<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/NCT03042689</url>
  </required_header>
  <id_info>
    <org_study_id>16-464</org_study_id>
    <nct_id>NCT03042689</nct_id>
  </id_info>
  <brief_title>Study of Regorafenib in Patients With Advanced Myeloid Malignancies</brief_title>
  <official_title>Phase I Study of Regorafenib in Patients With Advanced Myeloid Malignancies</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Massachusetts General Hospital</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Bayer</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>Massachusetts General Hospital</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 research study is studying a drug as a possible treatment for advanced myeloid&#xD;
      malignancies including AML (acute myeloid leukemia), MDS (myelodysplastic syndrome) and MPN&#xD;
      (myeloproliferative neoplasms)&#xD;
&#xD;
      The intervention involved in this study is:&#xD;
&#xD;
      -Regorafenib (Stivarga)&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This research study is a Phase I clinical trial, which tests the safety of an investigational&#xD;
      drug and also tries to define the appropriate dose of the investigational drug to use for&#xD;
      further studies. &quot;Investigational&quot; means that the drug is being studied.&#xD;
&#xD;
      The FDA (the U.S. Food and Drug Administration) has not approved Regorafenib for this&#xD;
      specific disease but it has been approved for other uses.&#xD;
&#xD;
      In this research study, the investigators are looking for the best dose of Regorafenib to&#xD;
      treat the participant's disease with. Researchers will also look at how effective the study&#xD;
      drug is in treating the participant's disease and if any side effects occur.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">April 17, 2017</start_date>
  <completion_date type="Anticipated">September 2023</completion_date>
  <primary_completion_date type="Actual">September 1, 2021</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 of regorafenib in patients with advanced myeloid malignancies</measure>
    <time_frame>2 years</time_frame>
    <description>To determine the maximum tolerated dose regorafenib in patients with advanced myeloid malignancies.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Pharmacodynamic effects of regorafenib on cell signaling pathways</measure>
    <time_frame>2 years</time_frame>
    <description>To assess pharmacodynamic effect of regorafenib on cell signaling pathways such as FLT-3, RAS and other specific mutations found in each patient's leukemia.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Progression Free Survival</measure>
    <time_frame>2 years</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall Survival</measure>
    <time_frame>2 years</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>To Measure Changes In Specific Markers Of Allele Burden</measure>
    <time_frame>2 years</time_frame>
    <description>Measure changes in allele burden with regorafenib treatment using next generation sequencing.</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">16</enrollment>
  <condition>Acute Myeloid Leukemia</condition>
  <arm_group>
    <arm_group_label>Regorafenib</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Regorafenib</intervention_name>
    <description>Regorafenib will be administered on a 28 day cycle Treatment will be administered on outpatient basis at a pre-determine dosage.</description>
    <arm_group_label>Regorafenib</arm_group_label>
    <other_name>Stivarga</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Diagnosis of relapsed/refractory advanced malignancies. Specifically: relapsed&#xD;
             refractory refractory acute myeloid leukemia that have failed one line of prior&#xD;
             therapy, myelodysplastic syndrome that have failed hypomethylating agents,&#xD;
             myelofibrosis that have failed ruxolitinib or are ineligible for this therapy.&#xD;
&#xD;
          -  18 years of age or greater.&#xD;
&#xD;
          -  ECOG performance status of 0-1.&#xD;
&#xD;
          -  Able to provide informed consent.&#xD;
&#xD;
          -  Subjects (men and women) of childbearing potential must agree to use adequate&#xD;
             contraception beginning at the signing of the ICF until at least 2 months after the&#xD;
             last dose of study drug. The definition of adequate contraception will be based on the&#xD;
             judgment of the principal investigator or a designated associate.&#xD;
&#xD;
          -  Able to swallow and retain oral medication.&#xD;
&#xD;
          -  Normal organ and marrow function defined as:&#xD;
&#xD;
               -  Total bilirubin ≤ 1.5 x the upper limits of normal (ULN) except for patients with&#xD;
                  Gilbert's disease.&#xD;
&#xD;
               -  Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 x ULN&#xD;
