<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/NCT01672736</url>
  </required_header>
  <id_info>
    <org_study_id>PMHOSI906-MM001</org_study_id>
    <nct_id>NCT01672736</nct_id>
  </id_info>
  <brief_title>A Trial of ASP7487 (OSI-906) in Combination With Bortezomib for the Treatment of Relapsed Multiple Myeloma</brief_title>
  <official_title>A Phase 1/2 Trial of ASP7487 OSI-906)in Combination With Bortezomib and Dexamethasone for the Treatment of Relapsed or Relapsed/Refractory Multiple Myeloma</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University Health Network, Toronto</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Multiple Myeloma Research Consortium</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Astellas Pharma Inc</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>University Health Network, Toronto</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      This is a multi-center, open-label, non-randomized study. Patients will receive ASP7487&#xD;
      (OSI-906) in combination with bortezomib and dexamethasone. Phase 1 involves dose escalation&#xD;
      of the combination, whereas Phase 2 involves the expansion of ASP7487 (OSI-906) combined with&#xD;
      bortezomib and dexamethasone at the MTD to establish the ORR. This trial will accrue patients&#xD;
      with relapsed or relapsed/refractory MM - a disease state for which bortezomib is approved to&#xD;
      treat by the FDA and Health Canada. The combination of ASP7487 (OSI-906) with bortezomib is&#xD;
      supported by pre-clinical work in MM in which the combination with an IGF1-R inhibitor&#xD;
      enhances anti-tumor activity of bortezomib.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The Phase 1 portion of the study will determine the MTD and DLTs of bortezomib administered&#xD;
      on days 1, 4, 8 and 11 of a 21-day cycle combined with ASP7487 (OSI-906) dosed twice daily&#xD;
      orally continuously. The combination of ASP7487 (OSI-906) with bortezomib has not previously&#xD;
      been tested. The active agent bortezomib will be used during Cycle 1 - 8 at the recommended&#xD;
      treatment dose of 1.3 mg/m2 days 1, 4, 8 and 11 and Cycles 9+ on days 1, 8, 15 and 22 of a&#xD;
      5-week cycle and ASP7487 (OSI-906) will be dose escalated form 75 mg to 150mg utilizing 3+3&#xD;
      design&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Terminated</overall_status>
  <why_stopped>
    The Sponsor decided to stop further manufacture the study drug 'Linsitinib' in Nov 2015.&#xD;
  </why_stopped>
  <start_date>September 2012</start_date>
  <completion_date type="Actual">December 27, 2017</completion_date>
  <primary_completion_date type="Actual">March 27, 2017</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>Maximum Tolerated Dose of the Combination of ASP7487 (OSI-906) With Velcade and Dexamethasone</measure>
    <time_frame>45 months</time_frame>
    <description>Phase 1: To determine the maximum tolerated dose (MTD) of ASP7487 (OSI-906) administered in combination with the recommended dose and schedule of bortezomib and dexamethasone;&#xD;
Phase 2: To evaluate the antitumor activity of ASP7487 (OSI-906) in combination with bortezomib and dexamethasone at the MTD established from the Phase 1 component.</description>
  </primary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">19</enrollment>
  <condition>Multiple Myeloma</condition>
  <arm_group>
    <arm_group_label>ASP7487, Velcade, Dexamethasone</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>ASP7487 administered orally 75, 100 and 150 mg) BID continuously for each cycle. Bortezomib administered at 1.3 mg/m2 twice weekly for the first 8 21 day cycles and once weekly beyond cycle 9 for 35 day cycles. Dexamethasone is administered on bortezomib administration days at 20 mg</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>ASP7487, Velcade, Dexamethasone</intervention_name>
    <description>ASP7487- Oral (75, 100, 150 mg)BID Bortezomib- 1.3 mg/m2 IV on days 1, 4, 8, 15 of each 21 day cycle up to cycle 8 and days 1, 5, 15, 22 of each 35 day cycle beyond cycle 9 Dexamethasone- 20 mg on the day of Bortezomib administration</description>
    <arm_group_label>ASP7487, Velcade, Dexamethasone</arm_group_label>
    <other_name>ASP7487</other_name>
    <other_name>Bortezomib</other_name>
    <other_name>Dexamethasone</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria&#xD;
&#xD;
          1. Males or females, age 18 years or older.&#xD;
&#xD;
          2. Relapsed or relapse/refractory MM with at least 1 prior line of therapy for phase 1&#xD;
             and 1 to 5 prior lines of therapy for phase 2.&#xD;
&#xD;
