<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/NCT04488003</url>
  </required_header>
  <id_info>
    <org_study_id>BVD-523-ABC</org_study_id>
    <nct_id>NCT04488003</nct_id>
  </id_info>
  <brief_title>Study of Ulixertinib for Patients With Advanced Malignancies Harboring MEK or Atypical BRAF Alterations</brief_title>
  <official_title>A Two-Part, Phase II, Multi-center Study of the ERK Inhibitor Ulixertinib (BVD-523) for Patients With Advanced Malignancies Harboring MEK or Atypical BRAF Alterations</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>BioMed Valley Discoveries, Inc</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>BioMed Valley Discoveries, Inc</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>
      This BVD-523-ABC study builds on the safety and clinical activity experience of previous&#xD;
      studies that have evaluated ulixertinib as a novel targeted cancer treatment in cohorts of&#xD;
      patients with specific genetic alterations and tumor histologies that result in aberrant MAPK&#xD;
      pathway signaling. Early clinical data have demonstrated anti-tumor activity with ulixertinib&#xD;
      treatment and have identified specific groups of patients for whom additional development is&#xD;
      warranted.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This multi-center, phase II study will be conducted in two parts and assess the clinical&#xD;
      benefit, safety, pharmacokinetics, and pharmacodynamics of ulixertinib (BVD-523) in patients&#xD;
      with advanced malignancies.&#xD;
&#xD;
      Part A (tumor histology agnostic) will be open label and enroll patients to one of six groups&#xD;
      based on their tumor alteration.&#xD;
&#xD;
        -  Group 1: Patients with tumors, other than colorectal cancer (CRC), having a BRAF&#xD;
           alteration that results in an amino acid change at positions G469, L485, or L597.&#xD;
&#xD;
        -  Group 2: Patients with tumors, other than CRC, having a defined Class 2 BRAF alteration&#xD;
           (see Appendix 2 of protocol).&#xD;
&#xD;
        -  Group 3: Patients with tumors, other than CRC, having an atypical BRAF alteration (non&#xD;
           V600) that is not specified in Group 1 or Group 2.&#xD;
&#xD;
        -  Group 4: Patients with CRC having any atypical BRAF alteration.&#xD;
&#xD;
        -  Group 5: Patients with tumors, other than CRC, harboring alterations in MEK1/2.&#xD;
&#xD;
        -  Group 6: Patients with CRC harboring alterations in MEK1/2.&#xD;
&#xD;
      Part B (tumor histology specific) will randomly enroll patients with one of up to three&#xD;
      specified tumor histologies to receive either ulixertinib or the physician's choice of&#xD;
      treatment in a 2:1 ratio. Tumors must harbor a specified MEK or atypical BRAF alteration. If&#xD;
      a patient progresses on physician's choice of treatment, crossover to the ulixertinib arm is&#xD;
      permitted.The specific histologies to be included in this part will be selected based on&#xD;
      available data and discussion with the clinical investigators, the medical monitor, and the&#xD;
      sponsor.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">November 3, 2020</start_date>
  <completion_date type="Anticipated">August 1, 2023</completion_date>
  <primary_completion_date type="Anticipated">August 1, 2023</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>Yes</has_expanded_access>
  <study_design_info>
    <allocation>Non-Randomized</allocation>
    <intervention_model>Sequential Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Part A: Overall Response Rate (ORR) according to RECIST 1.1</measure>
    <time_frame>Up to 30 months</time_frame>
    <description>ORR will be defined as the percentage of patients achieving a Best Overall Response (BOR) of confirmed Complete Response (CR) and/or Partial Response (PR). Patients will be evaluated at baseline &amp; at periodic follow-up visits through the time their participation in the study is complete.The best responses will occur at different time points for each patient.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Part B: Progression Free Survival (PFS) according to RECIST 1.1</measure>
    <time_frame>18 months</time_frame>
    <description>PFS will be defined as time from first day of study drug to disease progression as adjudicated by the independent review committee or death. Patients with no event will be censored at the last available tumor assessment.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Part A: Duration of Response (DOR) according to RECIST 1.1</measure>
    <time_frame>Up to 30 months</time_frame>
    <description>Time from first response to disease progression (DP) or death; assessed until DP, death, or initiation of subsequent anticancer therapy. Patients with no event will be censored at the last available tumor assessment.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Part A: Progression Free Survival (PFS) according to RECIST 1.1</measure>
    <time_frame>18 months</time_frame>