                  (≤ 5 x ULN for subjects with liver involvement of their cancer).&#xD;
&#xD;
               -  Alkaline phosphatase limit ≤ 2.5 x ULN (≤ 5 x ULN for subjects with liver or bone&#xD;
                  involvement of their cancer).&#xD;
&#xD;
               -  Serum creatinine ≤ 1.5 x the ULN.&#xD;
&#xD;
               -  International normalized ratio (INR)/ Partial thromboplastin time (PTT) ≤ 1.5 x&#xD;
                  ULN. (Subjects who are prophylactically treated with an agent such as warfarin or&#xD;
                  heparin will be allowed to participate provided that no prior evidence of&#xD;
                  underlying abnormality in coagulation parameters exists.)&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Previous assignment to treatment during this study. Subjects permanently withdrawn&#xD;
             from study participation will not be allowed to re-enter the study.&#xD;
&#xD;
          -  Systemic antineoplastic therapy in the past 14 days (excluding hydroxyurea).&#xD;
&#xD;
          -  Uncontrolled hypertension (systolic pressure &gt;140 mmHg or diastolic pressure &gt; 90 mmHg&#xD;
             on repeated measurement) despite optimal medical management.&#xD;
&#xD;
          -  Active or clinically significant cardiac disease including:&#xD;
&#xD;
               -  Congestive heart failure - New York Heart Association (NYHA) &gt; Class II.&#xD;
&#xD;
               -  Active coronary artery disease.&#xD;
&#xD;
               -  Cardiac arrhythmias requiring anti-arrhythmic therapy other than beta blockers or&#xD;
                  digoxin.&#xD;
&#xD;
               -  Unstable angina (anginal symptoms at rest), new-onset angina within 3 months&#xD;
                  before randomization, or myocardial infarction within 6 months before&#xD;
                  randomization.&#xD;
&#xD;
          -  Evidence or history of bleeding diathesis or coagulopathy.&#xD;
&#xD;
          -  Eligible for, have a suitable donor and are willing to undergo Hematopoietic Stem Cell&#xD;
             Transplantation (HSCT)&#xD;
&#xD;
          -  Any hemorrhage or bleeding event ≥ NCI CTCAE Grade 3 within 4 weeks prior to start of&#xD;
             study medication.&#xD;
&#xD;
          -  Thrombotic, embolic, venous or arterial events, such as cerebrovascular accident&#xD;
             (including transient ischemic attacks), deep vein thrombosis or pulmonary embolism&#xD;
             within 6 months of informed consent.&#xD;
&#xD;
          -  Previously untreated or concurrent cancer that is distinct in primary site or&#xD;
             histology except cervical cancer in-situ, treated ductal carcinoma in situ of the&#xD;
             breast, curatively treated non-melanoma skin carcinoma, noninvasive aerodigestive&#xD;
             neoplasms or superficial bladder tumor. Subjects surviving a cancer that was&#xD;
             curatively treated and without evidence of disease for more than 3 years before&#xD;
             registration are allowed. All cancer treatments must be completed at least 3 years&#xD;
             prior to registration.&#xD;
&#xD;
          -  Known history of human immunodeficiency virus (HIV) infection or current chronic or&#xD;
             active hepatitis B or C infection requiring treatment with antiviral therapy.&#xD;
&#xD;
          -  Presence of a non-healing wound, non-healing ulcer or bone fracture.&#xD;
&#xD;
          -  Major surgical procedure or significant traumatic injury within 28 days before start&#xD;
             of study medication.&#xD;
&#xD;
          -  Renal failure requiring hemo-or peritoneal dialysis.&#xD;
&#xD;
          -  Seizure disorder requiring medication.&#xD;
&#xD;
          -  Persistent proteinuria ≥ Grade 3 NCI-CTCAE v4.0 (&gt; 3.5 g/24 hrs, measured by urine&#xD;
             protein: creatinine ratio on a random urine sample).&#xD;
&#xD;
          -  Interstitial lung disease with ongoing signs and symptoms at the time of informed&#xD;
             consent.&#xD;
&#xD;
          -  Pleural effusion or ascites that causes respiratory compromise (≥ NCI-CTCAE version&#xD;
             4.0 Grade 2 dyspnea).&#xD;
&#xD;
          -  History of organ allograft (including corneal transplant). Known or suspected allergy&#xD;
             or hypersensitivity to any of the study drugs, study drug classes, or excipients of&#xD;
             the formulations given during the course of this trial.&#xD;
&#xD;
          -  Any malabsorption condition.&#xD;
&#xD;
          -  Women who are pregnant or breast-feeding, or intend to become pregnant during the&#xD;
             study. Women of childbearing potential must have a negative serum pregnancy test&#xD;
             performed within 7 days prior to the start of study drug. Post-menopausal women&#xD;
             (defined as no menses for at least 1 year) and surgically sterilized women are not&#xD;
