<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/NCT04430894</url>
  </required_header>
  <id_info>
    <org_study_id>19-568</org_study_id>
    <nct_id>NCT04430894</nct_id>
  </id_info>
  <brief_title>KRDI in Transplant-Eligible MM</brief_title>
  <official_title>A Phase II Study of Once Weekly Carfilzomib, Lenalidomide, Dexamethasone, and Isatuximab in Newly Diagnosed, Transplant-Eligible Multiple Myeloma</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Massachusetts General Hospital</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Amgen</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
    <collaborator>
      <agency>Sanofi</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>Massachusetts General Hospital</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      This research study is testing the efficacy of an experimental drug combination for people&#xD;
      with newly diagnosed multiple myeloma that are eligible for a stem cell transplant.&#xD;
&#xD;
      The names of the study drugs involved in this study are:&#xD;
&#xD;
        -  Carfilzomib&#xD;
&#xD;
        -  Isatuximab&#xD;
&#xD;
        -  Lenalidomide&#xD;
&#xD;
        -  Dexamethasone&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This is a phase II study to evaluate the efficacy of once weekly carfilzomib, lenalidomide,&#xD;
      dexamethasone, and isatuximab (KRDI) in patients with newly diagnosed, transplant-eligible&#xD;
      multiple myeloma. The research study procedures include screening for eligibility and study&#xD;
      treatment including evaluations and follow up visits. The study treatment portion of this&#xD;
      study is comprised of an induction phase and a maintenance phase.&#xD;
&#xD;
        -  Induction Phase :&#xD;
&#xD;
             -  All participants will receive the same study drugs (carfilzomib, isatuximab,&#xD;
                lenalidomide, and dexamethasone) for up to 8 cycles. Each cycle is 28 days in&#xD;
                length.&#xD;
&#xD;
             -  All participants will perform stem cell collection after 4 cycles of therapy. Based&#xD;
                on the recommendation participants may or may not proceed to an autologous stem&#xD;
                cell transplant (SCT) as part of induction therapy.&#xD;
&#xD;
        -  Maintenance Phase: During maintenance, participants will receive the study treatment for&#xD;
           up to two years after induction until progressive disease or unacceptable toxicity&#xD;
&#xD;
      It is expected that about 50 people will take part in this research study.&#xD;
&#xD;
      This research study is a Phase II clinical trial. Phase II clinical trials test the safety&#xD;
      and effectiveness of an investigational drug combination to learn whether the drug&#xD;
      combination works in treating a specific disease.&#xD;
&#xD;
      &quot;Investigational&quot; means that the drug combination is being studied.&#xD;
&#xD;
      The U.S. Food and Drug Administration (FDA) has approved carfilzomib or isatuximab as a&#xD;
      treatment for relapsed/refractory multiple myeloma.&#xD;
&#xD;
      The FDA has also approved lenalidomide and dexamethasone as a treatment option for&#xD;
      transplant-eligible multiple myeloma.&#xD;
&#xD;
      However, the FDA has not approved the combination of isatuximab, carfilzomib, lenalidomide,&#xD;
      and dexamethasone as an approved regimen. The combination is considered to be investigational&#xD;
      for the treatment of individuals with newly diagnosed multiple myeloma.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">July 10, 2020</start_date>
  <completion_date type="Anticipated">March 30, 2025</completion_date>
  <primary_completion_date type="Anticipated">July 30, 2022</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Non-Randomized</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Complete Response (CR + stringent CR) rate</measure>
    <time_frame>112 Days</time_frame>
    <description>International Myeloma Working Group (IMWG) Uniform Response criteria after 4 cycles of KRDI.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Overall Response Rate</measure>
    <time_frame>24 Months</time_frame>
    <description>Overall response rate will be percent of patients who achieve at least partial response (PR).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Minimal residual disease (MRD) Rate</measure>
    <time_frame>112 Days (4 Cycles)</time_frame>
    <description>Will be determined by deep sequencing of genomic deoxyribonucleic acid from bone marrow samples using rearranged Ig locus-specific primers (Adaptive, Seattle, WA)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Minimal residual disease (MRD) Rate</measure>
    <time_frame>168 Days (6 cycles, upfront transplant)</time_frame>
    <description>Will be determined by deep sequencing of genomic deoxyribonucleic acid from bone marrow samples using rearranged Ig locus-specific primers (Adaptive, Seattle, WA)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Minimal residual disease (MRD) Rate</measure>