    <description>PFS will be defined as time from first day of study drug to disease progression or death. Patients with no event will be censored at the last available tumor assessment. This analysis will be based on investigator assessment.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Part A: Overall Survival (OS) according to RECIST 1.1</measure>
    <time_frame>18 months</time_frame>
    <description>OS will be defined as time from first day of study drug to death. Patients with no event will be censored at the last date the patient is known to be alive.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Part A: Cmax of BVD-523 at steady state</measure>
    <time_frame>Single time point drawn at Visit 4/approximately day 15 (or whenever the patient reaches steady state).</time_frame>
    <description>Single time point taken prior to taking study drug (trough) at steady state. Steady state is defined as patients who have received at least 5 days, or 10 consecutive doses, of study drug.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Part B: Overall Survival (OS) of ulixertinib compared to physician's choice of treatment</measure>
    <time_frame>18 months</time_frame>
    <description>OS will be defined time from first day of study drug to death. Patients with no event will be censored at the last date the patient is known to be alive.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Part B: Overall Response Rate (ORR) of ulixertinib compared to physician's choice of treatment, according to RECIST 1.1</measure>
    <time_frame>Up to 30 months</time_frame>
    <description>ORR will be defined as the percentage of patients achieving a Best Overall Response (BOR) of confirmed Complete Response (CR) and/or Partial Response (PR). Patients will be evaluated at baseline &amp; at periodic follow-up visits through the time their participation in the study is complete.The best responses will occur at different time points for each patient.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Part B: Duration of Response (DOR) of ulixertinib compared to physician's choice of treatment, according to RECIST 1.1</measure>
    <time_frame>Up to 30 months</time_frame>
    <description>Time from first response to disease progression or death; assessed until DP, death, or initiation of subsequent anticancer therapy. Patients with no event will be censored at the last available tumor assessment.</description>
  </secondary_outcome>
  <number_of_arms>3</number_of_arms>
  <enrollment type="Actual">101</enrollment>
  <condition>Advanced Solid Tumor</condition>
  <condition>BRAF Gene Mutation</condition>
  <condition>BRAF Gene Alteration</condition>
  <condition>MEK Mutation</condition>
  <condition>MEK Alteration</condition>
  <condition>MAP2K1 Gene Mutation</condition>
  <condition>MAP2K1 Gene Alteration</condition>
  <condition>MAP2K2 Gene Mutation</condition>
  <condition>MAP2K2 Gene Alteration</condition>
  <arm_group>
    <arm_group_label>Part A: Ulixertinib</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Oral, 600 mg, twice daily, for 28-days in each treatment cycle</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Part B: Ulixertinib</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Oral, 600 mg, twice daily, for 28-days in each treatment cycle</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Part B: Physician's choice of treatment</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Physician's choice will be restricted to two approved (not off-label) treatments for each tumor histology (agents targeting BRAF or MEK kinases and experimental agents are not permitted as physician choice). If a patient progresses on physician's choice of treatment, crossover to the ulixertinib arm is permitted.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Ulixertinib</intervention_name>
    <description>Oral, 600 mg, twice daily, for 28-days in each treatment cycle</description>
    <arm_group_label>Part A: Ulixertinib</arm_group_label>
    <arm_group_label>Part B: Ulixertinib</arm_group_label>
    <other_name>BVD-523, BVD523</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Physician's Choice</intervention_name>
    <description>Physician's choice will be restricted to two approved (not off-label) treatments for each tumor histology (agents targeting BRAF or MEK kinases and experimental agents are not permitted as physician choice)).</description>
    <arm_group_label>Part B: Physician's choice of treatment</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Patients with a locally advanced or metastatic malignancy, that has progressed&#xD;
             following systemic therapy for their disease, if available, or for which the patient&#xD;
             is not a candidate or refuses.&#xD;
&#xD;
          -  Tumors harboring a MEK or atypical BRAF alteration.&#xD;
&#xD;
          -  Provide signed and dated informed consent prior to initiation of any study-related&#xD;
             procedures that are not considered standard of care (SoC).&#xD;
&#xD;
          -  Male or female patients aged ≥18 years.&#xD;
&#xD;
