<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/NCT02970747</url>
  </required_header>
  <id_info>
    <org_study_id>IOM-070337</org_study_id>
    <nct_id>NCT02970747</nct_id>
  </id_info>
  <brief_title>Non-interventional Study of Kyprolis® in Combination With Revlimid® and Dexamethasone or Dexamethasone Alone or in Combination With Darzalex® and Dexamethasone in Multiple Myeloma Patients</brief_title>
  <acronym>CARO</acronym>
  <official_title>A Non-interventional Study of Carfilzomib (Kyprolis®) in Combination With Lenalidomide (Revlimid®) and Dexamethasone or Carfilzomib in Combination With Dexamethasone Alone or Carfilzomib in Combination With Daratumumab (Darzalex®) and Dexamethasone in Patients With Multiple Myeloma Who Have Received at Least One Prior Therapy</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>iOMEDICO AG</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Amgen</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>iOMEDICO AG</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      The objective of this non-interventional study (NIS) is to evaluate patients' adherence and&#xD;
      persistence to carfilzomib therapy in combination with lenalidomide and dexamethasone or in&#xD;
      combination with dexamethasone alone or in combination with daratumumab and dexamethasone in&#xD;
      adult patients with multiple myeloma (MM) who have received at least one prior therapy in a&#xD;
      real-life setting.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The dual combination of lenalidomide (Revlimid®) (R) and dexamethasone (d) (Rd) as well as&#xD;
      the dual combination of bortezomib (Velcade®, V) and dexamethasone (Vd) are standard regimens&#xD;
      to treat MM patients who have received at least one prior therapy. Recently published&#xD;
      clinical data indicate that the next-generation proteasome inhibitor carfilzomib (Kyprolis®)&#xD;
      (K) may substantially change the treatment paradigm for patients with relapsed or refractory&#xD;
      MM (RRMM).1 Three pivotal trials were conducted leading to market authorization of&#xD;
      carfilzomib in combination with lenalidomide and dexamethasone or in combination with&#xD;
      dexamethasone alone or in combination with dexamethasone and daratumumab for the treatment of&#xD;
      MM patients who have received at least one prior therapy.&#xD;
&#xD;
      ASPIRE, NCT010803912 To compare the efficacy and safety of carfilzomib in combination with Rd&#xD;
      (KRd) with the dual combination therapy Rd, a randomized, multicenter, open-label phase III&#xD;
      study was performed in patients with relapsed MM (RMM). After cycle 18, carfilzomib was&#xD;
      discontinued in the KRd arm, but Rd administration was continued thereafter until disease&#xD;
      progression. The trial met its primary endpoint progression-free survival (PFS) (Hazard Ratio&#xD;
      (HR) for progression or death, 0.69; p=0.0001). Median PFS was 26.3 months with KRd treatment&#xD;
      compared to 17.6 months with Rd treatment. The study further demonstrates that carfilzomib&#xD;
      improves patients' overall survival (OS) rate at 24 months (KRd, 73.3% vs. Rd, 65.0%; HR for&#xD;
      death, 0.79; p=0.04) and overall response rate (ORR) (KRd, 87.1% vs. Rd, 66.7%; p&lt;0.001).&#xD;
      Objective assessment of adverse events (AEs) and patient-reported outcomes (PRO) revealed&#xD;
      that the benefit-risk ratio is favorable for the three-drug combination KRd.&#xD;
&#xD;
      ENDEAVOR, NCT015688663 To compare the efficacy and safety of the dual combination therapy Kd&#xD;
      with the dual combination therapy Vd, a randomized, multicenter, open-label phase III study&#xD;
      was performed in patients with RRMM. Patients in both arms received treatment until&#xD;
      progression. Results of the preplanned interim analysis show, that the trial met its primary&#xD;
      endpoint PFS (HR for progression or death, 0.53; p&lt;0.0001). Median PFS was 18.7 months with&#xD;
      Kd treatment compared to 9.4 months with Vd treatment. In addition, the Kd combination&#xD;
      therapy demonstrated superiority over the Vd combination therapy for secondary objectives,&#xD;
      like ORR (77% vs. 63%; p&lt;0.0001) and median duration of response (DOR) (21.3 months vs. 10.4&#xD;
      months). OS data were not available at time of analysis. Despite higher rates for cardiac and&#xD;
      renal failure as well as higher incidence of hypertension and dyspnea in the Kd arm,&#xD;
      carfilzomib given as a 30 min infusion has an acceptable safety profile, particularly with&#xD;