    <time_frame>224 Days (8 cycles transplant-deferred)</time_frame>
    <description>Will be determined by deep sequencing of genomic deoxyribonucleic acid from bone marrow samples using rearranged Ig locus-specific primers (Adaptive, Seattle, WA)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Minimal residual disease (MRD) Rate</measure>
    <time_frame>24 Months</time_frame>
    <description>Will be determined by deep sequencing of genomic deoxyribonucleic acid from bone marrow samples using rearranged Ig locus-specific primers (Adaptive, Seattle, WA)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Progression Free Survival</measure>
    <time_frame>time from first dose of study treatment to the first documentation of PD or death from any cause during study up to 3 years</time_frame>
    <description>Kaplan-Meier curves will be used to characterize the time-to-event outcomes</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall Survival</measure>
    <time_frame>First dose of study treatment to death from any cause up to 3 years</time_frame>
    <description>Kaplan-Meier curves will be used to characterize the time-to-event outcomes</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of Participants with Treatment-Related Adverse Events as NCI CTCAE Version 5.0 severity grades.</measure>
    <time_frame>From the time of first treatment to treatment discontinuation (30 days after last dose) up to 3 years</time_frame>
    <description>NCI CTCAE Version 5.0 severity grades.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Complete Response rate (Transplant)</measure>
    <time_frame>168 Days</time_frame>
    <description>IMWG Uniform Response Criteria Complete response (CR + stringent CR) rate after 6 cycles in patients who undergo transplant</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Complete Response rate (Transplant Deferred)</measure>
    <time_frame>224 Days</time_frame>
    <description>IMWG Uniform Response Criteria Complete response (CR + stringent CR) rate after 8 cycles in patients who do not undergo transplant</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Complete Response rate (All )</measure>
    <time_frame>24 Months</time_frame>
    <description>IMWG Uniform Response Criteria</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Body composition</measure>
    <time_frame>168</time_frame>
    <description>Total lean mass (cm^2), extremity lean mass (cm^2), total fat (cm^2) and trunk fat mass (cm^20, as well as visceral adipose tissue mass (cm^2) will be quantified using Hologic APEX 3.1 software (Hologic) after 6 cycles of treatment (upfront transplant)</description>
  </other_outcome>
  <other_outcome>
    <measure>Body composition</measure>
    <time_frame>224</time_frame>
    <description>Total lean mass (cm^2), extremity lean mass (cm^2), total fat (cm^2) and trunk fat mass (cm^20, as well as visceral adipose tissue mass (cm^2) will be quantified using Hologic APEX 3.1 software (Hologic) after 6 cycles of treatment (transplant-deferred)</description>
  </other_outcome>
  <number_of_arms>3</number_of_arms>
  <enrollment type="Anticipated">50</enrollment>
  <condition>Multiple Myeloma</condition>
  <arm_group>
    <arm_group_label>Induction</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>All participants will receive the same study drugs up to 8 cycles. Carfilzomib, Isatuximab, Lenalidomide, Dexamethasone: Each cycle is 28 days in length.&#xD;
Stem cell collection after 4 cycles of therapy. Based on the recommendation participants may or may not proceed to an autologous stem cell transplant (SCT) as part of induction therapy.&#xD;
Up Front Autologous Stem Cell Transplant:&#xD;
--- 4 cycles of treatment, followed by stem cell collection, high-dose chemotherapy, and autologous SCT followed by 2 additional cycles of therapy (called consolidation) and then maintenance.&#xD;
Deferring Stem Cell Transplant:&#xD;
Deferring SCT following collection: 4 cycles of treatment, followed by stem cell collection followed by 4 additional cycles of therapy and then maintenance</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Maintenance-High Risk</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Experimental: Maintenance The treatment participants will receive for maintenance will be based on the biological features (or cytogenetics) of participants myeloma and categorized into two groups: Standard-risk and High Risk.&#xD;
High Risk: All participants will receive study treatment for up to two years after induction until progressive disease (PD) or unacceptable toxicity&#xD;
Lenalidomide&#xD;
Carfilzomib&#xD;
Isatuximab</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Maintenance- Standard Risk</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>The treatment participants will receive for maintenance will be based on the biological features (or cytogenetics) of participants myeloma and categorized into two groups: Standard-risk and High Risk&#xD;