          -  Patients must have measurable disease by RECIST version 1.1.&#xD;
&#xD;
          -  Eastern Cooperative Oncology Group (ECOG) performance status of 0 - 2.&#xD;
&#xD;
          -  Adequate renal function [creatinine ≤1.5 times ULN (upper limit of normal)] or a&#xD;
             glomerular filtration rate (GFR) of ≥50 mL/min (using Cockcroft-Gault).&#xD;
&#xD;
          -  Adequate hepatic function [total bilirubin ≤1.5 times ULN; AST (aspartate&#xD;
             transaminase) and ALT (alanine transaminase) ≤3 times ULN or ≤5 times ULN if the&#xD;
             elevation is due to liver involvement by tumor].&#xD;
&#xD;
          -  Adequate bone marrow function (hemoglobin ≥9.0 g/dL; platelets ≥100 x 109 cells/L;&#xD;
             absolute neutrophil count ≥1.5 x 109 cells/L).&#xD;
&#xD;
          -  Adequate cardiac function: Left ventricular ejection fraction (LVEF) of &gt;50% as&#xD;
             assessed by multi-gated acquisition (MUGA) or ultrasound/echocardiography (ECHO); and&#xD;
             a corrected QT interval (QTc) &lt;480ms by the Fridericia method (QTcF).&#xD;
&#xD;
          -  Contraception - women: Negative pregnancy test for females of child-bearing potential;&#xD;
             must be surgically sterile, postmenopausal (no menstrual cycle for at least 12&#xD;
             consecutive months), or compliant with a medically approved contraceptive regimen&#xD;
             during and for 3 months after the last administration of study drug. Abstinence is not&#xD;
             considered an adequate contraceptive regimen.&#xD;
&#xD;
          -  Contraception - men: Must be surgically sterile, or compliant with a medically&#xD;
             approved contraceptive regimen during and for 3 months after the last administration&#xD;
             of study drug.&#xD;
&#xD;
          -  Willing and able to participate in the trial and comply with all trial requirements.&#xD;
&#xD;
          -  Patients with a prior or concurrent malignancy whose natural history or treatment does&#xD;
             not have the potential to interfere with the safety or efficacy assessment of the&#xD;
             investigational agent may be included after consultation with the medical monitor.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Gastrointestinal (GI) condition that could impair absorption of study medication&#xD;
             (specific cases e.g., remote history of GI surgery, may be enrolled after discussion&#xD;
             with the medical monitor) or inability to ingest study medication.&#xD;
&#xD;
          -  Uncontrolled or severe intercurrent medical condition.&#xD;
&#xD;
          -  Known uncontrolled brain metastases. Stable brain metastases either treated or being&#xD;
             treated with a stable dose of steroids/anticonvulsants, with no dose change in the&#xD;
             previous 4 weeks, can be allowed.&#xD;
&#xD;
          -  Having received any cancer-directed therapy (chemotherapy, hormonal therapy, biologic&#xD;
             or immunotherapy, etc.) within 28 days or 5 half-lives (whichever is shorter) prior to&#xD;
             the first dose of study drug. Patients previously treated with radiotherapy must have&#xD;
             recovered from the acute toxicities associated with such treatment.&#xD;
&#xD;
          -  Major surgery within 4 weeks prior to first dose.&#xD;
&#xD;
          -  Any use of an investigational drug within 28 days or 5 half-lives (whichever is&#xD;
             shorter) prior to the first dose of study drug. A minimum of 10 days between&#xD;
             termination of the prior investigational drug and administration of study drug is&#xD;
             required. In addition, any drug-related toxicity except alopecia should have recovered&#xD;
             to Grade 1 or less.&#xD;
&#xD;
          -  Prior therapy with any ERK inhibitor (e.g. LY3214996, LTT462).&#xD;
&#xD;
          -  Groups 1-4: Prior therapy with any BRAF and/or MEK inhibitor (e.g. encorafenib,&#xD;
             dabrafenib, vemurafenib, binimetinib, trametinib, cobimetinib) is excluded. Prior BRAF&#xD;
             and/or MEK inhibitor therapy is permitted for Groups 5 and 6.&#xD;
&#xD;
          -  For Part B, agents targeting BRAF or MEK kinases and experimental agents are not&#xD;
             permitted as physician's choice&#xD;
&#xD;
          -  Pregnant or breast-feeding women.&#xD;
&#xD;
          -  Any evidence of serious active infections. Patients are allowed to enroll if they have&#xD;
             been fever-free for at least 48 hours and are on an active treatment that is not&#xD;
             prohibited in Appendix 1 of the protocol.&#xD;
&#xD;
          -  Any important medical illness or abnormal laboratory finding that would increase the&#xD;
             risk of participating in this study (based on the investigator's judgment).&#xD;
&#xD;
          -  A history or current evidence/risk of retinal vein occlusion (RVO) or central serous&#xD;
             retinopathy (CSR).&#xD;
&#xD;
          -  Concurrent therapy with any other investigational agent.&#xD;
&#xD;