          3. Patients with measurable disease defined as at least one of the following&#xD;
&#xD;
               1. Serum M-protein ≥ 0.5 g/dl (≥ 5 g/l)&#xD;
&#xD;
               2. Urine M-protein ≥ 200 mg/24 h&#xD;
&#xD;
               3. Serum free light chains (FLC) assay: Involved FLC level ≥ 10 mg/dl (≥ 100 mg/l)&#xD;
                  and an abnormal serum free light chain ratio (&lt; 0.26 or &gt; 1.65)&#xD;
&#xD;
               4. Biopsy proven plasmacytoma. Prior biopsy is acceptable.&#xD;
&#xD;
               5. If the serum protein electrophoresis is unreliable for routine M-protein&#xD;
                  measurement, quantitative immunoglobulin levels on nephrolometry or turbidometry&#xD;
                  will be followed.&#xD;
&#xD;
          4. ECOG ≤ 2 OR Karnofsky ≥ 60%.&#xD;
&#xD;
          5. Predose mean QTc≤ 450 msec or QTcF ≤ 450 msec.&#xD;
&#xD;
          6. Negative pregnancy test for Females of childbearing potential.&#xD;
&#xD;
          7. Voluntary, written informed consent.&#xD;
&#xD;
          8. Ability to understand the purpose and risks of the study.&#xD;
&#xD;
          9. Must be able to take and retain oral medications.&#xD;
&#xD;
         10. Inclusion Clinical Laboratories Criteria&#xD;
&#xD;
               1. Absolute neutrophil count (ANC) &gt; 1,000 cells/dL (1.0 x 109/L)&#xD;
&#xD;
               2. Platelet count &gt; 50,000 cells/dL (50 x 109/L)&#xD;
&#xD;
               3. Hemoglobin ≥ 8.0 g/dL (4.96 mmol/L)&#xD;
&#xD;
               4. Serum AST or ALT ≤ 1.2 x ULN&#xD;
&#xD;
               5. Total bilirubin within normal limits&#xD;
&#xD;
               6. Creatinine clearance ≥ 30 mL/min&#xD;
&#xD;
               7. Serum creatinine ≤ 1.5 x ULN&#xD;
&#xD;
               8. Serum calcium (ionized or corrected for albumin) ≥ 2.0 mmol/L (8.0 mg/dL or 1.0&#xD;
                  mmol/L ionized calcium) to ≤ 1.2 x ULN.&#xD;
&#xD;
               9. Serum potassium, and magnesium within normal limits&#xD;
&#xD;
              10. HgbA1c of ≤ 7%&#xD;
&#xD;
              11. Troponin I or T within normal limits&#xD;
&#xD;
              12. BNP or NT-proBNP within normal limits&#xD;
&#xD;
              13. Fasting glucose of ≤126 mg/dL (7.0 mmol/L).&#xD;
&#xD;
         11. Resolution of prior treatment associated toxicities to ≤ grade 1&#xD;
&#xD;
        Exclusion Criteria&#xD;
&#xD;
          1. Bortezomib refractory patients are not permitted on the Phase 2 part of the study.&#xD;
&#xD;
          2. Diagnosed or treated for another malignancy within 3 years of enrollment, except&#xD;
             completely resected basal cell carcinoma or squamous cell carcinoma of the skin, an in&#xD;
             situ malignancy, or low-risk prostate cancer after curative therapy.&#xD;
&#xD;
          3. Patient has received other investigational drugs or chemotherapy within 21 days or&#xD;
             approved anti-myeloma therapy within 14 days.&#xD;
&#xD;
          4. History (within the last 6 months) of significant cardiovascular disease.&#xD;
&#xD;
          5. Mean QTcF interval &gt; 450 msec at screening.&#xD;
&#xD;
          6. Prior autologous, peripheral stem cell transplant within 12 weeks of the first dose of&#xD;
             study drug.&#xD;
&#xD;
          7. Daily requirement for corticosteroids (except for inhalation corticosteroids).&#xD;
&#xD;
          8. Patients with evidence of mucosal or internal bleeding and/or platelet transfusion&#xD;
             refractory (i.e., unable to maintain a platelet count ≥ 50,000 cells/dL).&#xD;
&#xD;
          9. Known active infection requiring parenteral or oral anti-infective treatment.&#xD;
&#xD;
         10. Serious psychiatric illness, active alcoholism, or drug addiction that may hinder or&#xD;
             confuse follow-up evaluation.&#xD;
&#xD;
         11. Use of any medical conditions that, in the Investigator's opinion, would impose&#xD;
             excessive risk to the patient.&#xD;
&#xD;
         12. Patient has hypersensitivity to any of the components of study drugs.&#xD;
&#xD;
         13. Known HIV or active hepatitis B or C viral infection.&#xD;
&#xD;
         14. Diabetes mellitus currently requiring insulin or insulinotropic therapy or prior&#xD;
             history of steroid induced diabetes.&#xD;
&#xD;
         15. History of cerebrovascular accident (CVA) within 6 months prior to registration or&#xD;
             that is not stable.&#xD;
&#xD;
         16. Prior therapy with an IGF-1R inhibitor.&#xD;
&#xD;
         17. Use of drugs that have a risk of causing QT interval prolongation and/or have a known&#xD;
             risk of causing Torsades de Pointes (TdP) before 14 days or the recommended 5&#xD;
             half-life.&#xD;
&#xD;
         18. Use of strong/moderate CYP1A2 inhibitors.&#xD;