Lenalidomide - Standard of care All participants will receive study treatment for up to two years after induction until progressive disease (PD) or unacceptable toxicity</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Carfilzomib</intervention_name>
    <description>Induction: protocol determine dose,via IV on 3 days per cycle up to 8 cycles, dependent on Upfront Stem Transplant or Deferring Stem Cell Transplant determination&#xD;
Maintenance: protocol determine dose,via IV on 2 days per cycle- Maintenance Cycle until progressive disease (PD) or unacceptable toxicity</description>
    <arm_group_label>Induction</arm_group_label>
    <arm_group_label>Maintenance-High Risk</arm_group_label>
    <other_name>Kyprolis</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Isatuximab</intervention_name>
    <description>Induction: At predetermined dose, via IV up to 8 cycles, dependent on Upfront Stem Transplant or Deferring Stem Cell Transplant determination:&#xD;
-- Cycles 1 and 2 once per week, Cycles 3-4 every other week, Cycles 5 and 6 every other week, Cycles 7 and 8 once every 4 weeks.&#xD;
Maintenance: At predetermined dose, via IV, once per cycle, Maintenance Cycle until progressive disease (PD) or unacceptable toxicity</description>
    <arm_group_label>Induction</arm_group_label>
    <arm_group_label>Maintenance-High Risk</arm_group_label>
    <other_name>Sarclisa</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Lenalidomide</intervention_name>
    <description>- Induction Predetermined Dose, oral, days 1-21 of up to 8 cycles, dependent on Upfront Stem Transplant or Deferring Stem Cell Transplant determination Maintenance: At predetermined dose, oral days 1-21 per cycle until progressive disease (PD) or unacceptable toxicity</description>
    <arm_group_label>Induction</arm_group_label>
    <arm_group_label>Maintenance- Standard Risk</arm_group_label>
    <arm_group_label>Maintenance-High Risk</arm_group_label>
    <other_name>REVLIMID</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Dexamethasone</intervention_name>
    <description>Induction: Predetermined dosage, oral, Predetermined times per cycle up to 8 cycles dependent on Upfront Stem Transplant or Deferring Stem Cell Transplant determination Maintenance: orally or IV will be administered as a preinfusion medication prior to isatuximab dosing</description>
    <arm_group_label>Induction</arm_group_label>
    <arm_group_label>Maintenance-High Risk</arm_group_label>
    <other_name>Decadron</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Subject must be at least 18 years of age.&#xD;
&#xD;
          -  Subject must have documented multiple myeloma satisfying the CRAB criteria and&#xD;
             measurable disease defined as:&#xD;
&#xD;
               -  Monoclonal plasma cells in the bone marrow ≥10% or presence of a biopsy-proven&#xD;
                  Plasmacytoma.&#xD;
&#xD;
               -  Measurable disease as defined by any of the following:&#xD;
&#xD;
               -  IgG myeloma: Serum monoclonal paraprotein (M-protein) level ≥.5 g/dL or urine&#xD;
                  M-protein level ≥200 mg/24 hours; or&#xD;
&#xD;
               -  IgA, IgM, or IgD multiple myeloma: serum M-protein level ≥0.25 g/dL or urine&#xD;
                  M-protein level ≥200 mg/24 hours; or&#xD;
&#xD;
               -  Light chain multiple myeloma: Serum immunoglobulin free light chain ≥10 mg/dL and&#xD;
                  abnormal serum immunoglobulin kappa lambda free light chain ratio.&#xD;
&#xD;
               -  Sixty percent or greater clonal plasma cells on bone marrow examination.&#xD;
&#xD;
               -  Serum involved / uninvolved free light chain ratio of 100 or greater, provided&#xD;
                  the absolute level of the involved free light chain is at least 100 mg/L (a&#xD;
                  patient's &quot;involved&quot; free light chain - either kappa or lambda - is the one that&#xD;
                  is above the normal reference range; the uninvolved light chain is the one that&#xD;
                  typically is in, or below, the normal range).&#xD;
&#xD;
               -  More than one focal lesion on magnetic resonance image (MRI) that is at least 5&#xD;
                  mm or greater in size.&#xD;
&#xD;
          -  Newly diagnosed and considered candidate for high-dose chemotherapy with stem cell&#xD;
             transplant.&#xD;
&#xD;
          -  Subject must have an Eastern Cooperative Oncology Group (ECOG) performance status&#xD;
             score of 0, 1, or 2.&#xD;
&#xD;
          -  Subject must have pretreatment clinical laboratory values meeting the following&#xD;
             criteria during the Screening Phase:&#xD;
&#xD;
               -  hemoglobin ≥ 7.5 g/dL (≥ mmol/L; prior RBC transfusion or recombinant human&#xD;
                  erythropoietin use is permitted);&#xD;