          -  Concurrent therapy with drugs known to be strong inhibitors or inducers of CYP1A2,&#xD;
             CYP2D6, and CYP3A4.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <location>
    <facility>
      <name>Mayo Clinic</name>
      <address>
        <city>Phoenix</city>
        <state>Arizona</state>
        <zip>85054</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hoag Memorial Hospital Presbyterian</name>
      <address>
        <city>Newport Beach</city>
        <state>California</state>
        <zip>92663</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Christiana Care Health Services / Helen F. Graham Cancer Center</name>
      <address>
        <city>Newark</city>
        <state>Delaware</state>
        <zip>19713</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Johns Hopkins Sibley Memorial Hospital</name>
      <address>
        <city>Washington</city>
        <state>District of Columbia</state>
        <zip>20016</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Florida</name>
      <address>
        <city>Gainesville</city>
        <state>Florida</state>
        <zip>32610</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Mayo Clinic</name>
      <address>
        <city>Jacksonville</city>
        <state>Florida</state>
        <zip>32224</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <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>
    <facility>
      <name>Mayo Clinic</name>
      <address>
        <city>Rochester</city>
        <state>Minnesota</state>
        <zip>55905</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Metro-Minnesota Community Oncology Research Consortium (MMCORC)</name>
      <address>
        <city>Saint Louis Park</city>
        <state>Minnesota</state>
        <zip>55416</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Washington University School of Medicine - Siteman Cancer Center</name>
      <address>
        <city>Saint Louis</city>
        <state>Missouri</state>
        <zip>63110</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Montefiore Medical Center</name>
      <address>
        <city>Bronx</city>
        <state>New York</state>
        <zip>10461</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Columbia University Irving Medical Center</name>
      <address>
        <city>New York</city>
        <state>New York</state>
        <zip>10032</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Duke University Medical Center / Duke Cancer Institute</name>
      <address>
        <city>Durham</city>
        <state>North Carolina</state>
        <zip>27710</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Kettering Cancer Center</name>
      <address>
        <city>Kettering</city>
        <state>Ohio</state>
        <zip>45429</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>UPMC Hillman Cancer Center</name>
      <address>
        <city>Pittsburgh</city>
        <state>Pennsylvania</state>
        <zip>15213</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Avera Cancer Institute</name>
      <address>
        <city>Sioux Falls</city>
        <state>South Dakota</state>
        <zip>57105</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Tennessee Oncology, PLLC - Sarah Cannon (SCRI)</name>
      <address>
        <city>Nashville</city>
        <state>Tennessee</state>
        <zip>37203</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>MD Anderson Cancer Center</name>
      <address>
        <city>Houston</city>
        <state>Texas</state>
        <zip>77030</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Virginia Cancer Specialists, PC</name>
      <address>
        <city>Fairfax</city>
        <state>Virginia</state>
        <zip>22031</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Washington/Seattle Cancer Care Alliance</name>
      <address>
        <city>Seattle</city>
        <state>Washington</state>
        <zip>98109</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Wisconsin Clinical Science Center</name>
      <address>
        <city>Madison</city>
        <state>Wisconsin</state>
        <zip>53792</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Marshfield Medical Center</name>
      <address>
        <city>Marshfield</city>
        <state>Wisconsin</state>
        <zip>54449</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <link>
    <url>https://biomed-valley.com/</url>
    <description>BioMed Valley Discoveries</description>
  </link>
  <reference>
    <citation>Germann UA, Furey BF, Markland W, Hoover RR, Aronov AM, Roix JJ, Hale M, Boucher DM, Sorrell DA, Martinez-Botella G, Fitzgibbon M, Shapiro P, Wick MJ, Samadani R, Meshaw K, Groover A, DeCrescenzo G, Namchuk M, Emery CM, Saha S, Welsch DJ. Targeting the MAPK Signaling Pathway in Cancer: Promising Preclinical Activity with the Novel Selective ERK1/2 Inhibitor BVD-523 (Ulixertinib). Mol Cancer Ther. 2017 Nov;16(11):2351-2363. doi: 10.1158/1535-7163.MCT-17-0456. Epub 2017 Sep 22.</citation>
    <PMID>28939558</PMID>
  </reference>
  <reference>
