<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/NCT01693601</url>
  </required_header>
  <id_info>
    <org_study_id>GCO 12-1225</org_study_id>
    <nct_id>NCT01693601</nct_id>
  </id_info>
  <brief_title>Panobinostat and Ruxolitinib In MyElofibrosis (PRIME Trial)</brief_title>
  <acronym>PRIME</acronym>
  <official_title>Panobinostat and Ruxolitinib In MyElofibrosis (PRIME STUDY) - Phase I/II Study of Combination Oral JAK2 Tyrosine Kinase Inhibitor (JAK2-TKI) and Histone Deacetylase Inhibitor (HDACI) Therapy in Patients With Myelofibrosis</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>John Mascarenhas</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Icahn School of Medicine at Mount Sinai</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      This is a single-center, single arm, dose finding study to assess safety and tolerability of&#xD;
      the oral combination of Panobinostat and Ruxolitinib in patients with myelofibrosis (MF) in&#xD;
      chronic and accelerated phase.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Phase I/II open label, single institution, combination therapy trial of induction Ruxolitinib&#xD;
      followed by combination with Panobinostat in dose escalation cohorts with a primary endpoint&#xD;
      of determining the safety and tolerability of combination therapy in patients with&#xD;
      myelofibrosis (MF) in chronic and accelerated phase. A 3+3standard dose escalation scheme&#xD;
      will be employed and the occurrence of dose limiting toxicities (DLTs) will be captured and&#xD;
      the occurrence of such events will determine dose cohort escalation by predetermined and&#xD;
      established rules. In addition to establishing the DLTs, maximally tolerated dose (MTD), and&#xD;
      recommended phase II dose (RPTD) in the phase I portion of this trial, exploratory biomarkers&#xD;
      will be evaluated within phase I as well. Pharmacodynamics and exploratory genetic and&#xD;
      epigenetic biomarkers will be explored as predictors of response to therapy. The RPTD cohort&#xD;
      will be expanded to incorporate a total of 22 patients, including 6 from phase I, in order to&#xD;
      assess clinical response as assessed by International Working Group for Myelofibrosis&#xD;
      Research and Treatment (IWG-MRT) as a primary endpoint for the phase II portion of this&#xD;
      trial.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>January 2013</start_date>
  <completion_date type="Actual">May 18, 2018</completion_date>
  <primary_completion_date type="Actual">May 18, 2018</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>number of patients that experience adverse events</measure>
    <time_frame>at least 28 days</time_frame>
    <description>Assess the safety and tolerability of Ruxolitinib in combination with Panobinostat in patients with MF</description>
  </primary_outcome>
  <primary_outcome>
    <measure>proportion of patients that achieve at least stable disease</measure>
    <time_frame>at least 6 months</time_frame>
    <description>Assess treatment response as defined by the International Working Group for Myelofibrosis Research and Treatment (IWG-MRT)</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Spleen size</measure>
    <time_frame>up to 14 months</time_frame>
    <description>Assess changes in spleen size by palpation and MRI</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>exploratory biomarkers</measure>
    <time_frame>up to 14 months</time_frame>
    <description>o evaluate changes in inflammatory cytokines to therapy</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>symptom response</measure>
    <time_frame>at least 6 months</time_frame>
    <description>Assess symptom response with a validated MPN tool (MPN-SAF)</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">20</enrollment>
  <condition>Myelofibrosis</condition>
  <arm_group>
    <arm_group_label>Panobinostat and Ruxolitinib</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Combination of Panobinostat and Ruxolitinib</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Panobinostat</intervention_name>
    <description>PO TIW QOW or PO TIW QW</description>
    <arm_group_label>Panobinostat and Ruxolitinib</arm_group_label>
    <other_name>LBH589</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Ruxolitinib</intervention_name>
    <description>PO BID x 28 days</description>
    <arm_group_label>Panobinostat and Ruxolitinib</arm_group_label>
    <other_name>INCB424, Jakafi</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Male or female patients aged ≥ 18 years old&#xD;
&#xD;
          -  Ability to provide written informed consent obtained prior to participation in the&#xD;
             study and any related procedures being performed&#xD;
&#xD;
          -  Intermediate-2 and higher by IWG-MRT Post PV/ET MF and PMF patients either in&#xD;
&#xD;
               1. Chronic Phase (MF-CP)&#xD;
&#xD;
               2. Accelerated Phase (MF-AP)&#xD;
&#xD;
          -  Patients must meet the following laboratory criteria:&#xD;
&#xD;
               1. ANC ≥ .750 x 109/L&#xD;
&#xD;
               2. Platelets ≥ 75 x 109/L&#xD;
&#xD;
               3. Creatinine ≤ 1.5 x ULN,&#xD;
