within 4 months prior to randomization, NYHA&#xD;
             Class III or IV heart failure, uncontrolled angina, uncontrolled hypertension,&#xD;
             (Uncontrolled hypertension, defined as an average systolic blood pressure ≥ 160 mmHg&#xD;
             or diastolic ≥ 100 mmHg despite optimal treatment (measured following European Society&#xD;
             of Hypertension/European Society of Cardiology 2013 guidelines), pulmonary embolia,&#xD;
             history of severe coronary artery disease, severe uncontrolled ventricular&#xD;
             arrhythmias, sick sinus syndrome, or electrocardiographic evidence of acute ischemia&#xD;
             or Grade 3 conduction system abnormalities unless subject has a pacemaker&#xD;
&#xD;
          -  Non-hematologic malignancy within the past 3 years with the exception of a) adequately&#xD;
             treated basal cell carcinoma, squamous cell skin cancer, or thyroid cancer; b)&#xD;
             carcinoma in situ of the cervix or breast; c) prostate cancer of Gleason Grade 6 or&#xD;
             less with stable prostate-specific antigen levels; or d) cancer considered cured by&#xD;
             surgical resection or unlikely to impact survival during the duration of the study,&#xD;
             such as localized transitional cell carcinoma of the bladder or benign tumors of the&#xD;
             adrenal or pancreas&#xD;
&#xD;
          -  Significant neuropathy (Grades 3-4, or Grade 2 with pain) within 14 days prior to&#xD;
             randomization as defined by National Cancer Institute Common Toxicity Criteria (NCI&#xD;
             CTCAE) 5.0&#xD;
&#xD;
          -  Known history of allergy to Captisol® (a cyclodextrin derivative used to solubilize&#xD;
             carfilzomib) and to PS80; prior hypersensitivity to sucrose, histidine (as base and&#xD;
             hydrochloride salt), or any of the components (active substance or excipients) of&#xD;
             study treatments that are not amenable to premedication with steroids, or H2 blockers,&#xD;
             that would prohibit further treatment with these agents.&#xD;
&#xD;
          -  Contraindication to any of the required concomitant drugs or supportive treatments,&#xD;
             including hypersensitivity to all anticoagulation and antiplatelet options, antiviral&#xD;
             drugs, or intolerance to hydration due to preexisting pulmonary or cardiac impairment&#xD;
&#xD;
          -  Any other clinically significant medical disease or condition that, in the&#xD;
             Investigator's opinion, may interfere with protocol adherence or a subject's ability&#xD;
             to give informed consent&#xD;
&#xD;
          -  Pregnant or breastfeeding woman or woman who intends to become pregnant during the&#xD;
             participation in the study. FCBP unwilling to prevent pregnancy by the use of 2&#xD;
             reliable methods of contraception for ≥4 weeks before the start of study treatment,&#xD;
             during treatment (including dose interruptions), and for at least 28 days following&#xD;
             discontinuation of study lenalidomide, or 30 days following discontinuation of&#xD;
             carfilzomib or for 5 months after discontinuation of isatuximab treatment, whichever&#xD;
             occurs last,&#xD;
&#xD;
          -  Male participants who disagree to practice true abstinence or disagree to use a condom&#xD;
             during sexual contact with a pregnant woman or a FCBP while participating in the&#xD;
             study, during dose interruptions, and for at least 28 days following discontinuation&#xD;
             of study lenalidomide, or 30 days following discontinuation of carfilzomib, or for 5&#xD;
             months after discontinuation of isatuximab treatment, whichever occurs last, even if&#xD;
             he has undergone a successful vasectomy.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>70 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <location>
    <facility>
      <name>University Hospital Ostrava</name>
      <address>
        <city>Ostrava</city>
        <country>Czechia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Klinik und Poliklinik für Innere Medizin III Klinikum Rechts der Isars der TU München</name>
      <address>
        <city>München</city>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Department of Clinical Therapeutics, University of Athens School of Medicine, Alexandra General Hospital of Athens</name>
      <address>
        <city>Athens</city>
        <country>Greece</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>ASST Spedali Civili di Brescia - Ematologia</name>
      <address>
        <city>Brescia</city>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>ErasmusMC, Rotterdam</name>
      <address>
        <city>Rotterdam</city>
        <country>Netherlands</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Oslo Myeloma Center</name>
      <address>
        <city>Oslo</city>
        <zip>0450</zip>
        <country>Norway</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Clinica Universidad de Navarra</name>
      <address>
        <city>Madrid</city>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Czechia</country>
    <country>Germany</country>
    <country>Greece</country>
    <country>Italy</country>
    <country>Netherlands</country>
    <country>Norway</country>
    <country>Spain</country>
