<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/NCT02204241</url>
  </required_header>
  <id_info>
    <org_study_id>IST-CAR-601</org_study_id>
    <nct_id>NCT02204241</nct_id>
  </id_info>
  <brief_title>Study of Carfilzomib, Cyclophosphamide and Dexamethasone in Newly Diagnosed Multiple Myeloma Patients</brief_title>
  <acronym>CCD</acronym>
  <official_title>A Multicenter, Open Label Phase I/II Study of Carfilzomib, Cyclophosphamide and Dexamethasone in Newly Diagnosed Multiple Myeloma (MM) Patients</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>European Myeloma Network</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Fondazione EMN Italy Onlus</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>European Myeloma Network</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      This protocol is a phase I/II multicenter study designed to assess the safety and the&#xD;
      efficacy of the proposed combinations as up-front treatment in elderly Multiple Myeloma (MM)&#xD;
      patients.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Treatment schedule for 9 cycles of induction:&#xD;
&#xD;
      Phase I:&#xD;
&#xD;
      In the phase I portion of the study, the following dose levels of carfilzomib will be studied&#xD;
      with fixed doses of dexamethasone and cyclophosphamide to define the maximum tolerated dose&#xD;
      (MTD):&#xD;
&#xD;
      Level-1:&#xD;
&#xD;
        1. Carfilzomib given 20 mg/m2 IV once daily on days 1-2 of Cycle 1 only followed by 36&#xD;
           mg/m2 on days 8-9, 15-16, of Cycle 1, then for all subsequent doses 36 mg/m2 IV once&#xD;
           daily on days 1-2, 8-9, 15-16.&#xD;
&#xD;
        2. Cyclophosphamide given orally at the dose of 300 mg/m2 on days 1, 8, 15&#xD;
&#xD;
        3. Dexamethasone given orally at the dose of 40 mg on days 1, 8, 15, 22 or 20 mg on days&#xD;
           1-2, 8-9, 15-16, 22-23&#xD;
&#xD;
      Level 0:&#xD;
&#xD;
        1. Carfilzomib given 20 mg/m2 IV once daily on days 1-2 of Cycle 1 only followed by 45&#xD;
           mg/m2 on days 8-9, 15-16, of Cycle 1, then for all subsequent doses 45 mg/m2 IV once&#xD;
           daily on days 1-2, 8-9, 15-16.&#xD;
&#xD;
        2. Cyclophosphamide given orally at the dose of 300 mg/m2 on days 1, 8, 15&#xD;
&#xD;
        3. Dexamethasone given orally at the dose of 40 mg on days 1, 8, 15, 22 or 20 mg on days&#xD;
           1-2, 8-9, 15-16, 22-23&#xD;
&#xD;
      Level +1:&#xD;
&#xD;
        1. Carfilzomib given 20 mg/m2 IV once daily on days 1-2 of Cycle 1 only followed by 56&#xD;
           mg/m2 on days 8-9, 15-16, of Cycle 1, then for all subsequent doses 56 mg/m2 IV once&#xD;
           daily on days 1-2, 8-9, 15-16.&#xD;
&#xD;
        2. Cyclophosphamide given orally at the dose of 300 mg/m2 on days 1, 8, 15&#xD;
&#xD;
        3. Dexamethasone given orally at the dose of 40 mg on days 1, 8, 15, 22 or 20 mg on days&#xD;
           1-2, 8-9, 15-16, 22-23&#xD;
&#xD;
      Level +2:&#xD;
&#xD;
        1. Carfilzomib given 20 mg/m2 IV once daily on days 1-2 of Cycle 1 only followed by 36&#xD;
           mg/m2 on days 8-9, 15-16, of Cycle 1, then for all subsequent doses 70 mg/m2 IV once&#xD;
           daily on days 1-2, 8-9, 15-16.&#xD;
&#xD;
        2. Cyclophosphamide given orally at the dose of 300 mg/m2 on days 1, 8, 15&#xD;
&#xD;
        3. Dexamethasone given orally at the dose of 40 mg on days 1, 8, 15, 22 or 20 mg on days&#xD;
           1-2, 8-9, 15-16, 22-23&#xD;
&#xD;
      Patient will be observed at the end of the second cycle of therapy for the assessment of side&#xD;
      effects and observation of DLTs. Dose escalation will proceed as follows:&#xD;
&#xD;
        -  3 patients will be entered at dose level 0&#xD;
&#xD;
        -  If 0/3 patients experience DLT, dose escalation will continue&#xD;
&#xD;
        -  If 1/3 patients experience DLT, 3 additional patients will be added to this cohort (max&#xD;
           6)&#xD;
&#xD;
        -  If no further patients experience DLT (1/6) dose escalation will continue&#xD;
&#xD;
        -  If 2/6 patients experience DLT, the MTD will have been exceeded and the MTD will be the&#xD;