&#xD;
         19. Gastro-intestinal abnormalities that could affect the absorption of study drug.&#xD;
&#xD;
         20. Peripheral neuropathy ≥ grade 2.&#xD;
&#xD;
         21. Significant liver disease or metastatic disease to the liver&#xD;
&#xD;
         22. History of amyloid, plasma cell leukemia or CNS involvement.&#xD;
&#xD;
         23. Radiation therapy or major surgical procedure within 4 weeks of the first dose.&#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>Suzanne Trudel, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>UHN-PMH</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Emory University Winship Cancer Institute</name>
      <address>
        <city>Atlanta</city>
        <state>Georgia</state>
        <zip>30322</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University Of Chicago Medical Center</name>
      <address>
        <city>Chicago</city>
        <state>Illinois</state>
        <zip>60637</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Queen Elizabeth II Health Sciences Center</name>
      <address>
        <city>Halifax</city>
        <state>Nova Scotia</state>
        <zip>B3H2Y9</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University Health Network-Princess Margaret Hospital</name>
      <address>
        <city>Toronto</city>
        <state>Ontario</state>
        <zip>M5G 2M9</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hôpital Maisonneuve-Rosemont</name>
      <address>
        <city>Montreal</city>
        <state>Quebec</state>
        <zip>H1T 2M4</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Sir Mortimer B. Davis-Jewish General Hospital</name>
      <address>
        <city>Montreal</city>
        <state>Quebec</state>
        <zip>H3T 1E3</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Canada</country>
    <country>United States</country>
  </location_countries>
  <verification_date>September 2018</verification_date>
  <study_first_submitted>August 1, 2012</study_first_submitted>
  <study_first_submitted_qc>August 22, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">August 27, 2012</study_first_posted>
  <results_first_submitted>March 15, 2018</results_first_submitted>
  <results_first_submitted_qc>September 12, 2018</results_first_submitted_qc>
  <results_first_posted type="Actual">September 13, 2018</results_first_posted>
  <last_update_submitted>September 12, 2018</last_update_submitted>
  <last_update_submitted_qc>September 12, 2018</last_update_submitted_qc>
  <last_update_posted type="Actual">September 13, 2018</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Relapsed or relapse/refractory Multiple Myeloma</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Multiple Myeloma</mesh_term>
    <mesh_term>Neoplasms, Plasma Cell</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Dexamethasone</mesh_term>
    <mesh_term>Dexamethasone acetate</mesh_term>
    <mesh_term>Bortezomib</mesh_term>
    <mesh_term>BB 1101</mesh_term>
  </intervention_browse>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol and Statistical Analysis Plan</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>March 1, 2014</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/36/NCT01672736/Prot_SAP_000.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <recruitment_details>Subject enrollment under this IND was stopped prematurely due to the drug manufacturer's decision to terminate the development of the study drug, Linsitinib (letter dated 1 November 2015). Therefore, the study did not proceed to Phase II portion of the study protocol. The available study drug supply at the study sites expired on 31 May 2016.</recruitment_details>
      <group_list>
        <group group_id="P1">
          <title>ASP7487, Velcade, Dexamethasone</title>
          <description>ASP7487 administered orally 75, 100 and 150 mg) BID continuously for each cycle. Bortezomib administered at 1.3 mg/m2 twice weekly for the first 8 21 day cycles and once weekly beyond cycle 9 for 35 day cycles. Dexamethasone is administered on bortezomib administration days at 20 mg&#xD;
ASP7487, Velcade, Dexamethasone: ASP7487- Oral (75, 100, 150 mg)BID Bortezomib- 1.3 mg/m2 IV on days 1, 4, 8, 15 of each 21 day cycle up to cycle 8 and days 1, 5, 15, 22 of each 35 day cycle beyond cycle 9 Dexamethasone- 20 mg on the day of Bortezomib administration</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="19">Phase I study part stopped early due to manufacturer's decision to stop further drug development.</participants>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="16">3 patients taken off study due to non-availability of further study (Linsitinib) drug supply.</participants>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="3"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Available drug expired on 31 May 16</title>