&#xD;
               -  absolute neutrophil count ≥1.0 x 109/L (granulocyte colony stimulating factor&#xD;
                  [GCSF] use is permitted);&#xD;
&#xD;
               -  platelet count ≥70 x 109/L for subjects in whom &lt;50% of bone marrow nucleated&#xD;
                  cells are plasma cells; otherwise platelet count &gt;50 × 109/L (transfusions are&#xD;
                  not permitted to achieve this minimum platelet count)&#xD;
&#xD;
               -  aspartate aminotransferase (AST) ≤2.5 x upper limit of normal (ULN);&#xD;
&#xD;
               -  alanine aminotransferase (ALT) ≤2.5 x ULN;&#xD;
&#xD;
               -  total bilirubin ≤2.0 x ULN, except in subjects with congenital bilirubinemia,&#xD;
                  such as Gilbert syndrome (direct bilirubin ≤2.0 x ULN)&#xD;
&#xD;
               -  creatinine clearance ≥30 mL/min&#xD;
&#xD;
               -  corrected serum calcium ≤14 mg/dL (≤3.5 mmol/L); or free ionized calcium &lt;6.5&#xD;
                  mg/dL (&lt;1.6 mmol/L).&#xD;
&#xD;
          -  Women of childbearing potential must commit to either abstain continuously from&#xD;
             heterosexual sexual intercourse or to use 2 methods of reliable birth control&#xD;
             simultaneously. This includes one highly effective form of contraception (tubal&#xD;
             ligation, intrauterine device [IUD], hormonal [birth control pills, injections,&#xD;
             hormonal patches, vaginal rings or implants] or partner's vasectomy) and one&#xD;
             additional effective contraceptive method (male latex or synthetic condom, diaphragm,&#xD;
             or cervical cap). Contraception must begin 4 weeks prior to dosing. Reliable&#xD;
             contraception is indicated even where there has been a history of infertility, unless&#xD;
             due to hysterectomy or bilateral oophorectomy.&#xD;
&#xD;
          -  A man who is sexually active with a woman of childbearing potential must agree to use&#xD;
             a latex or synthetic condom, even if they had a successful vasectomy. All men must&#xD;
             also not donate sperm during the study, for 4 weeks after the last dose of&#xD;
             lenalidomide, for 90 days after the last dose of carfilzomib, and for 4 months after&#xD;
             the last dose of isatuximab.&#xD;
&#xD;
          -  A woman of childbearing potential must have 2 negative serum or urine pregnancy tests&#xD;
             at Screening, first within 10 to 14 days prior to dosing and the second within 24&#xD;
             hours prior to dosing.&#xD;
&#xD;
          -  Each subject (or their legally acceptable representative) must sign an informed&#xD;
             consent form (ICF) indicating that he or she understands the purpose of and procedures&#xD;
             required for the study and are willing to participate in the study. Subject must be&#xD;
             willing and able to adhere to the prohibitions and restrictions specified in this&#xD;
             protocol, as referenced in the ICF.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Any potential subject who meets any of the following criteria will be excluded from&#xD;
             participating in the study.&#xD;
&#xD;
          -  Subject has a diagnosis of primary amyloidosis, monoclonal gammopathy of undetermined&#xD;
             significance, or smoldering multiple myeloma. Monoclonal gammopathy of undetermined&#xD;
             significance is defined by presence of serum M-protein &lt;3 g/dL; absence of lytic bone&#xD;
             lesions, anemia, hypercalcemia, and renal insufficiency related to the M-protein; and&#xD;
             (if determined) proportion of plasma cells in the bone marrow of 10% or less.&#xD;
             Smoldering multiple myeloma is defined as asymptomatic MM with absence of related&#xD;
             organ or tissue impairment end organ damage.&#xD;
&#xD;
          -  Subject has a diagnosis of Waldenström's disease, or other conditions in which IgM&#xD;
             M-protein is present in the absence of a clonal plasma cell infiltration with lytic&#xD;
             bone lesions&#xD;
&#xD;
          -  Subject has prior or current systemic therapy or SCT for MM, with the exception of an&#xD;
             emergency use of a short course (equivalent of dexamethasone 40 mg/day for a maximum 4&#xD;
             days) of corticosteroids before treatment.&#xD;
&#xD;
          -  Subject has a history of malignancy (other than MM) within 5 years before the date of&#xD;
             enrollment (exceptions are squamous and basal cell carcinomas of the skin and&#xD;
             carcinoma in situ of the cervix, or malignancy that in the opinion of the&#xD;
             investigator, with concurrence with the sponsor's medical monitor, is considered cured&#xD;
             with minimal risk of recurrence within 5 years).&#xD;
&#xD;
          -  Subject has had radiation therapy within 14 days of enrollment.&#xD;
