<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/NCT02257476</url>
  </required_header>
  <id_info>
    <org_study_id>IRB00071307</org_study_id>
    <secondary_id>WINSHIP2598-13</secondary_id>
    <nct_id>NCT02257476</nct_id>
  </id_info>
  <brief_title>Extended Infusion Carfilzomib on a Weekly Schedule in Patients With Advanced Solid Tumors</brief_title>
  <official_title>A Phase I Study of Extended Infusion Carfilzomib on a Weekly Schedule in Patients With Advanced Solid Malignancies</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Emory University</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Amgen</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>Emory University</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      The purpose of this study is to find the safest dose level of an approved drug, carfilzomib,&#xD;
      in solid tumors when given over a different period of time than normally used. The study will&#xD;
      also use markers in blood from routine blood draws to help check the levels of the drug.&#xD;
      Lastly, the study will check how well this drug works with regards to keeping cancer cells&#xD;
      from growing with the new time frame of delivery.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The role of the proteasome in carcinogenesis and cell survival has been well established, and&#xD;
      its inhibition associated with an accumulation of pro-apoptotic proteins and cell death.&#xD;
      Proteasome inhibitors, such has bortezomib, have been extensively studied and are widely used&#xD;
      as effective therapy in the treatment for hematologic malignancies, such as multiple myeloma&#xD;
      where circulating proteasome levels have been correlated with survival. Carfilzomib, a novel&#xD;
      irreversible proteasome inhibitor which specifically targets the chymotryptic site of the&#xD;
      proteasome has shown more potency than bortezomib and may be able to overcome bortezomib&#xD;
      resistance. Response rates between 25-54% were seen in patients with previously treated&#xD;
      myeloma in the phase 2 setting.&#xD;
&#xD;
      Given the effectiveness of proteasome inhibition in multiple myeloma, the role of proteasome&#xD;
      in solid tumors is under active investigation. Previous trials of bortezomib in breast,&#xD;
      prostate, lung, and pancreatic cancer have shown little activity of this agent in these&#xD;
      diseases. Whether the lack of activity may be mechanistically related (bortezomib inhibits&#xD;
      chymotrypsin-like and peptidyl-glutamyl peptide-hydrolyzing (PGPH)-like activities of the&#xD;
      proteasome), or a lack of potency in target inhibition, is unknown.&#xD;
&#xD;
      In a phase Ib/II study of 14 patients (phase I) and 51 patients (phase II) with advanced&#xD;
      solid tumors, Rosen and colleagues noted single-agent activity with carfilzomib. Carfilzomib&#xD;
      was dosed on days 1, 2, 8, 9, 15, and 16 of a 28 day cycle to a maximum of 12 cycles, with&#xD;
      20-36 mg/m² noted as the recommended phase 2 dose based on DLT data. A PR in both renal and&#xD;
      small cell lung cancer, and stable disease &gt; 16 weeks in mesothelioma, ovarian, renal, and&#xD;
      non-small cell lung cancer was observed. The treatment was tolerable with the most common&#xD;
      adverse events (AEs) including fatigue, headache, diarrhea, nausea and constipation.&#xD;
&#xD;
      Given the activity of carfilzomib seen in selected solid tumors, and unpublished data to&#xD;
      suggest weekly dosing may result in a similar pharmacokinetic profile including AUC, the&#xD;
      investigators propose to study the safety, tolerability, pharmacokinetics, and anti-tumor&#xD;
      activity of carfilzomib monotherapy given on a weekly dosing schedule. Weekly dosing has the&#xD;
      advantage of patient convenience, and if acceptable toxicity and pharmacokinetics, it allows&#xD;
      for easier integration of this schedule into subsequent combination therapy clinical trials.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">August 2014</start_date>
  <completion_date type="Actual">November 2016</completion_date>
  <primary_completion_date type="Actual">November 2016</primary_completion_date>
  <phase>Phase 1</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 (MTD) and recommended phase 2 dose (RP2D) of a weekly 4-hour carfilzomib infusion in patients with advanced solid malignancies</measure>
    <time_frame>Up to 18 months</time_frame>
    <description>Evaluate safety and tolerability of weekly dosed carfilzomib as assessed by using NCI Common Toxicity Criteria for Adverse Effects (CTCAE) v.4 criteria to determine DLTs, the MTD, and RP2D</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Pharmacokinetics (PK) of escalating doses of weekly intravenous carfilzomib</measure>
    <time_frame>1, 2, 4, 6, 8, 28 hours post-dose</time_frame>
    <description>Pharmacokinetic analysis (Tmax, Cmax, t1/2, AUC)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in pharmacodynamic (PD) biomarkers before and during treatment with carfilzomib using peripheral blood mononuclear cells (PBMC) and paired tumor biopsies</measure>
