<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/NCT01660633</url>
  </required_header>
  <id_info>
    <org_study_id>CDX-353-002</org_study_id>
    <nct_id>NCT01660633</nct_id>
  </id_info>
  <brief_title>Safety &amp; Efficacy Study High Dose Evomela Injection for MA Conditioning in MM Patients With Autologous Transplantation</brief_title>
  <official_title>A Phase IIb, Multicenter, Open-Label, Safety and Efficacy Study of High Dose Melphalan HCL for Injection (Propylene Glycol-Free)for Myeloablative Conditioning in Multiple Myeloma Patients Undergoing Autologous Transplantation</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Acrotech Biopharma Inc.</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Clinipace Worldwide</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
    <collaborator>
      <agency>Beckloff Associates, Inc.</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
    <collaborator>
      <agency>Kansas City Bioanalytical Laboratories</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Acrotech Biopharma Inc.</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      The purpose of this trial is to confirm the safety and efficacy of high-dose Melphalan HCL&#xD;
      for Injection (Propylene Glycol-Free) as a myeloablative conditioning regimen in multiple&#xD;
      myeloma patients (MM) undergoing autologous transplantation.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The sponsor of the current study is now Acrotech Biopharma, divested from Spectrum&#xD;
      Pharmaceuticals Inc. (Spectrum), which licensed the Melphalan HC1 for Injection (Propylene&#xD;
      Glycol-Free) product from Ligand Pharmaceuticals , formerly CyDex Pharmaceuticals, Inc.&#xD;
      (CyDex). This new injectable form of melphalan HCL incorporates Captisol®, β cyclodextrin&#xD;
      sulfobutyl ether sodium salts (also known as [SBE]7m-β-CD), into the product. Captisol is&#xD;
      present to facilitate the use of an all aqueous diluent (normal saline) for reconstitution&#xD;
      and administration of the freeze-dried product in place of the propylene glycol-ethanol&#xD;
      diluent necessary for the currently used melphalan intravenous product. Captisol provides for&#xD;
      solubilization and improved stability of the all aqueous reconstituted and diluted infusion&#xD;
      solution.&#xD;
&#xD;
      This is the second of two studies supporting product registration. This study will be a&#xD;
      multicenter study of high-dose Melphalan HCL for Injection (Propylene Glycol-Free) conducted&#xD;
      in 60 patients who have symptomatic MM and qualify for autologous stem cell transplantation&#xD;
      (ASCT).&#xD;
&#xD;
      During the Study Period, patients will receive 100mg/m2 of either Melphalan HCL for Injection&#xD;
      (Propylene Glycol-Free) on Day -3 and on Day -2 for a total dose of 200mg/m2. Blood samples&#xD;
      (5 timepoints post infusion) for population pharmacokinetic (PK) evaluation will be withdrawn&#xD;
      through an indwelling i.v. cannula on the first day of administration of melphalan (Day -3)&#xD;
      for all patients and then additional blood samples (2 timepoints post infusion) drawn in a&#xD;
      subset of patients on the second day of melphalan administration (Day -2).&#xD;
&#xD;
      Following one day of rest after the high dose myeloablative conditioning (Day -1), patients&#xD;
      will receive an autologous graft (Day 0).&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>December 2012</start_date>
  <completion_date type="Actual">August 2014</completion_date>
  <primary_completion_date type="Actual">February 2014</primary_completion_date>
  <phase>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>Number of Participants with Adverse Events as a Measure of Safety and Tolerability</measure>
    <time_frame>Up to Day +100</time_frame>
    <description>AE coding will be performed using the MedDRA Version 11.0 or greater. The severity of the toxicities will be graded according to the NCI CTCAE Version 4.0 whenever possible. AEs occurring when treatment starts on Day -3 through Day + 100 will be recorded in the AE section of the eCRF and causality will be assigned by the Principal Investigator.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Mucositis Severity according to World Health Organization Scoring System</measure>
    <time_frame>Until Day +30</time_frame>