              <participants_list>
                <participants group_id="P1" count="3"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>ASP7487, Velcade, Dexamethasone</title>
          <description>ASP7487 administered orally 75, 100 and 150 mg) BID continuously for each cycle. Bortezomib administered at 1.3 mg/m2 twice weekly for the first 8 21 day cycles and once weekly beyond cycle 9 for 35 day cycles. Dexamethasone is administered on bortezomib administration days at 20 mg&#xD;
ASP7487, Velcade, Dexamethasone: ASP7487- Oral (75, 100, 150 mg)BID Bortezomib- 1.3 mg/m2 IV on days 1, 4, 8, 15 of each 21 day cycle up to cycle 8 and days 1, 5, 15, 22 of each 35 day cycle beyond cycle 9 Dexamethasone- 20 mg on the day of Bortezomib administration</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="19"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>&lt;=18 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Between 18 and 65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="12"/>
                  </measurement_list>
                </category>
                <category>
                  <title>&gt;=65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="7"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Sex: Female, Male</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Female</title>
                  <measurement_list>
                    <measurement group_id="B1" value="12"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="7"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Ethnicity (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Not Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="17"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>American Indian or Alaska Native</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Asian</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Native Hawaiian or Other Pacific Islander</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Black or African American</title>
                  <measurement_list>
                    <measurement group_id="B1" value="4"/>
                  </measurement_list>
                </category>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="15"/>
                  </measurement_list>
                </category>
                <category>
                  <title>More than one race</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Region of Enrollment</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <title>Canada</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="18"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>United States</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Maximum Tolerated Dose of the Combination of ASP7487 (OSI-906) With Velcade and Dexamethasone</title>
        <description>Phase 1: To determine the maximum tolerated dose (MTD) of ASP7487 (OSI-906) administered in combination with the recommended dose and schedule of bortezomib and dexamethasone;&#xD;
Phase 2: To evaluate the antitumor activity of ASP7487 (OSI-906) in combination with bortezomib and dexamethasone at the MTD established from the Phase 1 component.</description>
        <time_frame>45 months</time_frame>
        <group_list>
          <group group_id="O1">
            <title>ASP7487, Velcade, Dexamethasone</title>
            <description>ASP7487 administered orally 75, 100 and 150 mg) BID continuously for each cycle. Bortezomib administered at 1.3 mg/m2 twice weekly for the first 8 21 day cycles and once weekly beyond cycle 9 for 35 day cycles. Dexamethasone is administered on bortezomib administration days at 20 mg&#xD;
ASP7487, Velcade, Dexamethasone: ASP7487- Oral (75, 100, 150 mg)BID Bortezomib- 1.3 mg/m2 IV on days 1, 4, 8, 15 of each 21 day cycle up to cycle 8 and days 1, 5, 15, 22 of each 35 day cycle beyond cycle 9 Dexamethasone- 20 mg on the day of Bortezomib administration</description>
          </group>
        </group_list>
        <measure>
          <title>Maximum Tolerated Dose of the Combination of ASP7487 (OSI-906) With Velcade and Dexamethasone</title>
          <description>Phase 1: To determine the maximum tolerated dose (MTD) of ASP7487 (OSI-906) administered in combination with the recommended dose and schedule of bortezomib and dexamethasone;&#xD;
Phase 2: To evaluate the antitumor activity of ASP7487 (OSI-906) in combination with bortezomib and dexamethasone at the MTD established from the Phase 1 component.</description>
