<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/NCT04462471</url>
  </required_header>
  <id_info>
    <org_study_id>20-053</org_study_id>
    <nct_id>NCT04462471</nct_id>
  </id_info>
  <brief_title>Vemurafenib Plus Copanlisib in Radioiodine-Refractory (RAIR) Thyroid Cancers</brief_title>
  <official_title>A Phase Ib Trial of Vemurafenib Plus Copanlisib to Enhance Radioiodine Avidity in Radioiodine-Refractory Thyroid Cancers</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Memorial Sloan Kettering Cancer Center</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Memorial Sloan Kettering Cancer Center</source>
  <oversight_info>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      The purpose of this study is to develop a new drug treatment to reverse tumor resistance to&#xD;
      radioiodine in BRAF mutant tumors so that radioiodine can be given to shrink tumors. This&#xD;
      study is also being done to find out the highest doses of copanlisib and vemurafenib that,&#xD;
      when given in combination, do not cause serious side effects, and whether the study treatment&#xD;
      will make radioiodine therapy work better in patients with BRAF-mutant thyroid cancers.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">June 26, 2020</start_date>
  <completion_date type="Anticipated">December 2024</completion_date>
  <primary_completion_date type="Anticipated">December 2023</primary_completion_date>
  <phase>Phase 1</phase>
  <study_type>Interventional</study_type>
  <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 vemurafenib plus copanlisib</measure>
    <time_frame>6 months</time_frame>
    <description>The primary objective of this study is to determine the MTD of vemurafenib plus copanlisib inpatients with advanced BRAF mutant RAIR thyroid cancer. The MTD is defined as the highest dose at which no more than 1 of 6 patients treated at that dose experience a DLT.</description>
  </primary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">8</enrollment>
  <condition>Thyroid Carcinoma</condition>
  <condition>Thyroid Cancer</condition>
  <condition>Thyroid Cancer, Follicular</condition>
  <condition>Thyroid Cancer (Follicular Cell)</condition>
  <condition>Thyroid Cancer, Papillary</condition>
  <condition>BRAF V600E Mutation Positive</condition>
  <arm_group>
    <arm_group_label>Participants with thyroid cancer</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Eligible participants will have a diagnosis of BRAF mutant RAIR thyroid cancer</description>
  </arm_group>
  <intervention>
    <intervention_type>Diagnostic Test</intervention_type>
    <intervention_name>I-124 PET/CT lesion dosimetry</intervention_name>
    <description>I-124 PET/CT scans will be performed during this process to quantify baseline RAI avidity in index metastatic lesion(s)</description>
    <arm_group_label>Participants with thyroid cancer</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Vemurafenib</intervention_name>
    <description>Dose level 1 &amp; 2: 960 mg PO bid Dose level -1: 720 mg PO bid Dose level -2: 480 mg PO bid</description>
    <arm_group_label>Participants with thyroid cancer</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Copanlisib</intervention_name>
    <description>Dose level 2: 60 mg IV weekly Dose level 1, -1, -2: 45 mg IV weekly</description>
    <arm_group_label>Participants with thyroid cancer</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Histologically or cytologically confirmed thyroid carcinoma of follicular origin&#xD;
             (including papillary, follicular, and poorly differentiated subtypes and their&#xD;
             respective variants).&#xD;
&#xD;
          -  A tumor sample (primary, recurrent, or metastatic tumors) possessing a BRAF V600&#xD;
             mutation, as confirmed in a CLIA-certified laboratory or using an FDA-approved assay&#xD;
&#xD;
          -  Measurable disease by RECIST v1.1 (tumors in previously irradiated fields may be&#xD;
             considered measurable if there is evidence of tumor progression after radiation&#xD;
             treatment)&#xD;
&#xD;
          -  RAIR disease, as defined by any one of the following:&#xD;
&#xD;
               -  A metastatic lesion that is not RAI-avid on a diagnostic radioiodine scan&#xD;
&#xD;
               -  An RAI-avid lesion that remained stable in size or progressed despite RAI&#xD;
                  treatment before entry in this study (there are no size limitations for the index&#xD;