&#xD;
          -  Subject has had plasmapheresis within 28 days of enrollment.&#xD;
&#xD;
          -  Subject is exhibiting clinical signs of meningeal involvement of MM.&#xD;
&#xD;
          -  Subject has known chronic obstructive pulmonary disease (COPD) (defined as a forced&#xD;
             expiratory volume [FEV] in 1 second &lt;60% of predicted normal), persistent asthma, or a&#xD;
             history of asthma within the last 2 years (intermittent asthma is allowed). Subjects&#xD;
             with known or suspected COPD or asthma must have a FEV1 test during screening.&#xD;
&#xD;
          -  Subject is known to be seropositive for history of human immunodeficiency virus (HIV)&#xD;
             or known to have active hepatitis B or hepatitis C.&#xD;
&#xD;
          -  Subject has any concurrent medical or psychiatric condition or disease (eg, active&#xD;
             systemic infection, uncontrolled diabetes, acute diffuse infiltrative pulmonary&#xD;
             disease) that is likely to interfere with the study procedures or results, or that in&#xD;
             the opinion of the investigator, would constitute a hazard for participating in this&#xD;
             study.&#xD;
&#xD;
          -  Subject has clinically significant cardiac disease, including:&#xD;
&#xD;
               -  myocardial infarction within 1 year before enrollment, or an unstable or&#xD;
                  uncontrolled disease/condition related to or affecting cardiac function (eg,&#xD;
                  unstable angina, congestive heart failure, New York Heart Association Class&#xD;
                  III-IV;&#xD;
&#xD;
               -  uncontrolled cardiac arrhythmia (National Cancer Institute Common Terminology&#xD;
                  Criteria for Adverse Events [NCI CTCAE] Version 4 Grade ≥2) or clinically&#xD;
                  significant ECG abnormalities;&#xD;
&#xD;
               -  screening 12-lead ECG showing a baseline QT interval as corrected by Fridericia's&#xD;
                  formula (QTcF) &gt;470 msec.&#xD;
&#xD;
               -  uncontrolled hypertension&#xD;
&#xD;
          -  Subject has known allergies, hypersensitivity, or intolerance to corticosteroids,&#xD;
             monoclonal antibodies or human proteins, or their excipients (refer to respective&#xD;
             package inserts or IB) or known sensitivity to mammalian-derived products.&#xD;
&#xD;
          -  Subject has plasma cell leukemia (according to World Health Organization [WHO]&#xD;
             criterion: ≥20% of cells in the peripheral blood with an absolute plasma cell count of&#xD;
             more than 2 × 109/L) or POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy,&#xD;
             monoclonal protein, and skin changes).&#xD;
&#xD;
          -  Subject is known or suspected of not being able to comply with the study protocol (eg,&#xD;
             because of alcoholism, drug dependency, or psychological disorder). Subject has any&#xD;
             condition for which, in the opinion of the investigator, participation would not be in&#xD;
             the best interest of the subject (eg, compromise the well-being) or that could&#xD;
             prevent, limit, or confound the protocol specified assessments.&#xD;
&#xD;
          -  Subject is a woman who is pregnant, or breast-feeding, or planning to become pregnant&#xD;
             while enrolled in this study within 30 days after the last dose of lenalidomide or&#xD;
             carfilzomib, or within 4 months after the last dose of isatuximab. Or, subject is a&#xD;
             man who plans to father a child while enrolled in this study, within 4 weeks after the&#xD;
             last dose of lenalidomide, within 90 days of the last dose of carfilzomib, or within 4&#xD;
             months after the last dose of isatuximab.&#xD;
&#xD;
          -  Subject has had major surgery within 2 weeks before enrollment or has not fully&#xD;
             recovered from surgery, or has surgery planned during the time the subject is expected&#xD;
             to participate in the study. Kyphoplasty or vertebroplasty is not considered major&#xD;
             surgery.&#xD;
&#xD;
          -  Subject has received an investigational drug (including investigational vaccines) or&#xD;
             used an invasive investigational medical device within 4 weeks before enrollment or is&#xD;
             currently enrolled in an interventional investigational study.&#xD;
&#xD;
          -  Subject has contraindications to required prophylaxis for deep vein thrombosis and&#xD;
             pulmonary embolism.&#xD;
&#xD;
          -  Incidence of gastrointestinal disease that may significantly alter the absorption of&#xD;
             oral drugs.&#xD;
&#xD;
          -  Peripheral neuropathy ≥ Grade 2 on clinical examination during the screening period.&#xD;
&#xD;
          -  Systemic treatment with strong inhibitors of CYP1A2 (fluvoxamine, enoxacin), strong&#xD;