    <time_frame>Days 1, 2, 3, 8, 15, 21</time_frame>
    <description>Pharmacodynamic (PD) evaluation of degree of 20S proteasomal inhibition in PBMC assays conducted at Emory University before treatment and at time of first restaging scan</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Preliminary anti-tumor efficacy (objective response rate)</measure>
    <time_frame>Up to 18 months</time_frame>
    <description>Objective Response Rate (CR + PR) by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria in patients who completed at least 2 cycles of protocol therapy</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Preliminary anti-tumor efficacy (clinical benefit rate)</measure>
    <time_frame>Up to 18 months</time_frame>
    <description>Clinical Benefit Rate (CR + PR + SD) by RECIST 1.1 criteria in patients who completed at least 2 cycles of protocol therapy</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Preliminary anti-tumor efficacy (progression free survival)</measure>
    <time_frame>Up to 18 months</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Preliminary anti-tumor efficacy (overall survival)</measure>
    <time_frame>Up to 18 months</time_frame>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">22</enrollment>
  <condition>Neoplasms</condition>
  <condition>Malignancies</condition>
  <arm_group>
    <arm_group_label>Carfilzomib</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients will receive single agent carfilzomib on a weekly dosing schedule (days 1, 8, 15) in a 21 day cycle. The initial dose will be 20 mg/m² for cycle 1, day 1. Dose escalation will proceed in a standard 3+3 fashion with the requirement that dose escalation to the next level can only proceed if 0 of 3 or ≤ 1 of 6 patients experience a dose limiting toxicity (DLT). Dexamethasone 8 mg PO/IV will be administered prior to all carfilzomib doses.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Carfilzomib</intervention_name>
    <description>Carfilzomib will be given as an IV infusion over 4 hours. Subjects will remain at the clinic under observation for at least 1 hour following each dose of carfilzomib in Cycle 1 and following the dose on Cycle 2 Day 1. During these observation times, post dose IV hydration may be given at physician's discretion.</description>
    <arm_group_label>Carfilzomib</arm_group_label>
    <other_name>PR-171</other_name>
    <other_name>Kyprolis</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Dexamethasone</intervention_name>
    <description>Dexamethasone 8 mg PO/IV will be administered prior to all carfilzomib doses.</description>
    <arm_group_label>Carfilzomib</arm_group_label>
    <other_name>Decadron</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Patient aged 18 years or older at the time of enrollment.&#xD;
&#xD;
          -  Advanced/metastatic solid tumor refractory to standard therapy.&#xD;
&#xD;
          -  Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 - 2.&#xD;
&#xD;
          -  Adequate organ function as assessed by the following:&#xD;
&#xD;
               -  Bone marrow:&#xD;
&#xD;
                    -  Hemoglobin greater than or equal to 9.0 g/dL&#xD;
&#xD;
                    -  Absolute neutrophil count (ANC) greater than or equal to 1,500/mm³&#xD;
&#xD;
                    -  Platelet count greater than or equal to 100,000/mm³&#xD;
&#xD;
               -  Hepatic:&#xD;
&#xD;
                    -  Total bilirubin less than or equal to 1.5 x ULN&#xD;
&#xD;
                    -  Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) &lt; 3 x&#xD;
                       ULN&#xD;
&#xD;
                    -  Prothrombin time (PT)-international normalized ratio (INR)/partial&#xD;
                       thromboplastin time (PTT) &lt; 1.5 x ULN except in patients receiving active&#xD;
                       anticoagulation&#xD;
&#xD;
               -  Renal:&#xD;
&#xD;
                    -  Serum creatinine ≤ 1.5 x upper limit of normal or&#xD;
&#xD;
                    -  Glomerular filtration rate (GFR) of 50 ml/minute or greater (if elevated&#xD;
                       serum creatinine level &gt; 1.5 x ULN)&#xD;
&#xD;
          -  Willingness to sign informed consent by patient or patient's legal representative.&#xD;
&#xD;
          -  Patient with known but adequately treated brain metastases and without central nervous&#xD;
             system (CNS) disease progression as determined by CT or MRI imaging within 4 weeks of&#xD;
             the first dose of study drug.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Treatment related residual toxicity &gt; grade 1.&#xD;
&#xD;
          -  Prior treatment with a proteasome inhibitor.&#xD;
&#xD;
          -  Uncontrolled systemic disease or intercurrent illness.&#xD;
&#xD;
          -  Recent history of myocardial infarction (MI) or symptomatic coronary artery disease&#xD;
             within the preceding 6 months.&#xD;
&#xD;
          -  History of uncontrolled hypertension (systolic &gt; 150 mmHg or diastolic pressure &gt; 90&#xD;
             mmHG despite optimal medical management).&#xD;
&#xD;