          <units>milligrams</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="19"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Linsitinib starting dose in milligrams</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="75"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Linsitinib maximum dose in milligrams</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="150"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>4 years and 10 months. This period includes the time period from study activation to the final data analysis, the results of which are presented here.The adverse event data was collected from study activation on 3 Oct 2012 up to 22 Aug 2017.</time_frame>
      <desc>Adverse Events were graded in accordance with CTCAE v4.03</desc>
      <group_list>
        <group group_id="E1">
          <title>ASP7487, Velcade, Dexamethasone</title>
          <description>ASP7487 administered orally 75, 100 and 150 mg) BID continuously for each cycle. Bortezomib administered at 1.3 mg/m2 twice weekly for the first 8 21 day cycles and once weekly beyond cycle 9 for 35 day cycles. Dexamethasone is administered on bortezomib administration days at 20 mg&#xD;
ASP7487, Velcade, Dexamethasone: ASP7487- Oral (75, 100, 150 mg)BID Bortezomib- 1.3 mg/m2 IV on days 1, 4, 8, 15 of each 21 day cycle up to cycle 8 and days 1, 5, 15, 22 of each 35 day cycle beyond cycle 9 Dexamethasone- 20 mg on the day of Bortezomib administration</description>
        </group>
      </group_list>
      <serious_events>
        <default_vocab>CTCAE v4.03</default_vocab>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, all-cause mortality</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="8" subjects_at_risk="19"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Cardiac disorders</title>
            <event_list>
              <event>
                <sub_title>Cardiac arrest</sub_title>
                <description>Probably related to bortezomib</description>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="19"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Death due to multiple myeloma</sub_title>
                <assessment>Non-systematic Assessment</assessment>
                <description>Death due to progressive disease</description>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>fever</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="19"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Lung infection</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="19"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>Alanine Aminitransferase Increased</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Asparate Aminotransferase increased</sub_title>
                <description>Occured in the same patient with increased Alanine Aminotransferase</description>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="19"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Back pain</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="19"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Delirium</sub_title>
                <description>not related to study drug</description>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="19"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>dyspnea</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="19"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>5</frequency_threshold>
        <default_vocab>CTCAE v4.03</default_vocab>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="19" subjects_at_risk="19"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Blood and lymphatic system disorders</title>
            <event_list>
              <event>
                <sub_title>Anemia</sub_title>
                <counts group_id="E1" subjects_affected="7" subjects_at_risk="19"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Diarrhea</sub_title>
                <counts group_id="E1" subjects_affected="7" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Nausea</sub_title>
                <counts group_id="E1" subjects_affected="8" subjects_at_risk="19"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Fatigue</sub_title>
                <counts group_id="E1" subjects_affected="7" subjects_at_risk="19"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Pneumonia/influenza</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="19"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>Creatinine Increased</sub_title>
                <counts group_id="E1" subjects_affected="8" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Platelet count decreased</sub_title>
                <counts group_id="E1" subjects_affected="13" subjects_at_risk="19"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Bone pain</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="19"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Headache</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Neuropathy</sub_title>