    <citation>Sullivan RJ, Infante JR, Janku F, Wong DJL, Sosman JA, Keedy V, Patel MR, Shapiro GI, Mier JW, Tolcher AW, Wang-Gillam A, Sznol M, Flaherty K, Buchbinder E, Carvajal RD, Varghese AM, Lacouture ME, Ribas A, Patel SP, DeCrescenzo GA, Emery CM, Groover AL, Saha S, Varterasian M, Welsch DJ, Hyman DM, Li BT. First-in-Class ERK1/2 Inhibitor Ulixertinib (BVD-523) in Patients with MAPK Mutant Advanced Solid Tumors: Results of a Phase I Dose-Escalation and Expansion Study. Cancer Discov. 2018 Feb;8(2):184-195. doi: 10.1158/2159-8290.CD-17-1119. Epub 2017 Dec 15.</citation>
    <PMID>29247021</PMID>
  </reference>
  <verification_date>December 2022</verification_date>
  <study_first_submitted>July 17, 2020</study_first_submitted>
  <study_first_submitted_qc>July 24, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">July 27, 2020</study_first_posted>
  <last_update_submitted>December 20, 2022</last_update_submitted>
  <last_update_submitted_qc>December 20, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">December 21, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>atypical BRAF, non-V600</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Neoplasms</mesh_term>
  </condition_browse>
  <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/NCT04488003
org study id: BVD-523-ABC
nct id: NCT04488003
lead sponsor: 
is fda regulated drug: Yes
is fda regulated device: No
This BVD-523-ABC study builds on the safety and clinical activity experience of previous
      studies that have evaluated ulixertinib as a novel targeted cancer treatment in cohorts of
      patients with specific genetic alterations and tumor histologies that result in aberrant MAPK
      pathway signaling. Early clinical data have demonstrated anti-tumor activity with ulixertinib
      treatment and have identified specific groups of patients for whom additional development is
      warranted.
This multi-center, phase II study will be conducted in two parts and assess the clinical
      benefit, safety, pharmacokinetics, and pharmacodynamics of ulixertinib (BVD-523) in patients
      with advanced malignancies.

      Part A (tumor histology agnostic) will be open label and enroll patients to one of six groups
      based on their tumor alteration.

        -  Group 1: Patients with tumors, other than colorectal cancer (CRC), having a BRAF
           alteration that results in an amino acid change at positions G469, L485, or L597.

        -  Group 2: Patients with tumors, other than CRC, having a defined Class 2 BRAF alteration
           (see Appendix 2 of protocol).

        -  Group 3: Patients with tumors, other than CRC, having an atypical BRAF alteration (non
           V600) that is not specified in Group 1 or Group 2.

        -  Group 4: Patients with CRC having any atypical BRAF alteration.

        -  Group 5: Patients with tumors, other than CRC, harboring alterations in MEK1/2.

        -  Group 6: Patients with CRC harboring alterations in MEK1/2.

      Part B (tumor histology specific) will randomly enroll patients with one of up to three
      specified tumor histologies to receive either ulixertinib or the physician's choice of
      treatment in a 2:1 ratio. Tumors must harbor a specified MEK or atypical BRAF alteration. If
      a patient progresses on physician's choice of treatment, crossover to the ulixertinib arm is
      permitted.The specific histologies to be included in this part will be selected based on
      available data and discussion with the clinical investigators, the medical monitor, and the
      sponsor.
allocation: Non-Randomized
intervention model: Sequential Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Part A: Overall Response Rate (ORR) according to RECIST 1.1
time frame: Up to 30 months
description: ORR will be defined as the percentage of patients achieving a Best Overall Response (BOR) of confirmed Complete Response (CR) and/or Partial Response (PR). Patients will be evaluated at baseline & at periodic follow-up visits through the time their participation in the study is complete.The best responses will occur at different time points for each patient.
measure: Part B: Progression Free Survival (PFS) according to RECIST 1.1
time frame: 18 months
description: PFS will be defined as time from first day of study drug to disease progression as adjudicated by the independent review committee or death. Patients with no event will be censored at the last available tumor assessment.
measure: Part A: Duration of Response (DOR) according to RECIST 1.1
time frame: Up to 30 months
description: Time from first response to disease progression (DP) or death; assessed until DP, death, or initiation of subsequent anticancer therapy. Patients with no event will be censored at the last available tumor assessment.
measure: Part A: Progression Free Survival (PFS) according to RECIST 1.1
time frame: 18 months
description: PFS will be defined as time from first day of study drug to disease progression or death. Patients with no event will be censored at the last available tumor assessment. This analysis will be based on investigator assessment.