    <description>The baseline measurement will be the last assessment prior to receiving the first dose of study treatment. The on-treatment period will be defined as the day after the first dose of study treatment to 30 days after the last dose of study treatment. The incidence of severe mucositis (WHO Grade 3 or 4) will be summarized by frequencies and percentages. In addition, the incidence of oral mucositis will be summarized by WHO grade. Time from start of the first dose of study medication to peak oral mucositis score will also be calculated.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Mouth Pain Scores according to a Visual Analog Scale</measure>
    <time_frame>Until Day +30</time_frame>
    <description>Baseline VAS for mouth pain and dysphagia will be the VAS score collected prior to receiving the first dose of study medication. Analyses of changes and/or percent changes from baseline in the VAS scores will be analyzed for each time point collected during the 30 day on-treatment period. The minimum and maximum VAS scores during the 30 day on-treatment period will also be calculated for mouth pain and dysphagia, and the time to the minimum and maximum VAS scores will be summarized descriptively.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Treatment Related Mortality</measure>
    <time_frame>Up to Day +100</time_frame>
    <description>TRM, which is defined as death not due to disease progression before Day +90/+100, will be calculated. This outcome measure will be summarized by the cumulative incidence estimated with 95% confidence intervals.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>MM response according to International Myeloma Working Group (IMWG) criteria.</measure>
    <time_frame>At the Day +100 visit</time_frame>
    <description>Definition of active MM, clonal bone marrow plasma cells &gt;10% or biopsy-proven bony or extramedullary plasmacytoma and any one or more of the following CRAB features and myeloma-defining events: Evidence of end organ damage that can be attributed to the underlying plasma cell proliferative disorder and one or more biomarkers of malignancy (MDEs) defined in the criteria.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Myeloablation</measure>
    <time_frame>Up to Day +30</time_frame>
    <description>Absolute neutrophil count (ANC) &lt;0.5 × 109/L, absolute lymphocyte count (ALC) &lt;0.1 × 109/L, platelet count &lt;20,000/mm3, or bleeding requiring transfusion.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Neutrophil engraftment</measure>
    <time_frame>Up to Day +100</time_frame>
    <description>ANC &gt;0.5 × 109/L × first 3 consecutive daily assessments</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Platelet engraftment</measure>
    <time_frame>Up to Day +100</time_frame>
    <description>Untransfused platelet measurement &gt;20,000/mm3 × first 3 consecutive daily assessments</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Non-engraftment</measure>
    <time_frame>Up to Day +100</time_frame>
    <description>Failure to reach an ANC &gt;0.5 × 109/L × 3 consecutive daily assessments by Day +100.</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">61</enrollment>
  <condition>Multiple Myeloma</condition>
  <arm_group>
    <arm_group_label>High-Dose Melphalan HCL for Injection (Propylene Glycol-Free)</arm_group_label>
    <arm_group_type>Other</arm_group_type>
    <description>Subjects will receive only High-Dose Melphalan HCL for Injection (Propylene Glycol-free) at 200mg/m2 (100mg/m2/day for two days).</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>High-Dose Melphalan HCL for Injection (Propylene Glycol-Free)</intervention_name>
    <description>200 mg melphalan/m2 will be divided into two separate, consecutive doses of 100 mg/m2 administered on day -3 and day -2 prior to ASCT. The High-Dose Melphaln HCL for Injection (Propylene Glycol-Free) will be reconstituted to 5 mg/mL (also containing 270 mg/mL of Captisol®). The Melphalan HCL for Injection (Propylene Glycol Free) will be further diluted with normal saline to a concentration of no greater than 0.45 mg/mL and infused over 30 minutes ( + or - 3 minutes)via a central venous catheter.</description>
    <arm_group_label>High-Dose Melphalan HCL for Injection (Propylene Glycol-Free)</arm_group_label>
    <other_name>Evomela</other_name>
    <other_name>Alkeran</other_name>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Autologous Transplantation</intervention_name>