      respect to lower peripheral neuropathy events. The number of patients who had ≥ grade 2&#xD;
      peripheral neuropathy was significantly higher in the Vd group than in the Kd group (32% vs.&#xD;
      6%). In conclusion, data of the ENDEAVOR study demonstrate, that carfilzomib given in&#xD;
      combination with dexamethasone has a favorable benefit-risk profile and provides an important&#xD;
      new treatment option for patients with RRMM.&#xD;
&#xD;
      CANDOR, NCT031586884-7 To compare the efficacy and safety of carfilzomib in combination with&#xD;
      dexamethasone and daratumumab (KdD) with the dual combination therapy Kd, a randomized,&#xD;
      multicenter, open-label phase III study was performed in patients with RRMM. Patients in both&#xD;
      arms received treatment until progression. The trial met its primary endpoint PFS (HR for&#xD;
      progression or death, 0.59). Median PFS was 28.6 months in the KdD arm and 15.2 months with&#xD;
      Kd treatment with a median follow-up time of 27.8 months and 27.0 months, respectively.&#xD;
      Further, KdD treatment demonstrates improved response rates by providing deeper responses.&#xD;
      ORR was 84% (with 29% complete response (CR) or better) for KdD treatment and 75% (with 10%&#xD;
      CR or better) for Kd treatment (p=0.0080). The minimal residual disease (MRD) negative CR&#xD;
      rate at 12 months is nearly 10-times higher with KdD (12.5%) compared to Kd (1.3%). Overall,&#xD;
      the safety profile is consistent with the known safety profiles of each agent, with the&#xD;
      exception of an imbalance in treatment-emergent fatal AEs, which might be partially explained&#xD;
      by longer treatment exposure, age, and frailty status.&#xD;
&#xD;
      Up to now, no real-life data on patients' adherence, persistence, quality of life (QoL) and&#xD;
      patterns of use, effectiveness and safety of the KRd,the Kd and the KdD regimen have been&#xD;
      systematically collected and analyzed. Thus, after market approval of KRd, Kd and KdD as&#xD;
      treatment for patients with MM who have received at least one prior therapy, the purpose of&#xD;
      the CARO NIS is to evaluate patients' adherence, persistence and QoL as well as effectiveness&#xD;
      and safety of both regimens in a real-life setting.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">October 25, 2016</start_date>
  <completion_date type="Anticipated">June 30, 2025</completion_date>
  <primary_completion_date type="Anticipated">June 30, 2025</primary_completion_date>
  <study_type>Observational</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <observational_model>Case-Only</observational_model>
    <time_perspective>Prospective</time_perspective>
  </study_design_info>
  <primary_outcome>
    <measure>Patients' adherence and persistence to carfilzomib therapy</measure>
    <time_frame>Duration of Carfilzomib therapy, up to 24 months after last patient in</time_frame>
    <description>Patients' adherence and persistence to carfilzomib therapy</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Patients' adherence and persistence to lenalidomide, dexamethasone and daratumumab therapy</measure>
    <time_frame>Duration of Carfilzomib therapy, up to 24 months after last patient in</time_frame>
    <description>Patients' adherence and persistence to lenalidomide, dexamethasone and daratumumab therapy</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Median Progression-free Survival (PFS)</measure>
    <time_frame>up to 24 months after last patient in</time_frame>
    <description>Median Progression-free Survival (PFS)</description>
  </other_outcome>
  <other_outcome>
    <measure>Overall Survival (OS) rate at 24 months</measure>
    <time_frame>24 months</time_frame>
    <description>Overall Survival (OS) rate at 24 months</description>
  </other_outcome>
  <other_outcome>
    <measure>Median Time to Response (TTR)</measure>
    <time_frame>up to 24 months after last patient in</time_frame>
    <description>Median Time to Response (TTR)</description>
  </other_outcome>
  <other_outcome>
    <measure>Median Duration of Response (DOR)</measure>
    <time_frame>up to 24 months after last patient in</time_frame>
    <description>Median Duration of Response (DOR)</description>
  </other_outcome>
  <other_outcome>
    <measure>Overall Response Rate (ORR)</measure>
    <time_frame>up to 24 months after last patient in</time_frame>
    <description>ORR is defined as ≥ Very Good Partial Response (VGPR) + Partial Response (PR)</description>
  </other_outcome>
  <other_outcome>
