<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/NCT02203643</url>
  </required_header>
  <id_info>
    <org_study_id>UNITO-MM-01 / FORTE</org_study_id>
    <nct_id>NCT02203643</nct_id>
  </id_info>
  <brief_title>Evaluation of the Safety and the Efficacy of Carfilzomib Combined With Cyclophosphamide and Dexamethasone (CCyd) or Lenalidomide and Dex (CRd) Followed by ASCT or 12 Cycles of Carf Combined With Dex and Len for Patients Eligible for ASCT With Newly Diagnosed Multiple Myeloma.</brief_title>
  <acronym>FORTE</acronym>
  <official_title>A MULTICENTER, RANDOMIZED, OPEN LABEL PHASE II STUDY OF CARFILZOMIB, CYCLOPHOSPHAMIDE AND DEXAMETHASONE (CCyd) as Pre Transplant INDUCTION and Post Transplant Consolidation or CARFILZOMIB, LENALIDOMIDE AND DEXAMETHASONE (CRd) as Pre Transplant INDUCTION and Post Transplant Consolidation or Continuous Treatment With CARFILZOMIB, LENALIDOMIDE AND DEXAMETHASONE (12 Cycles) Without Transplant, All Followed by MAINTENANCE With LENALIDOMIDE (R) Versus LENALIDOMIDE AND CARFILZOMIB (CR) IN NEWLY DIAGNOSED MULTIPLE MYELOMA (MM) PATIENTS ELEGIBLE FOR AUTOLOGOUS TRANSPLANT</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Mario Boccadoro</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>University of Turin, Italy</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      This study will evaluate the safety and the efficacy of carfilzomib combined with&#xD;
      cyclophosphamide and dexamethasone (CCyd) or lenalidomide and dexamethasone (CRd) followed by&#xD;
      autologous transplantation ASCT or 12 cycles of carfilzomib combined with dexamethasone and&#xD;
      lenalidomide for patients eligible for ASCT with newly diagnosed multiple myeloma. As a&#xD;
      secondary endpoint this study will evaluate the best maintenance treatment between&#xD;
      lenalidomide and lenalidomide combined with carfilzomib.&#xD;
&#xD;
      Four hundred seventy-seven patients, males and females aged &gt; 18 years, enrolled in several&#xD;
      sites, will take part in this study.&#xD;
&#xD;
      The duration of the study is approximately 5 years.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Active, not recruiting</overall_status>
  <start_date>February 2015</start_date>
  <completion_date type="Anticipated">October 2025</completion_date>
  <primary_completion_date type="Actual">October 2016</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Efficacy in term of at least Very Good Partial Response (VGPR)</measure>
    <time_frame>Up to 2 years</time_frame>
    <description>The efficacy, in term of at least VGPR, of the combination of carfilzomib, dexamethasone with cyclophosphamide or lenalidomide after 4 cycles of induction treatment in newly diagnosed MM patients eligible for ASCT.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>sCR rate</measure>
    <time_frame>up to 1 year</time_frame>
    <description>the stringent complete response (sCR) rate in the 3 arms after complete primary therapy (induction, ASCT and consolidation for the transplant arms and after 12 cycles in the long treatment arm) in an explorative manner.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Safety as incidence of grade 3/4 adverse events</measure>
    <time_frame>Up to 3 years</time_frame>
    <description>the safety in the 3 induction/consolidation arms and in the 2 maintenance arms.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Survival</measure>
    <time_frame>Up to 5 years</time_frame>
    <description>the survival in the 3 induction/consolidation arms and in the 2 maintenance arms.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Correlation between tumor response and outcome with baseline prognostic factors.</measure>
    <time_frame>up to 5 years</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Minimal Residual Disease (MRD)</measure>
    <time_frame>up to 5 years</time_frame>
    <description>Minimal Residual Disease</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Survival after relapse</measure>
    <time_frame>up to 7 years</time_frame>
    <description>the survival after relapse</description>
  </secondary_outcome>
  <number_of_arms>3</number_of_arms>
  <enrollment type="Actual">477</enrollment>
  <condition>MULTIPLE MYELOMA (MM)</condition>
  <arm_group>
    <arm_group_label>CCyd</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Carfilzomib Cyclophosphamide and Dexamethasone administered for 4 28-day cycles. This treatment will be followed by autologous stem cell transplantation (ASCT). Carfilzomib Cyclophosphamide and Dexamethasone administered for 4 28-day cycles, as consolidation treatment.&#xD;
After the end of consolidation all patients will be randomized to receive:&#xD;
Lenalidomide or Lenalidomide and Carfilzomib until any sign of progression or intolerance.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>CRd</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Carfilzomib Lenalidomide and Dexamethasone administered for 4 28-day cycles. This treatment will be followed by autologous stem cell transplantation (ASCT). Carfilzomib Cyclophosphamide and Dexamethasone administered for 4 28-day cycles, as consolidation treatment.&#xD;
After the end of consolidation all patients will be randomized to receive:&#xD;
Lenalidomide or Lenalidomide and Carfilzomib until any sign of progression or intolerance.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>CRd long treatment</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Carfilzomib Lenalidomide and Dexamethasone administered for 4 28-day cycles. Stem cells collection will be performed. Carfilzomib Lenalidomide and Dexamethasone administered for 8 28-day cycles.&#xD;