    <description>Patients who are myeloablative conditioning in multiple myeloma undergoing autologous transplantation( patients own blood-forming stem cells are collected to replace diseased bone marrow or bone marrow damaged by cancer treatment)</description>
    <arm_group_label>High-Dose Melphalan HCL for Injection (Propylene Glycol-Free)</arm_group_label>
    <other_name>Hematopoietic stem cell transplantation</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Patients with symptomatic MM based on IMWG guidelines requiring treatment who are&#xD;
             eligible for ASCT.&#xD;
&#xD;
          -  Patients who are 70 years of age or younger at time of transplant. Patients older than&#xD;
             70 years of age may be enrolled on a case-by-case basis if the patient meets local&#xD;
             institutional criteria to receive a total melphalan dose of 200 mg/m2 as a&#xD;
             conditioning regimen and if approved by the medical monitor.&#xD;
&#xD;
          -  Patients with an adequate autologous graft, defined as an unmanipulated,&#xD;
             cryopreserved, peripheral blood stem cell graft containing at least 2 × 106 CD34+&#xD;
             cells/kg based on patient body weight.&#xD;
&#xD;
        Patients with adequate organ function as measured by:&#xD;
&#xD;
          -  Cardiac function: Left ventricular ejection fraction at rest &gt;40% (documented within 8&#xD;
             weeks prior to Day -3).&#xD;
&#xD;
          -  Hepatic function: Bilirubin &lt;2 × the upper limit of normal and alanine&#xD;
             aminotransferase (ALT)/aspartate aminotransferase (AST) &lt;3 × upper limit of normal.&#xD;
&#xD;
          -  Renal function: Creatinine clearance &gt;40 mL/minute (measured or calculated/estimated).&#xD;
&#xD;
          -  Pulmonary function: Carbon monoxide diffusing capacity (DLCO)corrected for hemoglobin&#xD;
             (Hgb), forced expiratory volume in 1 second (FEV1), forced expiratory vital capacity&#xD;
             (FVC), and oxygen saturation &gt;92% on room air (documented within 4 weeks prior to Day&#xD;
             -3).&#xD;
&#xD;
          -  Patients with Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or&#xD;
             2.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Patients with smoldering MM not requiring therapy.&#xD;
&#xD;
          -  Patients with plasma cell leukemia.&#xD;
&#xD;
          -  Patients with systemic amyloid light chain amyloidosis.&#xD;
&#xD;
          -  Patients with uncontrolled hypertension.&#xD;
&#xD;
          -  Patients with an active bacterial, viral, or fungal infection.&#xD;
&#xD;
          -  Patients with a life expectancy of &lt; 6 months.&#xD;
&#xD;
          -  Patients with prior malignancies except resected basal cell carcinoma or treated&#xD;
             cervical carcinoma in situ. Cancer treated with curative intent &gt;5 years previously&#xD;
             will be allowed. Cancer treated with curative intent &lt;5 years previously will not be&#xD;
             allowed unless approved by the medical monitor.&#xD;
&#xD;
          -  Female patients who are pregnant or breastfeeding.&#xD;
&#xD;
          -  Female patients of childbearing potential who are unwilling to use adequate&#xD;
             contraceptive techniques during and for 3 months following study treatment with&#xD;
             Melphalan HCl for Injection (Propylene Glycol-Free).&#xD;
&#xD;
          -  Patients seropositive for Human Immunodeficiency Virus(HIV).&#xD;
&#xD;
          -  Patients who are unwilling to provide informed consent.&#xD;
&#xD;
          -  Patients receiving other concurrent anticancer therapy (including chemotherapy,&#xD;
             radiation, hormonal treatment, or immunotherapy, but excluding corticosteroids) within&#xD;
             30 days prior to the ASCT or planning to receive any of these treatments prior to Day&#xD;
             +30.&#xD;
&#xD;
          -  Patients concurrently participating in any other clinical study involving ASCT.&#xD;
&#xD;
          -  Patients who are hypersensitive or intolerant to any component of the study drug&#xD;
             formulation.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>N/A</minimum_age>
    <maximum_age>70 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Tim Freeman</last_name>
    <role>Study Director</role>
    <affiliation>Clinipace Worldwide</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Rush University Medical Center</name>
      <address>
        <city>Chicago</city>