  </location_countries>
  <verification_date>September 2023</verification_date>
  <study_first_submitted>June 23, 2020</study_first_submitted>
  <study_first_submitted_qc>July 20, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">July 23, 2020</study_first_posted>
  <last_update_submitted>September 6, 2023</last_update_submitted>
  <last_update_submitted_qc>September 6, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">September 7, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>newly diagnosed MM</keyword>
  <keyword>autologous stem cell transplantation</keyword>
  <keyword>Isatuximab</keyword>
  <keyword>Carfilzomib</keyword>
  <keyword>Lenalidomide</keyword>
  <keyword>Dexamethasone</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Multiple Myeloma</mesh_term>
    <mesh_term>Neoplasms, Plasma Cell</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Dexamethasone</mesh_term>
    <mesh_term>Dexamethasone acetate</mesh_term>
    <mesh_term>Lenalidomide</mesh_term>
    <mesh_term>BB 1101</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Undecided</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT04483739
org study id: EMN24
nct id: NCT04483739
lead sponsor: 
collaborator: 
collaborator: 
collaborator: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
This protocol is a phase III study designed to compare the efficacy and the safety of Isa-KRd
      induction, transplant, Isa-KRd post ASCT consolidation and Isa-KRd light consolidation vs KRd
      induction, transplant, KRd post ASCT consolidation and KRd light consolidation After
      confirmation of eligibility criteria patients will be randomized to one of the 2 treatment
      groups in a 1:1 randomization ratio.
This is a open-label randomized phase III study that enrolls newly diagnosed MM patient
      eligible for high-dose chemotherapy and ASCT. Patients will be randomized at enrolment (1:1,
      stratification according to ISS Stage [3 levels: I vs II vs III] and cytogenetic risk FISH [2
      levels: high-risk vs standard risk/missing] based on presence of t(4;14), t(14;16), and/or
      del 17p)) into 2 treatment arms: -ARM A: induction with 4 cycles of
      Isatuximab-Carfilzomib-Lenalidomide-dexamethasone (Isa-KRd) followed by cyclophophamide and
      stem cell collections, chemotherapy with Melphalan 200 mg/m2 followed by ASCT (Mel200-ASCT),
      4 cycles of Isa-KRd post ASCT consolidation and 12 cycles of
      Isatuximab-Lenalidomide-Carfilzomib-dexamethasone (IsaKRd) light consolidation; ARM B:
      induction with 4 cycles of Carfilzomib-Lenalidomide-dexamethasone (KRd) followed by
      cyclophophamide and stem cell collections, chemotherapy with Melphalan 200 mg/m2 followed by
      ASCT (Mel200-ASCT), 4 cycles of KRd post ASCT consolidation and 12 cycles of
      Carfilzomib-Lenalidomide-dexamethasone (KRd) light consolidation. Details of all treatments
      (dose and schedule) are given in paragraph 8. After light consolidation patients are allowed
      to receive Lenalidomide maintenance as per standard of care.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Rate of MRD negativity after ASCT consolidation treatment by NGS
time frame: The end of consolidation, average of 12 months
description: The rate of MRD negativity is determined as the proportion of patients with MRD negativity (≥10-5 sensitivity level) after ASCT consolidation treatment using ITT principle. For patients who withdraw from the study or are lost to follow up before four post ASCT consolidation cycles, the best MRD assessment will be considered. Patients will be classified as MRD positive if they have only MRD positive test results or do not undergo MRD assessment.
measure: Post induction MRD negativity rate by NGS
time frame: The end of induction, average of 4 months
description: The rate of MRD negativity after induction is determined as the proportion of patients with MRD negativity (≥10-5 sensitivity level, NGS) after the induction phase using ITT principle. Patients will be classified as MRD positive if they have only MRD positive test results or do not undergo MRD assessment/sample not adequate.
measure: Progression-free survival (PFS) in the 2 arms
time frame: approximately up to 5 years
description: PFS will be measured from the date of randomization to the date of first observation of PD, or death from any cause as an event. Subjects who have not progressed or who withdraw from the study will be censored at the time of the last complete disease assessment. All subjects who were lost to FU will also be censored at the time of last complete disease assessment
measure: Post light-consolidation MRD negativity rate by NGS
time frame: At the end of light-consolidation, average of 24 months
description: The rate of MRD negativity after light consolidation is determined as the proportion of patients with MRD negativity (≥10-5 sensitivity level, NGS) after light consolidation phase using ITT principle. Patients will be classified as MRD positive if they have only MRD positive test results or do not undergo MRD assessment/sample not adequate. Patients who withdraw from the study or are lost to follow up before MRD evaluation, the best MRD assessment will be considered
measure: Overall Response Rate (ORR) post-induction
time frame: Approx 4 months
description: Response rate (sCR, CR, VGPR, PR, ORR) will be evaluated according to IMWG Response criteria after induction.