&#xD;
               4. AST and ALT ≤ 2.5 x ULN&#xD;
&#xD;
               5. Serum bilirubin ≤ 1.5 x ULN (unless Gilbert's syndrome and evidence of hemolysis)&#xD;
&#xD;
               6. Serum potassium ≥ LLN&#xD;
&#xD;
               7. Total serum calcium [corrected for serum albumin] or ionized calcium ≥LLN,&#xD;
&#xD;
               8. Serum magnesium ≥ LLN&#xD;
&#xD;
               9. Serum phosphorus ≥ LLN&#xD;
&#xD;
              10. Free T4 within normal limits&#xD;
&#xD;
          -  ECOG Performance Status of ≤ 3&#xD;
&#xD;
          -  Any prior therapy with JAK2-TKI, hypomethylating agents, HDACI, mTORi, or iMiDs is&#xD;
             allowed as long as it is greater than 3 weeks since last dose of administration and in&#xD;
             the case of a JAK2-TKI or HDACI that discontinuation was not due to non-hematologic&#xD;
             drug toxicity. An exception to this criteria are patients currently on at least 10mg&#xD;
             BID of ruxolitinib for greater than 3 months and who have not shown an optimal&#xD;
             response (i.e. without 50% reduction in palpable splenomegaly or 50% reduction in&#xD;
             symptom burden). With a reduction of ruxolitinib to 10mg BID these patients may enter&#xD;
             onto the study without stopping ruxolitinib&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Patients who will need valproic acid for any medical condition during the study or&#xD;
             within 5 days prior to first PANOBINOSTAT treatment.&#xD;
&#xD;
          -  Impaired cardiac function or clinically significant cardiac diseases, including any&#xD;
             one of the following:&#xD;
&#xD;
               1. With permanent cardiac pacemaker&#xD;
&#xD;
               2. Resting bradycardia defined as &lt;50 beats per minute&#xD;
&#xD;
               3. QTcF &gt;450 msec on screening ECG&#xD;
&#xD;
               4. Complete Left bundle branch block, bifascicular block&#xD;
&#xD;
               5. Any clinically significant ST segment and/or T-wave abnormalities&#xD;
&#xD;
               6. Presence of unstable atrial fibrillation (ventricular response rate &gt;100 bpm).&#xD;
                  Patients with stable atrial fibrillation can be enrolled provided they do not&#xD;
                  meet other cardiac exclusion criteria.&#xD;
&#xD;
               7. Symptomatic congestive heart failure (NYHA class III-IV)&#xD;
&#xD;
          -  Impairment of GI function or GI disease that may significantly alter the absorption of&#xD;
             PANOBINOSTAT or RUXOLITINIB&#xD;
&#xD;
          -  Other concurrent severe and/or uncontrolled medical conditions (e.g., uncontrolled&#xD;
             diabetes or active or uncontrolled infection) including abnormal laboratory values,&#xD;
             that could cause unacceptable safety risks or compromise compliance with the protocol&#xD;
&#xD;
          -  Patients using medications that have a relative risk of prolonging the QT interval or&#xD;
             inducing torsade de pointes if treatment cannot be discontinued or switched to a&#xD;
             different medication prior to starting study drug&#xD;
&#xD;
          -  Concomitant use of CYP3A4 inhibitors&#xD;
&#xD;
          -  Patients who have received targeted agents within 2 weeks or within 5 half-lives of&#xD;
             the agent and active metabolites (whichever is longer) and who have not recovered from&#xD;
             side effects of those therapies.&#xD;
&#xD;
          -  Chemotherapy within 3 weeks prior to screening are excluded (other than hydroxyurea at&#xD;
             stable doses and will be discontinued 24 hours prior to starting study drug).&#xD;
&#xD;
          -  Patients with an active bleeding tendency or are receiving any treatment with&#xD;
             therapeutic doses of sodium warfarin (Coumadin®) or coumadin derivatives. Patients&#xD;
             will be allowed to enter study on aspirin at doses of 81mg/d.&#xD;
&#xD;
          -  Patients who have undergone major surgery ≤ 4 weeks prior to starting study drug or&#xD;
             who have not recovered from side effects of such therapy&#xD;
&#xD;
          -  Women who are pregnant or breast-feeding or women of childbearing potential (WOCBP)&#xD;
             not using an effective method of birth control. WOCBP are defined as sexually mature&#xD;
             women who have not undergone a hysterectomy or who have not been naturally&#xD;
             postmenopausal for at least 12 consecutive months (i.e., who has had menses any time&#xD;
             in the preceding 12 consecutive months). Women of childbearing potential must have a&#xD;
             negative serum pregnancy test within 24hrs of receiving the first dose of study&#xD;
             medication.&#xD;
&#xD;
          -  Male patients whose sexual partners are WOCBP not using effective birth control&#xD;
&#xD;
          -  Patients with a prior malignancy within the last 5 years (except for basal or squamous&#xD;
             cell carcinoma, or in situ cancer of the cervix)&#xD;
&#xD;
          -  Disease associated with secondary MF such as metastatic carcinoma, lymphoma,&#xD;
             myelodysplasia, hairy cell leukemia, mast cell disease or acute leukemia (including M7&#xD;