    <measure>To assess safety and tolerability measured by adverse events as graded by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v.4.03</measure>
    <time_frame>Duration of Carfilzomib therapy (+ 30 days), up to 25 months after last patient in</time_frame>
    <description>AE, SAE and ADR are documented in the eCRF and will be used for safety assessment.</description>
  </other_outcome>
  <other_outcome>
    <measure>To assess health-related QoL using the validated BOMET-QoL-10 questionnaire</measure>
    <time_frame>Baseline, 6, 12, 18, 24, End of Treatment (latest up to 24 months after last patient in)</time_frame>
    <description>QoL data will be collected at baseline, after 6, 12, 18, 24 months (during treatment) and at the end of Carfilzomib therapy</description>
  </other_outcome>
  <number_of_groups>3</number_of_groups>
  <enrollment type="Actual">359</enrollment>
  <condition>Multiple Myeloma in Relapse</condition>
  <arm_group>
    <arm_group_label>Car/Len/Dex (KRd)</arm_group_label>
    <description>Patients treated with carfilzomib, lenalidomide and dexamethasone dosage form, dosage, frequency and duration of treatment according to current SmPC</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Car/Dex (Kd)</arm_group_label>
    <description>Patients treated with carfilzomib and dexamethasone dosage form, dosage, frequency and duration of treatment according to current SmPC</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Car/Dex/Dara (KdD)</arm_group_label>
    <description>Patients treated with carfilzomib, dexamethasone and daratumumab dosage form, dosage, frequency and duration of treatment according to current SmPC</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Carfilzomib</intervention_name>
    <description>In accordance with SmPC.</description>
    <arm_group_label>Car/Dex (Kd)</arm_group_label>
    <arm_group_label>Car/Dex/Dara (KdD)</arm_group_label>
    <arm_group_label>Car/Len/Dex (KRd)</arm_group_label>
    <other_name>Kyprolis®</other_name>
  </intervention>
  <eligibility>
    <study_pop>
      <textblock>
        Adult patients with multiple myeloma (MM) who have received at least one prior therapy&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Aged 18 years or older.&#xD;
&#xD;
          -  Patients with MM who have received at least one prior therapy.&#xD;
&#xD;
          -  Indication for treatment as assessed by the treating physician.&#xD;
&#xD;
          -  Decision for second- or subsequent-line treatment with the combination therapy&#xD;
             carfilzomib/ lenalidomide/ dexamethasone or carfilzomib/ dexamethasone or carfilzomib/&#xD;
             dexamethasone/ daratumumab&#xD;
&#xD;
          -  Signed written informed consent.&#xD;
&#xD;
          -  Criteria according to the current Summary of Product Characteristics (SmPC) for&#xD;
             Kyprolis® (Carfilzomib)&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Contraindications according to the current SmPC for Kyprolis® (Carfilzomib)&#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>Wolfgang Knauf, Professor</last_name>
    <role>Principal Investigator</role>
    <affiliation>Centrum für Hämatologie und Onkologie Bethanien, Germany, 60389 Frankfurt a.M.</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Centrum für Hämatologie und Onkologie Bethanien</name>
      <address>
        <city>Frankfurt</city>
        <zip>60389</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Germany</country>
  </location_countries>
  <verification_date>July 2023</verification_date>
  <study_first_submitted>November 10, 2016</study_first_submitted>
  <study_first_submitted_qc>November 18, 2016</study_first_submitted_qc>
  <study_first_posted type="Estimate">November 22, 2016</study_first_posted>
  <last_update_submitted>July 7, 2023</last_update_submitted>
  <last_update_submitted_qc>July 7, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">July 10, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <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>
  <patient_data>
    <sharing_ipd>No</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/NCT02970747
org study id: IOM-070337
nct id: NCT02970747
lead sponsor: 
collaborator: 
has dmc: No
The objective of this non-interventional study (NIS) is to evaluate patients' adherence and
      persistence to carfilzomib therapy in combination with lenalidomide and dexamethasone or in
      combination with dexamethasone alone or in combination with daratumumab and dexamethasone in
      adult patients with multiple myeloma (MM) who have received at least one prior therapy in a
      real-life setting.