           previous dose at which &lt;2/6 experienced DLT&#xD;
&#xD;
        -  If 2/3 patients experience a DLT at any given dose, the MTD will have been exceeded and&#xD;
           the MTD will be the preceding dose at which &lt; 2/6 (or 1/3) patients experienced a DLT.&#xD;
&#xD;
      Phase II:&#xD;
&#xD;
      The dose used to treat patients in the phase II will be the MTD defined in the phase I of the&#xD;
      study.&#xD;
&#xD;
      Treatment schedule for maintenance until progression or intolerance:&#xD;
&#xD;
      Carfilzomib at the MTD defined by phase I study IV once daily on days 1-2, 15-16.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">June 2014</start_date>
  <completion_date type="Actual">April 2023</completion_date>
  <primary_completion_date type="Actual">June 2015</primary_completion_date>
  <phase>Phase 1/Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Dose Limiting Toxicity (DLT)</measure>
    <time_frame>1 year</time_frame>
    <description>Non-hematologic:&#xD;
Grade 2 neuropathy with pain&#xD;
any Grade 3 tox. (excluding nausea, vomiting, diarrhea)&#xD;
Grade 3 nausea, vomiting, or diarrhea despite maximal antiemetic/antidiarrheal therapy&#xD;
Grade 4 fatigue lasting for ≥ 7 days&#xD;
Any non-hematologic tox. requiring a dose reduction within Cycle 1&#xD;
Inability to receive Day 1 dose of Cycle 2 due to drug related tox. persisting from Cycle 1 or drug related tox. newly encountered on Day 1 of Cycle 2.&#xD;
Hematologic:&#xD;
Grade 4 neutropenia (ANC &lt; 0.5 x 109/L) lasting for ≥ 7 days&#xD;
Febrile neutropenia (ANC &lt; 1.0 x 109/L with a fever ≥ 38.3ºC)&#xD;
Grade 4 thrombocytopenia (platelets &lt; 25.0 x 109/L) lasting ≥ 7 days despite dose delay&#xD;
Grade 3-4 thrombocytopenia associated with bleeding&#xD;
Any hematologic tox. requiring a dose reduction within Cycle 1&#xD;
Inability to receive Day 1 dose of Cycle 2 due to drug related tox. persisting from Cycle 1 or drug related tox. newly encountered on Day 1 of Cycle 2.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Response rate (RR)</measure>
    <time_frame>3 years</time_frame>
    <description>Determine the response rate</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Progression-free survival (PFS)</measure>
    <time_frame>3 years</time_frame>
    <description>Determine the progression-free survival (PFS)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Time to progression (TTP)</measure>
    <time_frame>3 years</time_frame>
    <description>Determine the time to progression (TTP)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Duration of response (DOR)</measure>
    <time_frame>3 years</time_frame>
    <description>Determine the duration of response (DOR)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall survival (OS)</measure>
    <time_frame>3 years</time_frame>
    <description>Determine the overall survival (OS)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Time to next therapy (TTNT)</measure>
    <time_frame>3 years</time_frame>
    <description>Determine the time to next therapy (TTNT)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Responses</measure>
    <time_frame>3 years</time_frame>
    <description>Determine whether responses obtained with CCyd treatment are associated with a prolongation of PFS, in comparison with non-responding patients</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Response and survival</measure>
    <time_frame>3 years</time_frame>
    <description>Determine whether tumor response and outcome may change in subgroups with different prognosis according to current prognostic factors (β2-microglobulin, C-reactive protein (CRP), FISH, gene expression profile)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Maintenance</measure>
    <time_frame>3 years</time_frame>
    <description>Determine the benefit on PFS and OS of maintenance with carfilzomib</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Adverse event</measure>
    <time_frame>1 years</time_frame>