                  lesion used to satisfy this entry criterion)&#xD;
&#xD;
               -  The presence of at least 1 FDG-avid lesion&#xD;
&#xD;
          -  No receipt of treatment for thyroid cancer, defined as:&#xD;
&#xD;
               -  No I-131 therapy &lt; 6 months before initiation of the protocol (time of initiation&#xD;
                  of the protocol is defined as the first day of drug therapy with vemurafenib and&#xD;
                  copanlisib); diagnostic activities of I-131 (0-10m Ci) are allowed within 6months&#xD;
                  of initiating the protocol&#xD;
&#xD;
               -  No external beam radiation therapy &lt;4 weeks before initiation of the protocol&#xD;
&#xD;
               -  No chemotherapy or targeted therapy including TKIs &lt;4 weeks (or &lt;5 half lives of&#xD;
                  the drug) before the initiation of this protocol&#xD;
&#xD;
          -  Age of ≥ 18 years&#xD;
&#xD;
          -  ECOG performance status ≤ 2 or Karnofsky Performance Score (KPS) ≥ 70%&#xD;
&#xD;
          -  Tissue from the primary tumor or metastases available for correlative studies. Either&#xD;
             a paraffin block or at least 20 unstained slides are acceptable (30 unstained slides&#xD;
             is ideal); if &lt;20 unstained slides are available, and a paraffin block is not&#xD;
             available, the patient may be able to participate at the discretion of the&#xD;
             investigator&#xD;
&#xD;
          -  Able to swallow and retain an orally administered pill without any clinically&#xD;
             significant gastrointestinal abnormalities that may alter absorption, such as&#xD;
             malabsorption syndrome or major resection of the stomach or bowels&#xD;
&#xD;
          -  Agree to undergo 2 research biopsies of (a) malignant lesion(s). Tumor tissue obtained&#xD;
             before study consent or treatment can also be submitted in lieu of performance of the&#xD;
             first pretreatment biopsy if the Principal Investigator deems it to be of sufficient&#xD;
             quantity/quality/timeliness (tumor tissue obtained more than 3 years from time of&#xD;
             study consent would not be eligible). Patients may be exempt from biopsy if (1) the&#xD;
             investigator or person performing the biopsy judges that no tumor is accessible for&#xD;
             biopsy, (2) the investigator or person performing the biopsy feels that the biopsy&#xD;
             poses too great of a risk to the patient, or (3) the patient's platelet count is&#xD;
             &lt;100,000/mcL or the patient cannot be safely removed from anticoagulation therapy (if&#xD;
             the anticoagulation therapy needs to be temporarily held for the biopsy procedure). If&#xD;
             the investigator deems a second research biopsy to be high risk, the patient may be&#xD;
             exempt from the second biopsy.&#xD;
&#xD;
          -  Screening laboratory values meeting the following criteria:&#xD;
&#xD;
               -  WBC ≥ 2000/µL&#xD;
&#xD;
               -  Neutrophils ≥ 1500/µL&#xD;
&#xD;
               -  Platelets ≥ 100 × 10^3/µL&#xD;
&#xD;
               -  Hemoglobin &gt;9.0 g/dL&#xD;
&#xD;
               -  Lipase ≤ 1.5 × ULN&#xD;
&#xD;
               -  AST/ALT ≤ 3 × ULN&#xD;
&#xD;
               -  Total bilirubin ≤ 1.5 x ULN (except subjects with Gilbert syndrome, who can have&#xD;
                  total bilirubin &lt;3.0 mg/dL)&#xD;
&#xD;
               -  Serum creatinine ≤ 1.5 x ULN or creatinine clearance (CrCl) ≥ 40 mL/min (if using&#xD;
                  the Cockcroft-Gault formula below):&#xD;
&#xD;
        Female CrCl = (140 - age in years) x weight in kg x 0.85 / 82 x serum creatinine in mg/dL&#xD;
&#xD;
        Male CrCl = (140 - age in years) x weight in kg x 1.00 / 72 x serum creatinine in mg/dL&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Untreated metastatic brain or leptomeningeal tumors (metastatic brain or&#xD;
             leptomeningeal tumors treated with radiation and/or surgery are allowed)&#xD;
&#xD;
          -  Prior malignancy if diagnosed and treated within 2 years of trial drug initiation&#xD;
             (with the exception of nonmelanoma skin cancers or Stage I cancers treated with&#xD;
             curative intent).Patients may be included if they have completed therapy for a prior&#xD;
             malignancy &gt;2 years before drug initiation and currently have no evidence of disease&#xD;
&#xD;