measure: Overall Response Rate (ORR) post-transplant
time frame: Approximately 8 months
description: Response rate (sCR, CR, VGPR, PR, ORR) will be evaluated according to IMWG Response criteria after ASCT.
measure: Overall Response Rate (ORR) post-consolidation
time frame: Approximately 12 months
description: Response rate (sCR, CR, VGPR, PR, ORR) will be evaluated according to IMWG Response criteria after consolidation.
measure: Overall Response Rate (ORR) post light-consolidation
time frame: Approximately 24 months
description: Response rate (sCR, CR, VGPR, PR, ORR) will be evaluated according to IMWG Response criteria after light consolidation.
measure: Post ASCT MRD negativity rate by NGS
time frame: After ASCT, approximately 8 months.
description: The rate of MRD negativity after ASCT is determined as the proportion of patients with MRD negativity (≥10-5 sensitivity level), NGS using ITT principle. For patients who withdraw from the study or are lost to follow up before ASCT, the best MRD assessment will be considered. Patients will be classified as MRD positive if they have only MRD positive test results or do not undergo MRD assessment.
measure: MRD negativity rate by NGF post induction
time frame: Approximately 4 months
description: The rate of MRD negativity (by NGF) after induction is determined as the proportion of patients with MRD negativity (≥10-5 sensitivity level) after the specific phase using ITT principle. Patients will be classified as MRD positive if they have only MRD positive test results or do not undergo MRD assessment. Patients who withdraw from the study or are lost to follow up before MRD evaluation phase, the best MRD assessment will be considered.
measure: MRD negativity rate by NGF post induction
time frame: Approximately 8 months
description: The rate of MRD negativity (by NGF) after ASCT is determined as the proportion of patients with MRD negativity (≥10-5 sensitivity level) after the specific phase using ITT principle. Patients will be classified as MRD positive if they have only MRD positive test results or do not undergo MRD assessment. Patients who withdraw from the study or are lost to follow up before MRD evaluation phase, the best MRD assessment will be considered.
measure: MRD negativity rate by NGF post consolidation
time frame: Approximately 8 months
description: The rate of MRD negativity (by NGF) after consolidation is determined as the proportion of patients with MRD negativity (≥10-5 sensitivity level) after the specific phase using ITT principle. Patients will be classified as MRD positive if they have only MRD positive test results or do not undergo MRD assessment. Patients who withdraw from the study or are lost to follow up before MRD evaluation phase, the best MRD assessment will be considered.
measure: MRD negativity rate by NGF post light consolidation
time frame: Approximately 24 months
description: The rate of MRD negativity (by NGF) after light consolidation are determined as the proportion of patients with MRD negativity (≥10-5 sensitivity level) after the specific phase using ITT principle. Patients will be classified as MRD positive if they have only MRD positive test results or do not undergo MRD assessment. Patients who withdraw from the study or are lost to follow up before MRD evaluation phase, the best MRD assessment will be considered.
measure: Duration of response
time frame: approximately up to 9 years
description: Duration of response is defined as the time between first documentation of response (achievement of at least a PR) and PD with deaths owning to causes other than progression not counted, but censored. Responders without disease progression at the cut-off date of final analysis will be censored either at the time of lost to FU, at the time of death due to other cause than PD, or at the at the time of last contact
measure: Duration of MRD negativity (by NGS and NGF)
time frame: approximately up to 9 years
description: The duration of MRD Negativity (by NGS and NGF) is defined as time between first MRD Negativity and first MRD positivity. Patients without MRD positivity will be censored at last complete assessment
measure: Determine the rate of sustained for 1-year MRD negativity (by NGF and NGS) from post ASCT consolidation to post light consolidation
time frame: approximately up to 9 years
description: Rate of 1 year sustained MRD negativity by NGS (from post ASCT consolidation to post light consolidation) will be also evaluated.