After that all patients will be randomized to receive:&#xD;
Lenalidomide or Lenalidomide and Carfilzomib until any sign of progression or intolerance.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Carfilzomib</intervention_name>
    <arm_group_label>CCyd</arm_group_label>
    <arm_group_label>CRd</arm_group_label>
    <arm_group_label>CRd long treatment</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>Lenalidomide</intervention_name>
    <arm_group_label>CRd</arm_group_label>
    <arm_group_label>CRd long treatment</arm_group_label>
    <other_name>Revlimid</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Dexamethasone</intervention_name>
    <arm_group_label>CCyd</arm_group_label>
    <arm_group_label>CRd</arm_group_label>
    <arm_group_label>CRd long treatment</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
        Age ≥ 18 years Newly diagnosed MM based on standard CRAB criteria (see appendix B). Patient&#xD;
        &lt; 65 years eligible for ASCT. Patient has measurable disease according to IMWG&#xD;
        (International Myeloma Working Group) criteria.&#xD;
&#xD;
        Patient has given voluntary written informed consent. Patient agrees to use acceptable&#xD;
        methods for contraception. Patient has a Karnofsky performance status ≥ 60%&#xD;
&#xD;
        Pretreatment clinical laboratory values within 30 days of enrolment:&#xD;
&#xD;
        Platelet count ≥50 x 109/L (≥30 x 109 /L if myeloma involvement in the bone marrow is &gt;&#xD;
        50%) Absolute neutrophil count (ANC) ≥ 1 x 109/L without the use of growth factors&#xD;
        Corrected serum calcium ≤14 mg/dL (3.5 mmol/L) Alanine transaminase (ALT): ≤ 3 x the Upper&#xD;
        Limit Normal (ULN) Total bilirubin: ≤ 2 x the ULN Calculated or measured creatinine&#xD;
        clearance: ≥ 30 mL/minute. LVEF≥40%. 2-D transthoracic echocardiogram (ECHO) is the&#xD;
        preferred method of evaluation. Multigated Acquisition Scan (MUGA) is acceptable if ECHO is&#xD;
        not available Life expectancy ≥ 3 months&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
        Previous treatment with anti-myeloma therapy (does not include radiotherapy,&#xD;
        bisphosphonates, or a single short course of steroid &lt; to the equivalent of dexamethasone&#xD;
        40 mg/day for 4 days) Patients with non-secretory MM unless serum free-light chains are&#xD;
        present and the ratio is abnormal or a plasmocytoma with minimum largest diameters of &gt; 2&#xD;
        cm Patients ineligible for autologous transplantation Pregnant or lactating females&#xD;
&#xD;
        Presence of:&#xD;
&#xD;
        Clinical active infectious hepatitis type A, B, C or HIV Acute active infection requiring&#xD;
        antibiotics or infiltrative pulmonary disease Myocardial infarction or unstable angina ≤ 4&#xD;
        months or other clinically significant heart disease Peripheral neuropathy or neuropathic&#xD;
        pain grade 2 or higher, as defined by National Cancer Institute Common Toxicity Criteria&#xD;
        (NCI CTC) 4.0 Known history of allergy to Captisol ® (a cyclodextrin derivative used to&#xD;
        solubilize carfilzomib) Contraindication to any of the required drugs or supportive&#xD;
        treatments Invasive malignancy within the past 3 years Serious medical condition,&#xD;
        laboratory abnormality or psychiatric illness that prevented the subject from the enrolment&#xD;
        or place the subject at unacceptable risk.&#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>Antonio Palumbo, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Turin, Italy</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>IRCCS--CROB --CROB di Rionero in di Rionero in Vulture</name>
      <address>
        <city>Rionero in Vulture</city>
        <zip>85028</zip>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Italy</country>
  </location_countries>
  <verification_date>November 2022</verification_date>
  <study_first_submitted>June 30, 2014</study_first_submitted>
  <study_first_submitted_qc>July 28, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">July 30, 2014</study_first_posted>
  <last_update_submitted>November 2, 2022</last_update_submitted>
  <last_update_submitted_qc>November 2, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">November 3, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor-Investigator</responsible_party_type>
    <investigator_affiliation>University of Turin, Italy</investigator_affiliation>
    <investigator_full_name>Mario Boccadoro</investigator_full_name>
    <investigator_title>MD</investigator_title>
  </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>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Dexamethasone</mesh_term>
    <mesh_term>Cyclophosphamide</mesh_term>
    <mesh_term>Lenalidomide</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/NCT02203643
org study id: UNITO-MM-01 / FORTE
nct id: NCT02203643
lead sponsor: 
has dmc: Yes
This study will evaluate the safety and the efficacy of carfilzomib combined with
      cyclophosphamide and dexamethasone (CCyd) or lenalidomide and dexamethasone (CRd) followed by
      autologous transplantation ASCT or 12 cycles of carfilzomib combined with dexamethasone and
      lenalidomide for patients eligible for ASCT with newly diagnosed multiple myeloma. As a
      secondary endpoint this study will evaluate the best maintenance treatment between
      lenalidomide and lenalidomide combined with carfilzomib.