        <state>Illinois</state>
        <zip>60612</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Kansas Medical Center</name>
      <address>
        <city>Fairway</city>
        <state>Kansas</state>
        <zip>66205</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Massachusetts</name>
      <address>
        <city>Worcester</city>
        <state>Massachusetts</state>
        <zip>01655</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Washington University School of Medicine</name>
      <address>
        <city>Saint Louis</city>
        <state>Missouri</state>
        <zip>63110</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Wisconsin Hospital and Clinics</name>
      <address>
        <city>Madison</city>
        <state>Wisconsin</state>
        <zip>53792</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Medical College of Wisconsin/Froedtert Hospital</name>
      <address>
        <city>Milwaukee</city>
        <state>Wisconsin</state>
        <zip>53226</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>April 2020</verification_date>
  <study_first_submitted>August 2, 2012</study_first_submitted>
  <study_first_submitted_qc>August 6, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">August 9, 2012</study_first_posted>
  <disposition_first_submitted>February 13, 2015</disposition_first_submitted>
  <disposition_first_submitted_qc>May 11, 2015</disposition_first_submitted_qc>
  <disposition_first_posted type="Estimate">June 2, 2015</disposition_first_posted>
  <last_update_submitted>April 15, 2020</last_update_submitted>
  <last_update_submitted_qc>April 15, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">April 21, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Multiple Myeloma</keyword>
  <keyword>High-Dose Melphalan</keyword>
  <keyword>Propylene Glycol-Free</keyword>
  <keyword>Autologous Stem Cell Transplantation</keyword>
  <keyword>Captisol</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>Melphalan</mesh_term>
  </intervention_browse>
  <!-- Results have not yet been posted, but a results disposition has been submitted           -->
</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/NCT01660633
org study id: CDX-353-002
nct id: NCT01660633
lead sponsor: 
collaborator: 
collaborator: 
collaborator: 
has dmc: Yes
The purpose of this trial is to confirm the safety and efficacy of high-dose Melphalan HCL
      for Injection (Propylene Glycol-Free) as a myeloablative conditioning regimen in multiple
      myeloma patients (MM) undergoing autologous transplantation.
The sponsor of the current study is now Acrotech Biopharma, divested from Spectrum
      Pharmaceuticals Inc. (Spectrum), which licensed the Melphalan HC1 for Injection (Propylene
      Glycol-Free) product from Ligand Pharmaceuticals , formerly CyDex Pharmaceuticals, Inc.
      (CyDex). This new injectable form of melphalan HCL incorporates Captisol®, β cyclodextrin
      sulfobutyl ether sodium salts (also known as [SBE]7m-β-CD), into the product. Captisol is
      present to facilitate the use of an all aqueous diluent (normal saline) for reconstitution
      and administration of the freeze-dried product in place of the propylene glycol-ethanol
      diluent necessary for the currently used melphalan intravenous product. Captisol provides for
      solubilization and improved stability of the all aqueous reconstituted and diluted infusion
      solution.

      This is the second of two studies supporting product registration. This study will be a
      multicenter study of high-dose Melphalan HCL for Injection (Propylene Glycol-Free) conducted
      in 60 patients who have symptomatic MM and qualify for autologous stem cell transplantation
      (ASCT).

      During the Study Period, patients will receive 100mg/m2 of either Melphalan HCL for Injection
      (Propylene Glycol-Free) on Day -3 and on Day -2 for a total dose of 200mg/m2. Blood samples
      (5 timepoints post infusion) for population pharmacokinetic (PK) evaluation will be withdrawn
      through an indwelling i.v. cannula on the first day of administration of melphalan (Day -3)
      for all patients and then additional blood samples (2 timepoints post infusion) drawn in a
      subset of patients on the second day of melphalan administration (Day -2).

      Following one day of rest after the high dose myeloablative conditioning (Day -1), patients
      will receive an autologous graft (Day 0).