    <description>The toxicity is defined as the first occurrence of a grade 4 hematologic drug-related toxicity (grade 4 neutropenia must last longer than 3 days and grade 4 thrombocytopenia must last longer than 7 days in order to be considered a toxicity) excluding anemia. Assessment of adverse events will be performed at the end of third cycle according to the National Cancer Institute Common Terminology Criteria of Adverse Events (CTCAE version 4.0).</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">36</enrollment>
  <condition>Multiple Myeloma</condition>
  <arm_group>
    <arm_group_label>CCyd</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Treatment schedule for 9 cycles of induction:&#xD;
Cyclophosphamide given orally at the dose of 300 mg/m2 on days 1, 8, 15. Dexamethasone given orally at the dose of 40 mg on days 1, 8, 15, 22 or 20 mg on days 1-2, 8-9,15-16, 22-23.&#xD;
Carfilzomib given 20 mg/m2 IV once daily on Day 1-2 of Cycle 1 only followed by 36/45/56/70 mg/m2 on days 8-9, 15-16 of Cycle 1, then for all subsequent doses 36/45/56/70 mg/m2 IV once daily on days 1-2, 8-9, 15-16, followed by 12-day rest period (day 17 through 28).&#xD;
Treatment schedule for maintenance until progression or intolerance:&#xD;
Carfilzomib at the MTD defined by phase I study IV once daily on days 1-2, 15-16.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Carfilzomib</intervention_name>
    <arm_group_label>CCyd</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Cyclophosphamide</intervention_name>
    <arm_group_label>CCyd</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Dexamethasone</intervention_name>
    <arm_group_label>CCyd</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Patient is of a legally consenting age as defined by local regulations.&#xD;
&#xD;
          -  Patient is age ≥ 65 year of age or who are ineligible for autologous stem cell&#xD;
             transplantation.&#xD;
&#xD;
          -  Patient is, in the investigator(s) opinion, willing and able to comply with the&#xD;
             protocol requirements.&#xD;
&#xD;
          -  Patient has given voluntary written informed consent before performance of any&#xD;
             study-related procedure not part of normal medical care, with the understanding that&#xD;
             consent may be withdrawn by the patient at any time without prejudice to their future&#xD;
             medical care.&#xD;
&#xD;
          -  Women of childbearing potential must have a negative serum pregnancy test within the 7&#xD;
             days prior to study drug administration and a negative urine pregnancy test within the&#xD;
             3 days prior to the first study drug administration.&#xD;
&#xD;
          -  Women of childbearing potential and male subjects who are sexullay active with WOCBP&#xD;
             must agree to use 2 highly effective methods of contraception during the study and for&#xD;
             30 days following the last dose of study treatment including a male condom.&#xD;
&#xD;
          -  Patient is a newly diagnosed MM patient.&#xD;
&#xD;
          -  Patient has measurable disease, defined as follows: any quantifiable serum monoclonal&#xD;
             protein value (generally, but not necessarily, ≥ 0.5 g/dL of M-protein) and, where&#xD;
             applicable, urine light-chain excretion of &gt;200 mg/24 hours. For patients with oligo&#xD;
             or non-secretory MM, it is required that they have measurable plasmacytoma &gt; 2 cm as&#xD;
             determined by clinical examination or applicable radiographs (i.e. MRI, CT-Scan) or an&#xD;
             abnormal free light chain ratio (n.v.: 0.26-1.65). We anticipate that less than 10% of&#xD;
             patients admitted to this study will be oligo- or non-secretory MM with free light&#xD;
             chains only in order to maximize interpretation of benefit results.&#xD;
&#xD;
          -  Patient has a Karnofsky performance status ≥60%.&#xD;
&#xD;
          -  Patient has a life-expectancy &gt;3 months.&#xD;
&#xD;
          -  Patient has the following laboratory values within 14 days before Baseline (day 1 of&#xD;