The dual combination of lenalidomide (Revlimid®) (R) and dexamethasone (d) (Rd) as well as
      the dual combination of bortezomib (Velcade®, V) and dexamethasone (Vd) are standard regimens
      to treat MM patients who have received at least one prior therapy. Recently published
      clinical data indicate that the next-generation proteasome inhibitor carfilzomib (Kyprolis®)
      (K) may substantially change the treatment paradigm for patients with relapsed or refractory
      MM (RRMM).1 Three pivotal trials were conducted leading to market authorization of
      carfilzomib in combination with lenalidomide and dexamethasone or in combination with
      dexamethasone alone or in combination with dexamethasone and daratumumab for the treatment of
      MM patients who have received at least one prior therapy.

      ASPIRE, NCT010803912 To compare the efficacy and safety of carfilzomib in combination with Rd
      (KRd) with the dual combination therapy Rd, a randomized, multicenter, open-label phase III
      study was performed in patients with relapsed MM (RMM). After cycle 18, carfilzomib was
      discontinued in the KRd arm, but Rd administration was continued thereafter until disease
      progression. The trial met its primary endpoint progression-free survival (PFS) (Hazard Ratio
      (HR) for progression or death, 0.69; p=0.0001). Median PFS was 26.3 months with KRd treatment
      compared to 17.6 months with Rd treatment. The study further demonstrates that carfilzomib
      improves patients' overall survival (OS) rate at 24 months (KRd, 73.3% vs. Rd, 65.0%; HR for
      death, 0.79; p=0.04) and overall response rate (ORR) (KRd, 87.1% vs. Rd, 66.7%; p<0.001).
      Objective assessment of adverse events (AEs) and patient-reported outcomes (PRO) revealed
      that the benefit-risk ratio is favorable for the three-drug combination KRd.

      ENDEAVOR, NCT015688663 To compare the efficacy and safety of the dual combination therapy Kd
      with the dual combination therapy Vd, a randomized, multicenter, open-label phase III study
      was performed in patients with RRMM. Patients in both arms received treatment until
      progression. Results of the preplanned interim analysis show, that the trial met its primary
      endpoint PFS (HR for progression or death, 0.53; p<0.0001). Median PFS was 18.7 months with
      Kd treatment compared to 9.4 months with Vd treatment. In addition, the Kd combination
      therapy demonstrated superiority over the Vd combination therapy for secondary objectives,
      like ORR (77% vs. 63%; p<0.0001) and median duration of response (DOR) (21.3 months vs. 10.4
      months). OS data were not available at time of analysis. Despite higher rates for cardiac and
      renal failure as well as higher incidence of hypertension and dyspnea in the Kd arm,
      carfilzomib given as a 30 min infusion has an acceptable safety profile, particularly with
      respect to lower peripheral neuropathy events. The number of patients who had ≥ grade 2
      peripheral neuropathy was significantly higher in the Vd group than in the Kd group (32% vs.
      6%). In conclusion, data of the ENDEAVOR study demonstrate, that carfilzomib given in
      combination with dexamethasone has a favorable benefit-risk profile and provides an important
      new treatment option for patients with RRMM.

      CANDOR, NCT031586884-7 To compare the efficacy and safety of carfilzomib in combination with
      dexamethasone and daratumumab (KdD) with the dual combination therapy Kd, a randomized,
      multicenter, open-label phase III study was performed in patients with RRMM. Patients in both
      arms received treatment until progression. The trial met its primary endpoint PFS (HR for
      progression or death, 0.59). Median PFS was 28.6 months in the KdD arm and 15.2 months with
      Kd treatment with a median follow-up time of 27.8 months and 27.0 months, respectively.