             required to undergo a pregnancy test.&#xD;
&#xD;
          -  Substance abuse, medical, psychological or social conditions that may interfere with&#xD;
             the subject's participation in the study or evaluation of the study results.&#xD;
&#xD;
          -  Presence of unresolved toxicities from prior anticancer therapy, defined as having not&#xD;
             resolved to NCI CTCAE v4.03 grade 0 or 1 with the exception of alopecia. Subjects with&#xD;
             irreversible toxicity that is not reasonably expected to be exacerbated by regorafenib&#xD;
             (e.g. hearing loss, neuropathy) may be included after consultation with the principal&#xD;
             investigator.&#xD;
&#xD;
          -  Uncontrolled inter-current illness including, but not limited to, ongoing or active&#xD;
             infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable&#xD;
             angina pectoris, uncontrolled cardiac arrhythmia, or psychiatric illness/social&#xD;
             situations that would limit compliance with study requirements&#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>Gabriela Hobbs, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Massachusetts General Hospital</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Massachusetts general Hospital</name>
      <address>
        <city>Boston</city>
        <state>Massachusetts</state>
        <zip>02114</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>March 2023</verification_date>
  <study_first_submitted>January 24, 2017</study_first_submitted>
  <study_first_submitted_qc>February 2, 2017</study_first_submitted_qc>
  <study_first_posted type="Estimate">February 3, 2017</study_first_posted>
  <last_update_submitted>March 24, 2023</last_update_submitted>
  <last_update_submitted_qc>March 24, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">March 28, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Massachusetts General Hospital</investigator_affiliation>
    <investigator_full_name>Gabriela Hobbs</investigator_full_name>
    <investigator_title>Gabriela Hobbs, MD</investigator_title>
  </responsible_party>
  <keyword>AML</keyword>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- 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/NCT03042689
org study id: 16-464
nct id: NCT03042689
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
This research study is studying a drug as a possible treatment for advanced myeloid
      malignancies including AML (acute myeloid leukemia), MDS (myelodysplastic syndrome) and MPN
      (myeloproliferative neoplasms)

      The intervention involved in this study is:

      -Regorafenib (Stivarga)
This research study is a Phase I clinical trial, which tests the safety of an investigational
      drug and also tries to define the appropriate dose of the investigational drug to use for
      further studies. "Investigational" means that the drug is being studied.

      The FDA (the U.S. Food and Drug Administration) has not approved Regorafenib for this
      specific disease but it has been approved for other uses.

      In this research study, the investigators are looking for the best dose of Regorafenib to
      treat the participant's disease with. Researchers will also look at how effective the study
      drug is in treating the participant's disease and if any side effects occur.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Maximum tolerated dose of regorafenib in patients with advanced myeloid malignancies
time frame: 2 years
description: To determine the maximum tolerated dose regorafenib in patients with advanced myeloid malignancies.
measure: Pharmacodynamic effects of regorafenib on cell signaling pathways
time frame: 2 years
description: To assess pharmacodynamic effect of regorafenib on cell signaling pathways such as FLT-3, RAS and other specific mutations found in each patient's leukemia.
measure: Progression Free Survival
time frame: 2 years
measure: Overall Survival
time frame: 2 years
measure: To Measure Changes In Specific Markers Of Allele Burden
time frame: 2 years
description: Measure changes in allele burden with regorafenib treatment using next generation sequencing.
arm group label: Regorafenib
arm group type: Experimental
intervention type: Drug
intervention name: Regorafenib
description: Regorafenib will be administered on a 28 day cycle Treatment will be administered on outpatient basis at a pre-determine dosage.
arm group label: Regorafenib
other name: Stivarga
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Gabriela Hobbs, MD
role: Principal Investigator
affiliation: Massachusetts General Hospital
facility: 
country: United States
responsible party type: Principal Investigator
investigator affiliation: Massachusetts General Hospital
investigator full name: Gabriela Hobbs
investigator title: Gabriela Hobbs, MD
sharing ipd: No