measure: Part A: Overall Survival (OS) according to RECIST 1.1
time frame: 18 months
description: OS will be defined as time from first day of study drug to death. Patients with no event will be censored at the last date the patient is known to be alive.
measure: Part A: Cmax of BVD-523 at steady state
time frame: Single time point drawn at Visit 4/approximately day 15 (or whenever the patient reaches steady state).
description: Single time point taken prior to taking study drug (trough) at steady state. Steady state is defined as patients who have received at least 5 days, or 10 consecutive doses, of study drug.
measure: Part B: Overall Survival (OS) of ulixertinib compared to physician's choice of treatment
time frame: 18 months
description: OS will be defined time from first day of study drug to death. Patients with no event will be censored at the last date the patient is known to be alive.
measure: Part B: Overall Response Rate (ORR) of ulixertinib compared to physician's choice of treatment, according to RECIST 1.1
time frame: Up to 30 months
description: ORR will be defined as the percentage of patients achieving a Best Overall Response (BOR) of confirmed Complete Response (CR) and/or Partial Response (PR). Patients will be evaluated at baseline & at periodic follow-up visits through the time their participation in the study is complete.The best responses will occur at different time points for each patient.
measure: Part B: Duration of Response (DOR) of ulixertinib compared to physician's choice of treatment, according to RECIST 1.1
time frame: Up to 30 months
description: Time from first response to disease progression or death; assessed until DP, death, or initiation of subsequent anticancer therapy. Patients with no event will be censored at the last available tumor assessment.
arm group label: Part A: Ulixertinib
arm group type: Experimental
description: Oral, 600 mg, twice daily, for 28-days in each treatment cycle
arm group label: Part B: Ulixertinib
arm group type: Experimental
description: Oral, 600 mg, twice daily, for 28-days in each treatment cycle
arm group label: Part B: Physician's choice of treatment
arm group type: Experimental
description: Physician's choice will be restricted to two approved (not off-label) treatments for each tumor histology (agents targeting BRAF or MEK kinases and experimental agents are not permitted as physician choice). If a patient progresses on physician's choice of treatment, crossover to the ulixertinib arm is permitted.
intervention type: Drug
intervention name: Ulixertinib
description: Oral, 600 mg, twice daily, for 28-days in each treatment cycle
arm group label: Part A: Ulixertinib
arm group label: Part B: Ulixertinib
other name: BVD-523, BVD523
intervention type: Drug
intervention name: Physician's Choice
description: Physician's choice will be restricted to two approved (not off-label) treatments for each tumor histology (agents targeting BRAF or MEK kinases and experimental agents are not permitted as physician choice)).
arm group label: Part B: Physician's choice of treatment
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
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country: United States
url: https://biomed-valley.com/
description: BioMed Valley Discoveries
citation: Germann UA, Furey BF, Markland W, Hoover RR, Aronov AM, Roix JJ, Hale M, Boucher DM, Sorrell DA, Martinez-Botella G, Fitzgibbon M, Shapiro P, Wick MJ, Samadani R, Meshaw K, Groover A, DeCrescenzo G, Namchuk M, Emery CM, Saha S, Welsch DJ. Targeting the MAPK Signaling Pathway in Cancer: Promising Preclinical Activity with the Novel Selective ERK1/2 Inhibitor BVD-523 (Ulixertinib). Mol Cancer Ther. 2017 Nov;16(11):2351-2363. doi: 10.1158/1535-7163.MCT-17-0456. Epub 2017 Sep 22.
PMID: 28939558
citation: Sullivan RJ, Infante JR, Janku F, Wong DJL, Sosman JA, Keedy V, Patel MR, Shapiro GI, Mier JW, Tolcher AW, Wang-Gillam A, Sznol M, Flaherty K, Buchbinder E, Carvajal RD, Varghese AM, Lacouture ME, Ribas A, Patel SP, DeCrescenzo GA, Emery CM, Groover AL, Saha S, Varterasian M, Welsch DJ, Hyman DM, Li BT. First-in-Class ERK1/2 Inhibitor Ulixertinib (BVD-523) in Patients with MAPK Mutant Advanced Solid Tumors: Results of a Phase I Dose-Escalation and Expansion Study. Cancer Discov. 2018 Feb;8(2):184-195. doi: 10.1158/2159-8290.CD-17-1119. Epub 2017 Dec 15.
PMID: 29247021
responsible party type: Sponsor
mesh term: Neoplasms
sharing ipd: No