          -  Inability to follow a low-iodine diet or requiring a medication with a high content of&#xD;
             iodide (amiodarone)&#xD;
&#xD;
          -  Current congestive heart failure class &gt;2, as defined by the New York Heart&#xD;
             Association functional classification system&#xD;
&#xD;
          -  Myocardial infarction &lt; 6 months before the initiation of protocol&#xD;
&#xD;
          -  Unstable angina (angina symptoms at rest) or new-onset angina (begun within the last 3&#xD;
             months)&#xD;
&#xD;
          -  Uncontrolled hypertension (blood pressure &gt;150/90, despite optimal medical management)&#xD;
&#xD;
          -  Uncontrolled type I or II diabetes mellitus, as judged by the investigator, or Hgb A1C&#xD;
             of &gt;8.5&#xD;
&#xD;
          -  Arterial or venous thrombotic event or embolic event, such as a cerebrovascular&#xD;
             accident (including transient ischemic attacks), deep vein thrombosis, or pulmonary&#xD;
             embolism, within 3 months before the start of study medication&#xD;
&#xD;
          -  Nonhealing wound, ulcer, or bone fracture (tumor-related nonhealing wounds are&#xD;
             allowed)&#xD;
&#xD;
          -  Active, clinically serious infections CTCAE v5.0 grade &gt;2&#xD;
&#xD;
          -  History of concurrent condition of interstitial lung disease and/or severely impaired&#xD;
             lung function&#xD;
&#xD;
          -  Known history of HIV infection (all patients must be screened for HIV up to 28 days&#xD;
             before start of study)&#xD;
&#xD;
          -  Seizure disorder requiring medication&#xD;
&#xD;
          -  Therapy with a prohibited concomitant medication that cannot be temporarily held (at&#xD;
             least 2 weeks before initiation of vemurafenib plus copanlisib until 1 week after the&#xD;
             last dose) or replaced with a nonprohibited concomitant medication&#xD;
&#xD;
          -  Systemic corticosteroid therapy at a daily dose &gt;15 mg prednisone or equivalent&#xD;
             (previous corticosteroid therapy must be stopped or reduced to the allowed dose at&#xD;
             least 7 days before study registration)&#xD;
&#xD;
          -  Cytomegalovirus (CMV) PCR-positive at baseline&#xD;
&#xD;
          -  Evidence or history of a bleeding diathesis or any hemorrhage or bleeding CTCAE v5.0&#xD;
             grade ≥ 3 within 4 weeks before the start of study protocol&#xD;
&#xD;
          -  HBV or HCV infection. All patients must be screened for HBV and HCV up to 28 days&#xD;
             before the start of study medication using the routine hepatitis virus laboratorial&#xD;
             panel. Patients positive for HBsAg or HBcAb will be eligible if they are negative for&#xD;
             HBV-DNA (these patients should receive prophylactic HBV antiviral therapy). Patients&#xD;
             positive for anti-HCV antibody will be eligible if they are negative for HCV-RNA&#xD;
&#xD;
          -  Known hypersensitivity to any of the test drugs, test drug classes, or excipients in&#xD;
             the formulation&#xD;
&#xD;
          -  Substance abuse or medical, psychological, or social conditions that may interfere&#xD;
             with the patient's participation in the study or evaluation of the study results&#xD;
&#xD;
          -  Patients who are pregnant&#xD;
&#xD;
          -  Women of child-bearing potential, defined as all women physiologically capable of&#xD;
             becoming pregnant, unless they are using highly effective methods of contraception&#xD;
             during dosing and for 6 months after the last administration of study treatment.&#xD;
             Highly effective contraception methods include:&#xD;
&#xD;
               -  Total abstinence (when this is in line with the preferred and usual lifestyle of&#xD;
                  the patient). Periodic abstinence (e.g., calendar, ovulation, symptothermal,&#xD;
                  postovulation methods) and withdrawal are not acceptable methods of contraception&#xD;
&#xD;
               -  Female sterilization (have had surgical bilateral oophorectomy with or without&#xD;
                  hysterectomy), total hysterectomy, or tubal ligation at least 6 weeks before&#xD;
                  taking study treatment. In cases of oophorectomy alone, only when the&#xD;
                  reproductive status of the woman has been confirmed by follow-up hormone-level&#xD;