      Further, KdD treatment demonstrates improved response rates by providing deeper responses.
      ORR was 84% (with 29% complete response (CR) or better) for KdD treatment and 75% (with 10%
      CR or better) for Kd treatment (p=0.0080). The minimal residual disease (MRD) negative CR
      rate at 12 months is nearly 10-times higher with KdD (12.5%) compared to Kd (1.3%). Overall,
      the safety profile is consistent with the known safety profiles of each agent, with the
      exception of an imbalance in treatment-emergent fatal AEs, which might be partially explained
      by longer treatment exposure, age, and frailty status.

      Up to now, no real-life data on patients' adherence, persistence, quality of life (QoL) and
      patterns of use, effectiveness and safety of the KRd,the Kd and the KdD regimen have been
      systematically collected and analyzed. Thus, after market approval of KRd, Kd and KdD as
      treatment for patients with MM who have received at least one prior therapy, the purpose of
      the CARO NIS is to evaluate patients' adherence, persistence and QoL as well as effectiveness
      and safety of both regimens in a real-life setting.
observational model: Case-Only
time perspective: Prospective
measure: Patients' adherence and persistence to carfilzomib therapy
time frame: Duration of Carfilzomib therapy, up to 24 months after last patient in
description: Patients' adherence and persistence to carfilzomib therapy
measure: Patients' adherence and persistence to lenalidomide, dexamethasone and daratumumab therapy
time frame: Duration of Carfilzomib therapy, up to 24 months after last patient in
description: Patients' adherence and persistence to lenalidomide, dexamethasone and daratumumab therapy
measure: Median Progression-free Survival (PFS)
time frame: up to 24 months after last patient in
description: Median Progression-free Survival (PFS)
measure: Overall Survival (OS) rate at 24 months
time frame: 24 months
description: Overall Survival (OS) rate at 24 months
measure: Median Time to Response (TTR)
time frame: up to 24 months after last patient in
description: Median Time to Response (TTR)
measure: Median Duration of Response (DOR)
time frame: up to 24 months after last patient in
description: Median Duration of Response (DOR)
measure: Overall Response Rate (ORR)
time frame: up to 24 months after last patient in
description: ORR is defined as ≥ Very Good Partial Response (VGPR) + Partial Response (PR)
measure: To assess safety and tolerability measured by adverse events as graded by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v.4.03
time frame: Duration of Carfilzomib therapy (+ 30 days), up to 25 months after last patient in
description: AE, SAE and ADR are documented in the eCRF and will be used for safety assessment.
measure: To assess health-related QoL using the validated BOMET-QoL-10 questionnaire
time frame: Baseline, 6, 12, 18, 24, End of Treatment (latest up to 24 months after last patient in)
description: QoL data will be collected at baseline, after 6, 12, 18, 24 months (during treatment) and at the end of Carfilzomib therapy
arm group label: Car/Len/Dex (KRd)
description: Patients treated with carfilzomib, lenalidomide and dexamethasone dosage form, dosage, frequency and duration of treatment according to current SmPC
arm group label: Car/Dex (Kd)
description: Patients treated with carfilzomib and dexamethasone dosage form, dosage, frequency and duration of treatment according to current SmPC
arm group label: Car/Dex/Dara (KdD)
description: Patients treated with carfilzomib, dexamethasone and daratumumab dosage form, dosage, frequency and duration of treatment according to current SmPC
intervention type: Drug
intervention name: Carfilzomib
description: In accordance with SmPC.
arm group label: Car/Dex (Kd)
arm group label: Car/Dex/Dara (KdD)
arm group label: Car/Len/Dex (KRd)
other name: Kyprolis®
study pop: 
sampling method: Probability Sample
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Wolfgang Knauf, Professor
role: Principal Investigator
affiliation: Centrum für Hämatologie und Onkologie Bethanien, Germany, 60389 Frankfurt a.M.
facility: 
country: Germany
responsible party type: Sponsor
mesh term: Multiple Myeloma
mesh term: Neoplasms, Plasma Cell
sharing ipd: No