measure: Determine the time to progression (TTP)
time frame: approximately up to 9 years
description: From the date of randomization to the date of first disease progression or death per PD, whichever occurs first
measure: Overall Survival (OS)
time frame: approximately up to 9 years
description: Overall Survival (OS), measured from the date of from randomization to the date the subject's death
measure: Time to next therapy (TNT)
time frame: approximately up to 9 years
description: TNT will be measured from the date of randomization to the date of next anti-myeloma therapy. Death due to any cause before starting therapy will be considered an event. Subjects who have not progressed or who withdraw from the study will be censored at the time of the last complete disease assessment. Subjects lost to FU will also be censored at the time of last contact.
measure: Progression-free survival on the next line of therapy (PFS2)
time frame: approximately up to 9 years
description: Progression-free survival on the next line of therapy (PFS2) is defined as the time from randomization to progression on the next line of treatment or death, whichever comes first.
arm group label: Krd Induction
arm group type: Experimental
description: 4 28 day cycles of Carfilzomib = 20 mg/m2 IV on day 1 cycle 1 only, followed by 56 mg/m2 IV on days 8, 15 cycle 1 and on days 1, 8, 15 for cycles 2-4 Lenalidomide= 25 mg orally daily on days 1-21 Dexamethasone = 40 mg orally/IV on days 1, 8, 15, 22
arm group label: Isa-KRd induction
arm group type: Experimental
description: Isatuximab= 10 mg/kg IV on day 1, 8, 15, and 22 during Cycle 1, followed by 10 mg/kg IV on days 1 and 15 during Cycles 2 to 4.
Carfilzomib = 20 mg/m2 IV on day 1 cycle 1 only, followed by 56 mg/m2 IV on days 8, 15 cycle 1 and on days 1, 8, 15 for cycles 2-4 Lenalidomide= 25 mg orally daily on days 1-21 Dexamethasone = 40 mg orally/IV on days 1, 8, 15, 22
arm group label: KRd post ASCT consolidation
arm group type: Experimental
description: 4 28 day cycles of Carfilzomib = 56 mg/m2 IV on days 1, 8, 15 cycle 5-8 Lenalidomide= 25 mg orally daily on days 1-21 Dexamethasone = 40 mg orally/IV on days 1, 8, 15, 22
arm group label: Isa-KRd post ASCT consolidation:
arm group type: Experimental
description: 4 28 day cycles of Isatuximab= 10 mg/kg IV on days 1 and 15 on cycles 5-8 Carfilzomib = 56 mg/m2 IV on days 1, 8, 15 cycle 5-8 Lenalidomide= 25 mg orally daily on days 1-21 Dexamethasone = 40 mg orally/IV on days 1, 8, 15, 22
arm group label: KRd light consolidation
arm group type: Experimental
description: 12 28 day cycles of Carfilzomib = 56 mg/m2 IV on days 1, 15 Lenalidomide = 10 mg orally on days 1-21 Dexamethasone = 20 mg orally/IV on days 1, 15
arm group label: Isa-KRd light consolidation
arm group type: Experimental
description: Isatuximab= 10 mg/kg IV on day 1 Carfilzomib = 56 mg/m2 IV on days 1, 15 Lenalidomide = 10 mg orally on days 1-21 Dexamethasone = 20 mg orally/IV on days 1, 15
intervention type: Drug
intervention name: Carfilzomib Lenalidomide Dexamethasone
description: Isatuximab-Carfilzomib-Lenalidomide-Dexamethasone (Isa-KRd) versus Carfilzomib-Lenalidomide-Dexamethasone (KRd) in newly diagnosed multiple myeloma patients eligible for autologous stem cell transplantation
arm group label: KRd light consolidation
arm group label: KRd post ASCT consolidation
arm group label: Krd Induction
other name: KRd
intervention type: Drug
intervention name: Isatuximab Carfilzomib Lenalidomide Dexamethasone
description: Isatuximab-Carfilzomib-Lenalidomide-Dexamethasone (Isa-KRd) versus Carfilzomib-Lenalidomide-Dexamethasone (KRd) in newly diagnosed multiple myeloma patients eligible for autologous stem cell transplantation
arm group label: Isa-KRd induction
arm group label: Isa-KRd light consolidation
arm group label: Isa-KRd post ASCT consolidation:
other name: Isa-KRD
criteria: 
gender: All
minimum age: 18 Years
maximum age: 70 Years
healthy volunteers: No
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
country: Czechia
country: Germany
country: Greece
country: Italy
country: Netherlands
country: Norway
country: Spain
responsible party type: Sponsor
mesh term: Multiple Myeloma
mesh term: Neoplasms, Plasma Cell
mesh term: Dexamethasone
mesh term: Dexamethasone acetate
mesh term: Lenalidomide
mesh term: BB 1101
sharing ipd: Undecided