             the Cycle 1, before study drug administration):&#xD;
&#xD;
               -  Platelet count ≥50 x 109/L (≥30 x 109 /L if myeloma involvement in the bone&#xD;
                  marrow is &gt; 50%) within 14 days prior to drug administration.&#xD;
&#xD;
               -  Absolute neutrophil count (ANC) ≥ 1 x 109/L without the use of growth factors.&#xD;
&#xD;
               -  Corrected serum calcium ≤14 mg/dL (3.5 mmol/L)&#xD;
&#xD;
               -  Alanine transaminase (ALT): ≤ 3 x the ULN.&#xD;
&#xD;
               -  Total bilirubin: ≤ 2 x the ULN.&#xD;
&#xD;
               -  Calculated or measured creatinine clearance: ≥ 15 mL/minute&#xD;
&#xD;
               -  LVEF ≥40%. 2D transthoracic ECHO is the preferred method of evaluation.&#xD;
                  Multigated Acquisition Scan is acceptable if ECHO is not available&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Patients with non-secretory MM, unless serum free light chains are present and the&#xD;
             ratio is abnormal.&#xD;
&#xD;
          -  Women who are pregnant and/or breast feeding.&#xD;
&#xD;
          -  Patient has active infectious hepatitis type B or C or HIV.&#xD;
&#xD;
          -  Pulmonary Hypertension.&#xD;
&#xD;
          -  QTc Interval ≥ 450 msec.&#xD;
&#xD;
          -  Uncontrolled Atrial Fibrillation/Flutter.&#xD;
&#xD;
          -  History of Torsade de pointe, Ventricular Tachycardia, Ventricular Fibrillation.&#xD;
&#xD;
          -  Uncontrolled Infection.&#xD;
&#xD;
          -  Patients with myocardial infarction or unstable angina ≤ 4 months or other clinically&#xD;
             significant heart disease (e.g., CHF NY Heart Association class III or IV,&#xD;
             uncontrolled hypertension, history of labile hypertension, or history of poor&#xD;
             compliance with an antihypertensive regimen).&#xD;
&#xD;
          -  Patient with peripheral neuropathy &gt; CTCAE grade 2.&#xD;
&#xD;
          -  Known history of allergy to Captisol (a cyclodextrin derivative used to solubilize&#xD;
             carfilzomib).&#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;
          -  Subjects with pleural effusions requiring thoracentesis or ascites requiring&#xD;
             paracentesis within 14 days prior to baseline.&#xD;
&#xD;
          -  Patient has any other clinically significant illness that would, in the investigator's&#xD;
             opinion, increase the patient's risk for toxicity.&#xD;
&#xD;
          -  Patients with a prior malignancy within the last 5 years (except for basal or squamous&#xD;
             cell carcinoma, or in situ cancer of the cervix or breast, or localized prostate&#xD;
             cancer of Gleason score &lt;7 with a stable PSA).&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>65 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <location>
    <facility>
      <name>Fondazione EMN Italy Onlus</name>
      <address>
        <city>Torino</city>
        <zip>10126</zip>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Italy</country>
  </location_countries>
  <verification_date>May 2023</verification_date>
  <study_first_submitted>July 4, 2014</study_first_submitted>
  <study_first_submitted_qc>July 29, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">July 30, 2014</study_first_posted>
  <last_update_submitted>June 29, 2023</last_update_submitted>
  <last_update_submitted_qc>June 29, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">July 3, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Multiple myeloma</keyword>
  <keyword>Diagnosis</keyword>
  <keyword>CCyd</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>Cyclophosphamide</mesh_term>
  </intervention_browse>
  <!-- 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/NCT02204241
org study id: IST-CAR-601
nct id: NCT02204241
lead sponsor: 
collaborator: 
has dmc: No
This protocol is a phase I/II multicenter study designed to assess the safety and the
      efficacy of the proposed combinations as up-front treatment in elderly Multiple Myeloma (MM)
      patients.
Treatment schedule for 9 cycles of induction:

      Phase I:

      In the phase I portion of the study, the following dose levels of carfilzomib will be studied
      with fixed doses of dexamethasone and cyclophosphamide to define the maximum tolerated dose
      (MTD):

      Level-1:

        1. Carfilzomib given 20 mg/m2 IV once daily on days 1-2 of Cycle 1 only followed by 36
           mg/m2 on days 8-9, 15-16, of Cycle 1, then for all subsequent doses 36 mg/m2 IV once
           daily on days 1-2, 8-9, 15-16.

        2. Cyclophosphamide given orally at the dose of 300 mg/m2 on days 1, 8, 15

        3. Dexamethasone given orally at the dose of 40 mg on days 1, 8, 15, 22 or 20 mg on days
           1-2, 8-9, 15-16, 22-23

      Level 0:

        1. Carfilzomib given 20 mg/m2 IV once daily on days 1-2 of Cycle 1 only followed by 45
           mg/m2 on days 8-9, 15-16, of Cycle 1, then for all subsequent doses 45 mg/m2 IV once
           daily on days 1-2, 8-9, 15-16.

        2. Cyclophosphamide given orally at the dose of 300 mg/m2 on days 1, 8, 15

        3. Dexamethasone given orally at the dose of 40 mg on days 1, 8, 15, 22 or 20 mg on days
           1-2, 8-9, 15-16, 22-23

      Level +1:

        1. Carfilzomib given 20 mg/m2 IV once daily on days 1-2 of Cycle 1 only followed by 56
           mg/m2 on days 8-9, 15-16, of Cycle 1, then for all subsequent doses 56 mg/m2 IV once
           daily on days 1-2, 8-9, 15-16.

        2. Cyclophosphamide given orally at the dose of 300 mg/m2 on days 1, 8, 15

        3. Dexamethasone given orally at the dose of 40 mg on days 1, 8, 15, 22 or 20 mg on days
           1-2, 8-9, 15-16, 22-23

      Level +2:

        1. Carfilzomib given 20 mg/m2 IV once daily on days 1-2 of Cycle 1 only followed by 36
           mg/m2 on days 8-9, 15-16, of Cycle 1, then for all subsequent doses 70 mg/m2 IV once
           daily on days 1-2, 8-9, 15-16.

        2. Cyclophosphamide given orally at the dose of 300 mg/m2 on days 1, 8, 15

        3. Dexamethasone given orally at the dose of 40 mg on days 1, 8, 15, 22 or 20 mg on days
           1-2, 8-9, 15-16, 22-23

      Patient will be observed at the end of the second cycle of therapy for the assessment of side
      effects and observation of DLTs. Dose escalation will proceed as follows:

        -  3 patients will be entered at dose level 0

        -  If 0/3 patients experience DLT, dose escalation will continue

        -  If 1/3 patients experience DLT, 3 additional patients will be added to this cohort (max
           6)

        -  If no further patients experience DLT (1/6) dose escalation will continue

        -  If 2/6 patients experience DLT, the MTD will have been exceeded and the MTD will be the
           previous dose at which <2/6 experienced DLT

        -  If 2/3 patients experience a DLT at any given dose, the MTD will have been exceeded and
           the MTD will be the preceding dose at which < 2/6 (or 1/3) patients experienced a DLT.

      Phase II:

      The dose used to treat patients in the phase II will be the MTD defined in the phase I of the
      study.