                <counts group_id="E1" subjects_affected="6" subjects_at_risk="19"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Cough</sub_title>
                <counts group_id="E1" subjects_affected="6" subjects_at_risk="19"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>Principal Investigators are NOT employed by the organization sponsoring the study.</pi_employee>
      <restrictive_agreement>The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.</restrictive_agreement>
    </certain_agreements>
    <limitations_and_caveats>Patient enrollment was stopped prematurely due to the drug manufacturer's decision to terminate the development of the study drug, Linsitinib. The study did not proceed to Phase II portion of the study protocol.</limitations_and_caveats>
    <point_of_contact>
      <name_or_title>Dr. Suzanne Trudel</name_or_title>
      <organization>University Health Network - Princess Margaret Cancer Centre</organization>
      <phone>416-946-4501 ext 4566</phone>
      <email>Suzanne.Trudel@uhn.ca</email>
    </point_of_contact>
  </clinical_results>
</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/NCT01672736
org study id: PMHOSI906-MM001
nct id: NCT01672736
lead sponsor: 
collaborator: 
collaborator: 
has dmc: Yes
This is a multi-center, open-label, non-randomized study. Patients will receive ASP7487
      (OSI-906) in combination with bortezomib and dexamethasone. Phase 1 involves dose escalation
      of the combination, whereas Phase 2 involves the expansion of ASP7487 (OSI-906) combined with
      bortezomib and dexamethasone at the MTD to establish the ORR. This trial will accrue patients
      with relapsed or relapsed/refractory MM - a disease state for which bortezomib is approved to
      treat by the FDA and Health Canada. The combination of ASP7487 (OSI-906) with bortezomib is
      supported by pre-clinical work in MM in which the combination with an IGF1-R inhibitor
      enhances anti-tumor activity of bortezomib.
The Phase 1 portion of the study will determine the MTD and DLTs of bortezomib administered
      on days 1, 4, 8 and 11 of a 21-day cycle combined with ASP7487 (OSI-906) dosed twice daily
      orally continuously. The combination of ASP7487 (OSI-906) with bortezomib has not previously
      been tested. The active agent bortezomib will be used during Cycle 1 - 8 at the recommended
      treatment dose of 1.3 mg/m2 days 1, 4, 8 and 11 and Cycles 9+ on days 1, 8, 15 and 22 of a
      5-week cycle and ASP7487 (OSI-906) will be dose escalated form 75 mg to 150mg utilizing 3+3
      design
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Maximum Tolerated Dose of the Combination of ASP7487 (OSI-906) With Velcade and Dexamethasone
time frame: 45 months
description: Phase 1: To determine the maximum tolerated dose (MTD) of ASP7487 (OSI-906) administered in combination with the recommended dose and schedule of bortezomib and dexamethasone;
Phase 2: To evaluate the antitumor activity of ASP7487 (OSI-906) in combination with bortezomib and dexamethasone at the MTD established from the Phase 1 component.
arm group label: ASP7487, Velcade, Dexamethasone
arm group type: Experimental
description: ASP7487 administered orally 75, 100 and 150 mg) BID continuously for each cycle. Bortezomib administered at 1.3 mg/m2 twice weekly for the first 8 21 day cycles and once weekly beyond cycle 9 for 35 day cycles. Dexamethasone is administered on bortezomib administration days at 20 mg
intervention type: Drug
intervention name: ASP7487, Velcade, Dexamethasone
description: ASP7487- Oral (75, 100, 150 mg)BID Bortezomib- 1.3 mg/m2 IV on days 1, 4, 8, 15 of each 21 day cycle up to cycle 8 and days 1, 5, 15, 22 of each 35 day cycle beyond cycle 9 Dexamethasone- 20 mg on the day of Bortezomib administration
arm group label: ASP7487, Velcade, Dexamethasone
other name: ASP7487
other name: Bortezomib
other name: Dexamethasone
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Suzanne Trudel, MD
role: Principal Investigator
affiliation: UHN-PMH
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
country: Canada
country: United States
responsible party type: Sponsor
mesh term: Multiple Myeloma
mesh term: Neoplasms, Plasma Cell
mesh term: Dexamethasone
mesh term: Dexamethasone acetate
mesh term: Bortezomib
mesh term: BB 1101
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
limitations and caveats: Patient enrollment was stopped prematurely due to the drug manufacturer's decision to terminate the development of the study drug, Linsitinib. The study did not proceed to Phase II portion of the study protocol.
point of contact: 