                  assessment (FSH level in the postmenopausal range) is this acceptable&#xD;
&#xD;
               -  Male sterilization (at least 6 months before screening). The vasectomized male&#xD;
                  partner should be the sole partner for that patient&#xD;
&#xD;
               -  Use of oral, injected, or implanted hormonal methods of contraception or&#xD;
                  placement of an intrauterine device or intrauterine system or other forms of&#xD;
                  hormonal contraception that have comparable efficacy (failure rate &lt;1%)-for&#xD;
                  example, hormone vaginal ring or transdermal hormone contraception. Note: In&#xD;
                  cases of use of oral contraception, women should have been stable, on the same&#xD;
                  pill for a minimum of 3 months before taking study treatment&#xD;
&#xD;
               -  Women are considered postmenopausal and not of child-bearing potential if they&#xD;
                  have had 12 months of natural (spontaneous) amenorrhea with an appropriate&#xD;
                  clinical profile (i.e., age appropriate, history of vasomotor symptoms) or have&#xD;
                  had surgical bilateral oophorectomy (with or without hysterectomy), total&#xD;
                  hysterectomy, or tubal ligation at least 6 weeks ago. In cases of oophorectomy&#xD;
                  alone, only when the reproductive status of the woman has been confirmed by&#xD;
                  follow-up hormone-level assessment is she considered not of child-bearing&#xD;
                  potential.&#xD;
&#xD;
          -  Sexually active men, unless they use a condom during intercourse while on treatment&#xD;
             and for 6 months after stopping treatment with study drugs (men should not father a&#xD;
             child in this period). A condom is required to be used by vasectomized men as well&#xD;
             during intercourse to prevent delivery of the drug via semen.&#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>Alan L Ho, MD, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Memorial Sloan Kettering Cancer Center</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Memorial Sloan Kettering Basking Ridge (Limited Protocol Activities)</name>
      <address>
        <city>Basking Ridge</city>
        <state>New Jersey</state>
        <zip>07920</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Memorial Sloan Kettering Monmouth (Limited protocol activities)</name>
      <address>
        <city>Middletown</city>
        <state>New Jersey</state>
        <zip>07748</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Memorial Sloan Kettering Bergen (Limited Protocol Activities)</name>
      <address>
        <city>Montvale</city>
        <state>New Jersey</state>
        <zip>07645</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Memorial Sloan Kettering Cancer Center @ Commack (Limited Protocol Activities)</name>
      <address>
        <city>Commack</city>
        <state>New York</state>
        <zip>11725</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Memorial Sloan Kettering Westchester (Limited protocol activities)</name>
      <address>
        <city>Harrison</city>
        <state>New York</state>
        <zip>10604</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Memorial Sloan-Kettering Cancer Center (All protocol activities)</name>
      <address>
        <city>New York</city>
        <state>New York</state>
        <zip>10065</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Memorial Sloan Kettering Nassau (Limited protocol activities)</name>
      <address>
        <city>Rockville Centre</city>
        <state>New York</state>
        <zip>11553</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <link>
    <url>http://www.mskcc.org</url>
    <description>Memorial Sloan Kettering Cancer Center</description>
  </link>
  <verification_date>June 2023</verification_date>
  <study_first_submitted>July 2, 2020</study_first_submitted>
  <study_first_submitted_qc>July 2, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">July 8, 2020</study_first_posted>
  <last_update_submitted>June 29, 2023</last_update_submitted>
  <last_update_submitted_qc>June 29, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">July 3, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>thyroid carcinoma of follicular origin</keyword>
  <keyword>thyroid cancer</keyword>
  <keyword>thyroid cancer, follicular</keyword>
  <keyword>thyroid cancer, papillary</keyword>