      Treatment schedule for maintenance until progression or intolerance:

      Carfilzomib at the MTD defined by phase I study IV once daily on days 1-2, 15-16.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Dose Limiting Toxicity (DLT)
time frame: 1 year
description: Non-hematologic:
Grade 2 neuropathy with pain
any Grade 3 tox. (excluding nausea, vomiting, diarrhea)
Grade 3 nausea, vomiting, or diarrhea despite maximal antiemetic/antidiarrheal therapy
Grade 4 fatigue lasting for ≥ 7 days
Any non-hematologic tox. requiring a dose reduction within Cycle 1
Inability to receive Day 1 dose of Cycle 2 due to drug related tox. persisting from Cycle 1 or drug related tox. newly encountered on Day 1 of Cycle 2.
Hematologic:
Grade 4 neutropenia (ANC < 0.5 x 109/L) lasting for ≥ 7 days
Febrile neutropenia (ANC < 1.0 x 109/L with a fever ≥ 38.3ºC)
Grade 4 thrombocytopenia (platelets < 25.0 x 109/L) lasting ≥ 7 days despite dose delay
Grade 3-4 thrombocytopenia associated with bleeding
Any hematologic tox. requiring a dose reduction within Cycle 1
Inability to receive Day 1 dose of Cycle 2 due to drug related tox. persisting from Cycle 1 or drug related tox. newly encountered on Day 1 of Cycle 2.
measure: Response rate (RR)
time frame: 3 years
description: Determine the response rate
measure: Progression-free survival (PFS)
time frame: 3 years
description: Determine the progression-free survival (PFS)
measure: Time to progression (TTP)
time frame: 3 years
description: Determine the time to progression (TTP)
measure: Duration of response (DOR)
time frame: 3 years
description: Determine the duration of response (DOR)
measure: Overall survival (OS)
time frame: 3 years
description: Determine the overall survival (OS)
measure: Time to next therapy (TTNT)
time frame: 3 years
description: Determine the time to next therapy (TTNT)
measure: Responses
time frame: 3 years
description: Determine whether responses obtained with CCyd treatment are associated with a prolongation of PFS, in comparison with non-responding patients
measure: Response and survival
time frame: 3 years
description: Determine whether tumor response and outcome may change in subgroups with different prognosis according to current prognostic factors (β2-microglobulin, C-reactive protein (CRP), FISH, gene expression profile)
measure: Maintenance
time frame: 3 years
description: Determine the benefit on PFS and OS of maintenance with carfilzomib
measure: Adverse event
time frame: 1 years
description: The toxicity is defined as the first occurrence of a grade 4 hematologic drug-related toxicity (grade 4 neutropenia must last longer than 3 days and grade 4 thrombocytopenia must last longer than 7 days in order to be considered a toxicity) excluding anemia. Assessment of adverse events will be performed at the end of third cycle according to the National Cancer Institute Common Terminology Criteria of Adverse Events (CTCAE version 4.0).
arm group label: CCyd
arm group type: Experimental
description: Treatment schedule for 9 cycles of induction:
Cyclophosphamide given orally at the dose of 300 mg/m2 on days 1, 8, 15. Dexamethasone given orally at the dose of 40 mg on days 1, 8, 15, 22 or 20 mg on days 1-2, 8-9,15-16, 22-23.
Carfilzomib given 20 mg/m2 IV once daily on Day 1-2 of Cycle 1 only followed by 36/45/56/70 mg/m2 on days 8-9, 15-16 of Cycle 1, then for all subsequent doses 36/45/56/70 mg/m2 IV once daily on days 1-2, 8-9, 15-16, followed by 12-day rest period (day 17 through 28).
Treatment schedule for maintenance until progression or intolerance:
Carfilzomib at the MTD defined by phase I study IV once daily on days 1-2, 15-16.
intervention type: Drug
intervention name: Carfilzomib
arm group label: CCyd
intervention type: Drug
intervention name: Cyclophosphamide
arm group label: CCyd
intervention type: Drug
intervention name: Dexamethasone
arm group label: CCyd
criteria: 
gender: All
minimum age: 65 Years
maximum age: N/A
healthy volunteers: No
facility: 
country: Italy
responsible party type: Sponsor
mesh term: Multiple Myeloma
mesh term: Neoplasms, Plasma Cell
mesh term: Dexamethasone
mesh term: Cyclophosphamide