      Four hundred seventy-seven patients, males and females aged > 18 years, enrolled in several
      sites, will take part in this study.

      The duration of the study is approximately 5 years.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Efficacy in term of at least Very Good Partial Response (VGPR)
time frame: Up to 2 years
description: The efficacy, in term of at least VGPR, of the combination of carfilzomib, dexamethasone with cyclophosphamide or lenalidomide after 4 cycles of induction treatment in newly diagnosed MM patients eligible for ASCT.
measure: sCR rate
time frame: up to 1 year
description: the stringent complete response (sCR) rate in the 3 arms after complete primary therapy (induction, ASCT and consolidation for the transplant arms and after 12 cycles in the long treatment arm) in an explorative manner.
measure: Safety as incidence of grade 3/4 adverse events
time frame: Up to 3 years
description: the safety in the 3 induction/consolidation arms and in the 2 maintenance arms.
measure: Survival
time frame: Up to 5 years
description: the survival in the 3 induction/consolidation arms and in the 2 maintenance arms.
measure: Correlation between tumor response and outcome with baseline prognostic factors.
time frame: up to 5 years
measure: Minimal Residual Disease (MRD)
time frame: up to 5 years
description: Minimal Residual Disease
measure: Survival after relapse
time frame: up to 7 years
description: the survival after relapse
arm group label: CCyd
arm group type: Experimental
description: Carfilzomib Cyclophosphamide and Dexamethasone administered for 4 28-day cycles. This treatment will be followed by autologous stem cell transplantation (ASCT). Carfilzomib Cyclophosphamide and Dexamethasone administered for 4 28-day cycles, as consolidation treatment.
After the end of consolidation all patients will be randomized to receive:
Lenalidomide or Lenalidomide and Carfilzomib until any sign of progression or intolerance.
arm group label: CRd
arm group type: Experimental
description: Carfilzomib Lenalidomide and Dexamethasone administered for 4 28-day cycles. This treatment will be followed by autologous stem cell transplantation (ASCT). Carfilzomib Cyclophosphamide and Dexamethasone administered for 4 28-day cycles, as consolidation treatment.
After the end of consolidation all patients will be randomized to receive:
Lenalidomide or Lenalidomide and Carfilzomib until any sign of progression or intolerance.
arm group label: CRd long treatment
arm group type: Experimental
description: Carfilzomib Lenalidomide and Dexamethasone administered for 4 28-day cycles. Stem cells collection will be performed. Carfilzomib Lenalidomide and Dexamethasone administered for 8 28-day cycles.
After that all patients will be randomized to receive:
Lenalidomide or Lenalidomide and Carfilzomib until any sign of progression or intolerance.
intervention type: Drug
intervention name: Carfilzomib
arm group label: CCyd
arm group label: CRd
arm group label: CRd long treatment
intervention type: Drug
intervention name: Cyclophosphamide
arm group label: CCyd
intervention type: Drug
intervention name: Lenalidomide
arm group label: CRd
arm group label: CRd long treatment
other name: Revlimid
intervention type: Drug
intervention name: Dexamethasone
arm group label: CCyd
arm group label: CRd
arm group label: CRd long treatment
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Antonio Palumbo, MD
role: Principal Investigator
affiliation: University of Turin, Italy
facility: 
country: Italy
responsible party type: Sponsor-Investigator
investigator affiliation: University of Turin, Italy
investigator full name: Mario Boccadoro
investigator title: MD
mesh term: Multiple Myeloma
mesh term: Neoplasms, Plasma Cell
mesh term: Dexamethasone
mesh term: Cyclophosphamide
mesh term: Lenalidomide