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Number of Participants with Adverse Events as a Measure of Safety and Tolerability
time frame: Up to Day +100
description: AE coding will be performed using the MedDRA Version 11.0 or greater. The severity of the toxicities will be graded according to the NCI CTCAE Version 4.0 whenever possible. AEs occurring when treatment starts on Day -3 through Day + 100 will be recorded in the AE section of the eCRF and causality will be assigned by the Principal Investigator.
measure: Mucositis Severity according to World Health Organization Scoring System
time frame: Until Day +30
description: The baseline measurement will be the last assessment prior to receiving the first dose of study treatment. The on-treatment period will be defined as the day after the first dose of study treatment to 30 days after the last dose of study treatment. The incidence of severe mucositis (WHO Grade 3 or 4) will be summarized by frequencies and percentages. In addition, the incidence of oral mucositis will be summarized by WHO grade. Time from start of the first dose of study medication to peak oral mucositis score will also be calculated.
measure: Mouth Pain Scores according to a Visual Analog Scale
time frame: Until Day +30
description: Baseline VAS for mouth pain and dysphagia will be the VAS score collected prior to receiving the first dose of study medication. Analyses of changes and/or percent changes from baseline in the VAS scores will be analyzed for each time point collected during the 30 day on-treatment period. The minimum and maximum VAS scores during the 30 day on-treatment period will also be calculated for mouth pain and dysphagia, and the time to the minimum and maximum VAS scores will be summarized descriptively.
measure: Treatment Related Mortality
time frame: Up to Day +100
description: TRM, which is defined as death not due to disease progression before Day +90/+100, will be calculated. This outcome measure will be summarized by the cumulative incidence estimated with 95% confidence intervals.
measure: MM response according to International Myeloma Working Group (IMWG) criteria.
time frame: At the Day +100 visit
description: Definition of active MM, clonal bone marrow plasma cells >10% or biopsy-proven bony or extramedullary plasmacytoma and any one or more of the following CRAB features and myeloma-defining events: Evidence of end organ damage that can be attributed to the underlying plasma cell proliferative disorder and one or more biomarkers of malignancy (MDEs) defined in the criteria.
measure: Myeloablation
time frame: Up to Day +30
description: Absolute neutrophil count (ANC) <0.5 × 109/L, absolute lymphocyte count (ALC) <0.1 × 109/L, platelet count <20,000/mm3, or bleeding requiring transfusion.
measure: Neutrophil engraftment
time frame: Up to Day +100
description: ANC >0.5 × 109/L × first 3 consecutive daily assessments
measure: Platelet engraftment
time frame: Up to Day +100
description: Untransfused platelet measurement >20,000/mm3 × first 3 consecutive daily assessments
measure: Non-engraftment
time frame: Up to Day +100
description: Failure to reach an ANC >0.5 × 109/L × 3 consecutive daily assessments by Day +100.
arm group label: High-Dose Melphalan HCL for Injection (Propylene Glycol-Free)
arm group type: Other
description: Subjects will receive only High-Dose Melphalan HCL for Injection (Propylene Glycol-free) at 200mg/m2 (100mg/m2/day for two days).
intervention type: Drug
intervention name: High-Dose Melphalan HCL for Injection (Propylene Glycol-Free)
description: 200 mg melphalan/m2 will be divided into two separate, consecutive doses of 100 mg/m2 administered on day -3 and day -2 prior to ASCT. The High-Dose Melphaln HCL for Injection (Propylene Glycol-Free) will be reconstituted to 5 mg/mL (also containing 270 mg/mL of Captisol®). The Melphalan HCL for Injection (Propylene Glycol Free) will be further diluted with normal saline to a concentration of no greater than 0.45 mg/mL and infused over 30 minutes ( + or - 3 minutes)via a central venous catheter.
arm group label: High-Dose Melphalan HCL for Injection (Propylene Glycol-Free)
other name: Evomela
other name: Alkeran
intervention type: Other
intervention name: Autologous Transplantation
description: Patients who are myeloablative conditioning in multiple myeloma undergoing autologous transplantation( patients own blood-forming stem cells are collected to replace diseased bone marrow or bone marrow damaged by cancer treatment)
arm group label: High-Dose Melphalan HCL for Injection (Propylene Glycol-Free)
other name: Hematopoietic stem cell transplantation
criteria: 
gender: All
minimum age: N/A
maximum age: 70 Years
healthy volunteers: No
last name: Tim Freeman
role: Study Director
affiliation: Clinipace Worldwide
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
country: United States
responsible party type: Sponsor
mesh term: Multiple Myeloma
mesh term: Neoplasms, Plasma Cell
mesh term: Melphalan