          -  Ejection fraction &lt; 50%.&#xD;
&#xD;
          -  Known and actively treated infection with human immunodeficiency virus (HIV),&#xD;
             hepatitis B or C.&#xD;
&#xD;
          -  Major surgery or significant traumatic injury within 4 weeks of first study treatment&#xD;
             from which the subject has not fully recovered.&#xD;
&#xD;
          -  Pregnant or breast feeding women.&#xD;
&#xD;
          -  Female patient of child-bearing potential or male patient with partner of&#xD;
             child-bearing potential but unable or unwilling to use effective contraception (double&#xD;
             barrier such as condoms, contraceptive sponge, diaphragm or vaginal ring with&#xD;
             spermicidal jellies or cream; or hormonal method such as oral, parenteral or&#xD;
             transdermal hormonal agents for at least three months prior to study drug&#xD;
             administration).&#xD;
&#xD;
          -  Corticosteroid doses greater than equivalent of prednisone 7.5 mg PO daily.&#xD;
&#xD;
          -  Recent therapy with any active anticancer agent within 4 weeks of the 1st dose of the&#xD;
             study drugs.&#xD;
&#xD;
          -  Any other current malignancy or previous malignancies within 3 years of enrollment&#xD;
             except: curatively treated in situ carcinoma of the cervix uteri; localized basal or&#xD;
             squamous cell carcinoma of the skin, curatively treated in situ breast carcinoma, and&#xD;
             early stage prostate cancer.&#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 randomization.&#xD;
&#xD;
          -  Any other clinically significant medical disease or condition that, in the&#xD;
             Investigator's opinion, may interfere with protocol adherence or a subject's ability&#xD;
             to give informed consent.&#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>Bradley C. Carthon, MD, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Emory University</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_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>February 2017</verification_date>
  <study_first_submitted>September 26, 2014</study_first_submitted>
  <study_first_submitted_qc>October 2, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">October 6, 2014</study_first_posted>
  <last_update_submitted>February 3, 2017</last_update_submitted>
  <last_update_submitted_qc>February 3, 2017</last_update_submitted_qc>
  <last_update_posted type="Estimate">February 7, 2017</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Emory University</investigator_affiliation>
    <investigator_full_name>Bradley Carthon MD, PhD</investigator_full_name>
    <investigator_title>Assistant Professor</investigator_title>
  </responsible_party>
  <keyword>carfilzomib</keyword>
  <keyword>advanced solid malignancies</keyword>
  <keyword>advanced solid cancers</keyword>
  <keyword>prostate</keyword>
  <keyword>bladder</keyword>
  <keyword>colon</keyword>
  <keyword>breast</keyword>
  <keyword>lung</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Neoplasms</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Dexamethasone</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/NCT02257476
org study id: IRB00071307
secondary id: WINSHIP2598-13
nct id: NCT02257476
lead sponsor: 
collaborator: 
has dmc: Yes
The purpose of this study is to find the safest dose level of an approved drug, carfilzomib,
      in solid tumors when given over a different period of time than normally used. The study will
      also use markers in blood from routine blood draws to help check the levels of the drug.
      Lastly, the study will check how well this drug works with regards to keeping cancer cells
      from growing with the new time frame of delivery.
The role of the proteasome in carcinogenesis and cell survival has been well established, and
      its inhibition associated with an accumulation of pro-apoptotic proteins and cell death.
      Proteasome inhibitors, such has bortezomib, have been extensively studied and are widely used
      as effective therapy in the treatment for hematologic malignancies, such as multiple myeloma
      where circulating proteasome levels have been correlated with survival. Carfilzomib, a novel
      irreversible proteasome inhibitor which specifically targets the chymotryptic site of the
      proteasome has shown more potency than bortezomib and may be able to overcome bortezomib
      resistance. Response rates between 25-54% were seen in patients with previously treated
      myeloma in the phase 2 setting.

      Given the effectiveness of proteasome inhibition in multiple myeloma, the role of proteasome
      in solid tumors is under active investigation. Previous trials of bortezomib in breast,
      prostate, lung, and pancreatic cancer have shown little activity of this agent in these
      diseases. Whether the lack of activity may be mechanistically related (bortezomib inhibits
      chymotrypsin-like and peptidyl-glutamyl peptide-hydrolyzing (PGPH)-like activities of the
      proteasome), or a lack of potency in target inhibition, is unknown.