             disease or acute panmyelosis with MF)&#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>John Mascarenhas, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Icahn School of Medicine at Mount Sinai</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Icahn School of Medicine at Mount Sinai</name>
      <address>
        <city>New York</city>
        <state>New York</state>
        <zip>10029</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>February 2019</verification_date>
  <study_first_submitted>September 14, 2012</study_first_submitted>
  <study_first_submitted_qc>September 24, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">September 26, 2012</study_first_posted>
  <last_update_submitted>February 28, 2019</last_update_submitted>
  <last_update_submitted_qc>February 28, 2019</last_update_submitted_qc>
  <last_update_posted type="Actual">March 4, 2019</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor-Investigator</responsible_party_type>
    <investigator_affiliation>Icahn School of Medicine at Mount Sinai</investigator_affiliation>
    <investigator_full_name>John Mascarenhas</investigator_full_name>
    <investigator_title>Associate Professor of Medicine, Hematology and Medical Oncology</investigator_title>
  </responsible_party>
  <keyword>Myelofibrosis</keyword>
  <keyword>Panobinostat</keyword>
  <keyword>Ruxolitinib</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Primary Myelofibrosis</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Panobinostat</mesh_term>
  </intervention_browse>
  <pending_results>
    <submitted>March 17, 2023</submitted>
    <returned>April 12, 2023</returned>
  </pending_results>
  <!-- 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/NCT01693601
org study id: GCO 12-1225
nct id: NCT01693601
lead sponsor: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
This is a single-center, single arm, dose finding study to assess safety and tolerability of
      the oral combination of Panobinostat and Ruxolitinib in patients with myelofibrosis (MF) in
      chronic and accelerated phase.
Phase I/II open label, single institution, combination therapy trial of induction Ruxolitinib
      followed by combination with Panobinostat in dose escalation cohorts with a primary endpoint
      of determining the safety and tolerability of combination therapy in patients with
      myelofibrosis (MF) in chronic and accelerated phase. A 3+3standard dose escalation scheme
      will be employed and the occurrence of dose limiting toxicities (DLTs) will be captured and
      the occurrence of such events will determine dose cohort escalation by predetermined and
      established rules. In addition to establishing the DLTs, maximally tolerated dose (MTD), and
      recommended phase II dose (RPTD) in the phase I portion of this trial, exploratory biomarkers
      will be evaluated within phase I as well. Pharmacodynamics and exploratory genetic and
      epigenetic biomarkers will be explored as predictors of response to therapy. The RPTD cohort
      will be expanded to incorporate a total of 22 patients, including 6 from phase I, in order to
      assess clinical response as assessed by International Working Group for Myelofibrosis
      Research and Treatment (IWG-MRT) as a primary endpoint for the phase II portion of this
      trial.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: number of patients that experience adverse events
time frame: at least 28 days
description: Assess the safety and tolerability of Ruxolitinib in combination with Panobinostat in patients with MF
measure: proportion of patients that achieve at least stable disease
time frame: at least 6 months
description: Assess treatment response as defined by the International Working Group for Myelofibrosis Research and Treatment (IWG-MRT)
measure: Spleen size
time frame: up to 14 months
description: Assess changes in spleen size by palpation and MRI
measure: exploratory biomarkers
time frame: up to 14 months
description: o evaluate changes in inflammatory cytokines to therapy
measure: symptom response
time frame: at least 6 months
description: Assess symptom response with a validated MPN tool (MPN-SAF)
arm group label: Panobinostat and Ruxolitinib
arm group type: Experimental
description: Combination of Panobinostat and Ruxolitinib
intervention type: Drug
intervention name: Panobinostat
description: PO TIW QOW or PO TIW QW
arm group label: Panobinostat and Ruxolitinib
other name: LBH589
intervention type: Drug
intervention name: Ruxolitinib
description: PO BID x 28 days
arm group label: Panobinostat and Ruxolitinib
other name: INCB424, Jakafi
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: John Mascarenhas, MD
role: Principal Investigator
affiliation: Icahn School of Medicine at Mount Sinai
facility: 
country: United States
responsible party type: Sponsor-Investigator
investigator affiliation: Icahn School of Medicine at Mount Sinai
investigator full name: John Mascarenhas
investigator title: Associate Professor of Medicine, Hematology and Medical Oncology
mesh term: Primary Myelofibrosis
mesh term: Panobinostat
submitted: March 17, 2023
returned: April 12, 2023