             inhibitors of CYP3A (clarithromycin, telithromycin, itraconazole, voriconazole,&#xD;
             ketoconazole, nefazodone, posaconazole) or strong CYP3A inducers (rifampin,&#xD;
             rifapentine, rifabutin, carbamazepine, phenytoin, phenobartital), or use of Ginkgo&#xD;
             biloba, St. John's wort within 14 days before the first dose of study treatment.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Elizabeth O'Donnell, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Massachusetts General Hospital</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Elizabeth O'Donnell, MD</last_name>
    <phone>ekodonnell@partners.org</phone>
    <email>ekodonnell@partners.org</email>
  </overall_contact>
  <location>
    <facility>
      <name>Massachusetts General Hospital</name>
      <address>
        <city>Boston</city>
        <state>Massachusetts</state>
        <zip>02115</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Elizabeth O'Donnell, MD</last_name>
      <phone>617-724-4000</phone>
      <email>ekodonnell@partners.org</email>
    </contact>
    <investigator>
      <last_name>Elizabeth O'Donnell, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Beth Israel Deaconess Medical Center</name>
      <address>
        <city>Boston</city>
        <state>Massachusetts</state>
        <zip>02215</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Not yet recruiting</status>
    <contact>
      <last_name>Jacalyn Rosenblatt, MD</last_name>
      <phone>617-667-9920</phone>
      <email>jrosenb1@bidmc.harvard.edu</email>
    </contact>
    <investigator>
      <last_name>Jacalyn Rosenblatt, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Dana Farber Cancer Institute</name>
      <address>
        <city>Boston</city>
        <state>Massachusetts</state>
        <zip>02215</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Omar Nadeem, MD</last_name>
      <phone>617-632-3823</phone>
      <email>Omar_nadeem@dfci.harvard.edu</email>
    </contact>
    <investigator>
      <last_name>Omar Nadeem, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>April 2022</verification_date>
  <study_first_submitted>June 11, 2020</study_first_submitted>
  <study_first_submitted_qc>June 11, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">June 12, 2020</study_first_posted>
  <last_update_submitted>April 8, 2022</last_update_submitted>
  <last_update_submitted_qc>April 8, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">April 12, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Massachusetts General Hospital</investigator_affiliation>
    <investigator_full_name>Elizabeth O'Donnell</investigator_full_name>
    <investigator_title>Principal Investigator</investigator_title>
  </responsible_party>
  <keyword>Multiple Myeloma</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>Lenalidomide</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Yes</sharing_ipd>
    <ipd_description>The Dana-Farber / Harvard Cancer Center encourages and supports the responsible and ethical sharing of data from clinical trials. De-identified participant data from the final research dataset used in the published manuscript may only be shared under the terms of a Data Use Agreement. Requests may be directed to Sponsor Investigator or designee. The protocol and statistical analysis plan will be made available on Clinicaltrials.gov only as required by federal regulation or as a condition of awards and agreements supporting the research.</ipd_description>
    <ipd_info_type>Study Protocol</ipd_info_type>
    <ipd_info_type>Statistical Analysis Plan (SAP)</ipd_info_type>
    <ipd_info_type>Informed Consent Form (ICF)</ipd_info_type>
    <ipd_time_frame>Data can be shared no earlier than 1 year following the date of publication</ipd_time_frame>
    <ipd_access_criteria>MGH - Contact the Partners Innovations team at http://www.partners.org/innovation</ipd_access_criteria>
  </patient_data>
  <provided_document_section>
    <provided_document>
      <document_type>Informed Consent Form</document_type>
      <document_has_protocol>No</document_has_protocol>
      <document_has_icf>Yes</document_has_icf>
      <document_has_sap>No</document_has_sap>
      <document_date>December 18, 2020</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/94/NCT04430894/ICF_000.pdf</document_url>
    </provided_document>
  </provided_document_section>
  <pending_results>
    <submitted>August 14, 2023</submitted>
    <returned>September 11, 2023</returned>
  </pending_results>
  <!-- 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/NCT04430894
org study id: 19-568
nct id: NCT04430894
lead sponsor: 
collaborator: 
collaborator: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
This research study is testing the efficacy of an experimental drug combination for people
      with newly diagnosed multiple myeloma that are eligible for a stem cell transplant.