  <keyword>thyroid cancer, poorly differentiated</keyword>
  <keyword>BRAF V600</keyword>
  <keyword>RAIR disease</keyword>
  <keyword>Memorial Sloan Kettering Cancer Center</keyword>
  <keyword>20-053</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Thyroid Neoplasms</mesh_term>
    <mesh_term>Thyroid Cancer, Papillary</mesh_term>
    <mesh_term>Thyroid Diseases</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Vemurafenib</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Yes</sharing_ipd>
    <ipd_description>Memorial Sloan Kettering Cancer Center supports the international committee of medical journal editors (ICMJE) and the ethical obligation of responsible sharing of data from clinical trials. The protocol summary, a statistical summary, and informed consent form will be made available on clinicaltrials.gov when required as a condition of Federal awards, other agreements supporting the research and/or as otherwise required. Requests for deidentified individual participant data can be made beginning 12 months after publication and for up to 36 months post publication. Deidentified individual participant data reported in the manuscript will be shared under the terms of a Data Use Agreement and may only be used for approved proposals. Requests may be made to: crdatashare@mskcc.org.</ipd_description>
  </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/NCT04462471
org study id: 20-053
nct id: NCT04462471
lead sponsor: 
is fda regulated drug: Yes
is fda regulated device: No
The purpose of this study is to develop a new drug treatment to reverse tumor resistance to
      radioiodine in BRAF mutant tumors so that radioiodine can be given to shrink tumors. This
      study is also being done to find out the highest doses of copanlisib and vemurafenib that,
      when given in combination, do not cause serious side effects, and whether the study treatment
      will make radioiodine therapy work better in patients with BRAF-mutant thyroid cancers.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Maximum tolerated dose of vemurafenib plus copanlisib
time frame: 6 months
description: The primary objective of this study is to determine the MTD of vemurafenib plus copanlisib inpatients with advanced BRAF mutant RAIR thyroid cancer. The MTD is defined as the highest dose at which no more than 1 of 6 patients treated at that dose experience a DLT.
arm group label: Participants with thyroid cancer
arm group type: Experimental
description: Eligible participants will have a diagnosis of BRAF mutant RAIR thyroid cancer
intervention type: Diagnostic Test
intervention name: I-124 PET/CT lesion dosimetry
description: I-124 PET/CT scans will be performed during this process to quantify baseline RAI avidity in index metastatic lesion(s)
arm group label: Participants with thyroid cancer
intervention type: Drug
intervention name: Vemurafenib
description: Dose level 1 & 2: 960 mg PO bid Dose level -1: 720 mg PO bid Dose level -2: 480 mg PO bid
arm group label: Participants with thyroid cancer
intervention type: Drug
intervention name: Copanlisib
description: Dose level 2: 60 mg IV weekly Dose level 1, -1, -2: 45 mg IV weekly
arm group label: Participants with thyroid cancer
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Alan L Ho, MD, PhD
role: Principal Investigator
affiliation: Memorial Sloan Kettering Cancer Center
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
country: United States
url: http://www.mskcc.org
description: Memorial Sloan Kettering Cancer Center
responsible party type: Sponsor
mesh term: Thyroid Neoplasms
mesh term: Thyroid Cancer, Papillary
mesh term: Thyroid Diseases
mesh term: Vemurafenib
sharing ipd: Yes
ipd description: Memorial Sloan Kettering Cancer Center supports the international committee of medical journal editors (ICMJE) and the ethical obligation of responsible sharing of data from clinical trials. The protocol summary, a statistical summary, and informed consent form will be made available on clinicaltrials.gov when required as a condition of Federal awards, other agreements supporting the research and/or as otherwise required. Requests for deidentified individual participant data can be made beginning 12 months after publication and for up to 36 months post publication. Deidentified individual participant data reported in the manuscript will be shared under the terms of a Data Use Agreement and may only be used for approved proposals. Requests may be made to: crdatashare@mskcc.org.