      In a phase Ib/II study of 14 patients (phase I) and 51 patients (phase II) with advanced
      solid tumors, Rosen and colleagues noted single-agent activity with carfilzomib. Carfilzomib
      was dosed on days 1, 2, 8, 9, 15, and 16 of a 28 day cycle to a maximum of 12 cycles, with
      20-36 mg/m² noted as the recommended phase 2 dose based on DLT data. A PR in both renal and
      small cell lung cancer, and stable disease > 16 weeks in mesothelioma, ovarian, renal, and
      non-small cell lung cancer was observed. The treatment was tolerable with the most common
      adverse events (AEs) including fatigue, headache, diarrhea, nausea and constipation.

      Given the activity of carfilzomib seen in selected solid tumors, and unpublished data to
      suggest weekly dosing may result in a similar pharmacokinetic profile including AUC, the
      investigators propose to study the safety, tolerability, pharmacokinetics, and anti-tumor
      activity of carfilzomib monotherapy given on a weekly dosing schedule. Weekly dosing has the
      advantage of patient convenience, and if acceptable toxicity and pharmacokinetics, it allows
      for easier integration of this schedule into subsequent combination therapy clinical trials.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of a weekly 4-hour carfilzomib infusion in patients with advanced solid malignancies
time frame: Up to 18 months
description: Evaluate safety and tolerability of weekly dosed carfilzomib as assessed by using NCI Common Toxicity Criteria for Adverse Effects (CTCAE) v.4 criteria to determine DLTs, the MTD, and RP2D
measure: Pharmacokinetics (PK) of escalating doses of weekly intravenous carfilzomib
time frame: 1, 2, 4, 6, 8, 28 hours post-dose
description: Pharmacokinetic analysis (Tmax, Cmax, t1/2, AUC)
measure: Changes in pharmacodynamic (PD) biomarkers before and during treatment with carfilzomib using peripheral blood mononuclear cells (PBMC) and paired tumor biopsies
time frame: Days 1, 2, 3, 8, 15, 21
description: Pharmacodynamic (PD) evaluation of degree of 20S proteasomal inhibition in PBMC assays conducted at Emory University before treatment and at time of first restaging scan
measure: Preliminary anti-tumor efficacy (objective response rate)
time frame: Up to 18 months
description: Objective Response Rate (CR + PR) by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria in patients who completed at least 2 cycles of protocol therapy
measure: Preliminary anti-tumor efficacy (clinical benefit rate)
time frame: Up to 18 months
description: Clinical Benefit Rate (CR + PR + SD) by RECIST 1.1 criteria in patients who completed at least 2 cycles of protocol therapy
measure: Preliminary anti-tumor efficacy (progression free survival)
time frame: Up to 18 months
measure: Preliminary anti-tumor efficacy (overall survival)
time frame: Up to 18 months
arm group label: Carfilzomib
arm group type: Experimental
description: Patients will receive single agent carfilzomib on a weekly dosing schedule (days 1, 8, 15) in a 21 day cycle. The initial dose will be 20 mg/m² for cycle 1, day 1. Dose escalation will proceed in a standard 3+3 fashion with the requirement that dose escalation to the next level can only proceed if 0 of 3 or ≤ 1 of 6 patients experience a dose limiting toxicity (DLT). Dexamethasone 8 mg PO/IV will be administered prior to all carfilzomib doses.
intervention type: Drug
intervention name: Carfilzomib
description: Carfilzomib will be given as an IV infusion over 4 hours. Subjects will remain at the clinic under observation for at least 1 hour following each dose of carfilzomib in Cycle 1 and following the dose on Cycle 2 Day 1. During these observation times, post dose IV hydration may be given at physician's discretion.
arm group label: Carfilzomib
other name: PR-171
other name: Kyprolis
intervention type: Drug
intervention name: Dexamethasone
description: Dexamethasone 8 mg PO/IV will be administered prior to all carfilzomib doses.
arm group label: Carfilzomib
other name: Decadron
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Bradley C. Carthon, MD, PhD
role: Principal Investigator
affiliation: Emory University
facility: 
country: United States
responsible party type: Principal Investigator
investigator affiliation: Emory University
investigator full name: Bradley Carthon MD, PhD
investigator title: Assistant Professor
mesh term: Neoplasms
mesh term: Dexamethasone