      The names of the study drugs involved in this study are:

        -  Carfilzomib

        -  Isatuximab

        -  Lenalidomide

        -  Dexamethasone
This is a phase II study to evaluate the efficacy of once weekly carfilzomib, lenalidomide,
      dexamethasone, and isatuximab (KRDI) in patients with newly diagnosed, transplant-eligible
      multiple myeloma. The research study procedures include screening for eligibility and study
      treatment including evaluations and follow up visits. The study treatment portion of this
      study is comprised of an induction phase and a maintenance phase.

        -  Induction Phase :

             -  All participants will receive the same study drugs (carfilzomib, isatuximab,
                lenalidomide, and dexamethasone) for up to 8 cycles. Each cycle is 28 days in
                length.

             -  All participants will perform stem cell collection after 4 cycles of therapy. Based
                on the recommendation participants may or may not proceed to an autologous stem
                cell transplant (SCT) as part of induction therapy.

        -  Maintenance Phase: During maintenance, participants will receive the study treatment for
           up to two years after induction until progressive disease or unacceptable toxicity

      It is expected that about 50 people will take part in this research study.

      This research study is a Phase II clinical trial. Phase II clinical trials test the safety
      and effectiveness of an investigational drug combination to learn whether the drug
      combination works in treating a specific disease.

      "Investigational" means that the drug combination is being studied.

      The U.S. Food and Drug Administration (FDA) has approved carfilzomib or isatuximab as a
      treatment for relapsed/refractory multiple myeloma.

      The FDA has also approved lenalidomide and dexamethasone as a treatment option for
      transplant-eligible multiple myeloma.

      However, the FDA has not approved the combination of isatuximab, carfilzomib, lenalidomide,
      and dexamethasone as an approved regimen. The combination is considered to be investigational
      for the treatment of individuals with newly diagnosed multiple myeloma.
allocation: Non-Randomized
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Complete Response (CR + stringent CR) rate
time frame: 112 Days
description: International Myeloma Working Group (IMWG) Uniform Response criteria after 4 cycles of KRDI.
measure: Overall Response Rate
time frame: 24 Months
description: Overall response rate will be percent of patients who achieve at least partial response (PR).
measure: Minimal residual disease (MRD) Rate
time frame: 112 Days (4 Cycles)
description: Will be determined by deep sequencing of genomic deoxyribonucleic acid from bone marrow samples using rearranged Ig locus-specific primers (Adaptive, Seattle, WA)
measure: Minimal residual disease (MRD) Rate
time frame: 168 Days (6 cycles, upfront transplant)
description: Will be determined by deep sequencing of genomic deoxyribonucleic acid from bone marrow samples using rearranged Ig locus-specific primers (Adaptive, Seattle, WA)
measure: Minimal residual disease (MRD) Rate
time frame: 224 Days (8 cycles transplant-deferred)
description: Will be determined by deep sequencing of genomic deoxyribonucleic acid from bone marrow samples using rearranged Ig locus-specific primers (Adaptive, Seattle, WA)
measure: Minimal residual disease (MRD) Rate
time frame: 24 Months
description: Will be determined by deep sequencing of genomic deoxyribonucleic acid from bone marrow samples using rearranged Ig locus-specific primers (Adaptive, Seattle, WA)
measure: Progression Free Survival
time frame: time from first dose of study treatment to the first documentation of PD or death from any cause during study up to 3 years
description: Kaplan-Meier curves will be used to characterize the time-to-event outcomes
measure: Overall Survival
time frame: First dose of study treatment to death from any cause up to 3 years
description: Kaplan-Meier curves will be used to characterize the time-to-event outcomes
measure: Number of Participants with Treatment-Related Adverse Events as NCI CTCAE Version 5.0 severity grades.
time frame: From the time of first treatment to treatment discontinuation (30 days after last dose) up to 3 years
description: NCI CTCAE Version 5.0 severity grades.
measure: Complete Response rate (Transplant)
time frame: 168 Days
description: IMWG Uniform Response Criteria Complete response (CR + stringent CR) rate after 6 cycles in patients who undergo transplant
measure: Complete Response rate (Transplant Deferred)
time frame: 224 Days
description: IMWG Uniform Response Criteria Complete response (CR + stringent CR) rate after 8 cycles in patients who do not undergo transplant
measure: Complete Response rate (All )
time frame: 24 Months
description: IMWG Uniform Response Criteria
measure: Body composition
time frame: 168
description: Total lean mass (cm^2), extremity lean mass (cm^2), total fat (cm^2) and trunk fat mass (cm^20, as well as visceral adipose tissue mass (cm^2) will be quantified using Hologic APEX 3.1 software (Hologic) after 6 cycles of treatment (upfront transplant)
measure: Body composition
time frame: 224
description: Total lean mass (cm^2), extremity lean mass (cm^2), total fat (cm^2) and trunk fat mass (cm^20, as well as visceral adipose tissue mass (cm^2) will be quantified using Hologic APEX 3.1 software (Hologic) after 6 cycles of treatment (transplant-deferred)
arm group label: Induction
arm group type: Experimental
description: All participants will receive the same study drugs up to 8 cycles. Carfilzomib, Isatuximab, Lenalidomide, Dexamethasone: Each cycle is 28 days in length.
Stem cell collection after 4 cycles of therapy. Based on the recommendation participants may or may not proceed to an autologous stem cell transplant (SCT) as part of induction therapy.
Up Front Autologous Stem Cell Transplant:
--- 4 cycles of treatment, followed by stem cell collection, high-dose chemotherapy, and autologous SCT followed by 2 additional cycles of therapy (called consolidation) and then maintenance.
Deferring Stem Cell Transplant:
Deferring SCT following collection: 4 cycles of treatment, followed by stem cell collection followed by 4 additional cycles of therapy and then maintenance
arm group label: Maintenance-High Risk
arm group type: Experimental
description: Experimental: Maintenance The treatment participants will receive for maintenance will be based on the biological features (or cytogenetics) of participants myeloma and categorized into two groups: Standard-risk and High Risk.
High Risk: All participants will receive study treatment for up to two years after induction until progressive disease (PD) or unacceptable toxicity
Lenalidomide
Carfilzomib
Isatuximab
arm group label: Maintenance- Standard Risk
arm group type: Experimental
description: The treatment participants will receive for maintenance will be based on the biological features (or cytogenetics) of participants myeloma and categorized into two groups: Standard-risk and High Risk
Lenalidomide - Standard of care All participants will receive study treatment for up to two years after induction until progressive disease (PD) or unacceptable toxicity
intervention type: Drug
intervention name: Carfilzomib
description: Induction: protocol determine dose,via IV on 3 days per cycle up to 8 cycles, dependent on Upfront Stem Transplant or Deferring Stem Cell Transplant determination
Maintenance: protocol determine dose,via IV on 2 days per cycle- Maintenance Cycle until progressive disease (PD) or unacceptable toxicity
arm group label: Induction
arm group label: Maintenance-High Risk
other name: Kyprolis
intervention type: Drug
intervention name: Isatuximab
description: Induction: At predetermined dose, via IV up to 8 cycles, dependent on Upfront Stem Transplant or Deferring Stem Cell Transplant determination:
-- Cycles 1 and 2 once per week, Cycles 3-4 every other week, Cycles 5 and 6 every other week, Cycles 7 and 8 once every 4 weeks.
Maintenance: At predetermined dose, via IV, once per cycle, Maintenance Cycle until progressive disease (PD) or unacceptable toxicity
arm group label: Induction
arm group label: Maintenance-High Risk
other name: Sarclisa
intervention type: Drug
intervention name: Lenalidomide
description: - Induction Predetermined Dose, oral, days 1-21 of up to 8 cycles, dependent on Upfront Stem Transplant or Deferring Stem Cell Transplant determination Maintenance: At predetermined dose, oral days 1-21 per cycle until progressive disease (PD) or unacceptable toxicity
arm group label: Induction
arm group label: Maintenance- Standard Risk
arm group label: Maintenance-High Risk
other name: REVLIMID
intervention type: Drug
intervention name: Dexamethasone
description: Induction: Predetermined dosage, oral, Predetermined times per cycle up to 8 cycles dependent on Upfront Stem Transplant or Deferring Stem Cell Transplant determination Maintenance: orally or IV will be administered as a preinfusion medication prior to isatuximab dosing
arm group label: Induction
arm group label: Maintenance-High Risk
other name: Decadron
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Elizabeth O'Donnell, MD
role: Principal Investigator
affiliation: Massachusetts General Hospital
last name: Elizabeth O'Donnell, MD
phone: ekodonnell@partners.org
email: ekodonnell@partners.org
facility: 
status: Recruiting
contact: 
investigator: 
facility: 
status: Not yet recruiting
contact: 
investigator: 
facility: 
status: Recruiting
contact: 
investigator: 
country: United States
responsible party type: Principal Investigator
investigator affiliation: Massachusetts General Hospital
investigator full name: Elizabeth O'Donnell
investigator title: Principal Investigator
mesh term: Multiple Myeloma
mesh term: Neoplasms, Plasma Cell
mesh term: Dexamethasone
mesh term: Lenalidomide
sharing ipd: Yes
ipd description: The Dana-Farber / Harvard Cancer Center encourages and supports the responsible and ethical sharing of data from clinical trials. De-identified participant data from the final research dataset used in the published manuscript may only be shared under the terms of a Data Use Agreement. Requests may be directed to Sponsor Investigator or designee. The protocol and statistical analysis plan will be made available on Clinicaltrials.gov only as required by federal regulation or as a condition of awards and agreements supporting the research.
ipd info type: Study Protocol
ipd info type: Statistical Analysis Plan (SAP)
ipd info type: Informed Consent Form (ICF)
ipd time frame: Data can be shared no earlier than 1 year following the date of publication
ipd access criteria: MGH - Contact the Partners Innovations team at http://www.partners.org/innovation
provided document: 
submitted: August 14, 2023
returned: September 11, 2023