<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/NCT04494958</url>
  </required_header>
  <id_info>
    <org_study_id>PALBOBIN</org_study_id>
    <nct_id>NCT04494958</nct_id>
  </id_info>
  <brief_title>Palbociclib and Binimetinib in Advanced Triple Negative Breast Cancer</brief_title>
  <acronym>PALBOBIN</acronym>
  <official_title>Phase IB Clinical Trial of Palbociclib and Binimetinib in Advanced Triple Negative Breast Cancer With Hyperactivation of ERK and/or CDK4/6</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Fundacion Oncosur</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Pfizer</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
    <collaborator>
      <agency>Apices Soluciones S.L.</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
    <collaborator>
      <agency>Pierre Fabre Ibérica, S.A.</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>Fundacion Oncosur</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      This study is an interventional, prospective, multicentric, single-arm, open label, phase Ib&#xD;
      clinical trial. This study will be carried out in patients diagnosed of metastatic or locally&#xD;
      advanced unresectable triple negative breast cancer with activation of ERK and/or CDK4/6 in&#xD;
      which the following will be assesed: the overall response rate, the aggregation of antitumor&#xD;
      effect depending on the different kinome profiles and the safety profile to the combination&#xD;
      of palbociclib and binimetinib.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">November 18, 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 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>
    <intervention_model_description>Prospective, multicentric, single-arm, open label, phase IB clinical trial.</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Progression Free survival</measure>
    <time_frame>3 months</time_frame>
    <description>Time from the date of first dose of study treatment to the date of progression or death (from any cause).</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Overall Response Rate</measure>
    <time_frame>1 year</time_frame>
    <description>Percentage of patients that achieve complete response or partial response according to RECIST 1.1 criteria</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Incidence of treatment-Emergent Adverse Event</measure>
    <time_frame>1 year</time_frame>
    <description>Percentage of patients with each adverse event</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">24</enrollment>
  <condition>Triple Negative Breast Cancer</condition>
  <arm_group>
    <arm_group_label>Palbociclib + Binimetinib</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Combination, Palbociclib + Binimetinib</intervention_name>
    <description>Patients will then start treatment with continuous oral binimetinib 45 mg/BID and palbociclib 100 mg daily, 21 days on / 7 days off, until disease progression. Study treatment will continue until disease progression.&#xD;
If treatment tolerance is good, after a full cycle patients will be allowed to escalate palbociclib to 125 mg, according to the study investigators' decision. Alternatively, patients with non tolerable grade 2 events will resume at 30 mg/BID of binimetinib upon recovery, maintaining palbociclib at 100 mg 21-on/7-off. Depending on the side-effects, in case of clear relationship with palbociclib is established, palbociclib -instead of binimetinib - will be reduced to 75 mg daily.</description>
    <arm_group_label>Palbociclib + Binimetinib</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Women &gt;18 years-old.&#xD;
&#xD;
          2. Diagnostic of metastatic or locally advanced non-resectable TNBC.&#xD;
&#xD;
          3. Patient that have received at least one and up to two previous lines of therapy for&#xD;
             metastatic TNBC and failed to last treatment. Previous treatments can be of any nature&#xD;
             (chemotherapy, immunotherapy, antiangiogenics, experimental therapy, etc.).&#xD;
&#xD;
             Women with known BRCA1/BRCA2 germline mutations must have received a platinum based&#xD;
             treatment or treatment with a PARP inhibitor.&#xD;
&#xD;
          4. Patient must have experienced disease progression to the previous treatment line&#xD;
             according to the RECIST 1.1 or iRECIST criteria.&#xD;
&#xD;
          5. Availability of tumor tissue for ERK and CDK4/6 testing is mandatory prior to study&#xD;
             inclusion, preferably obtained after last treatment or the most recent sample as&#xD;
             possible (from metastatic site or first diagnosis according to sample availability).&#xD;
             If the patient has not a tumor sample available prior to study inclusion, the patient&#xD;
             will not be allowed to participate in the study.&#xD;
&#xD;
          6. Ability to understand and signing of the written patient information/informed consent&#xD;
             form (PIS/ICF) for ERK and CDK4/6 testing. ERK and CDK4/6 testing will be performed&#xD;
             centrally at CNIO.&#xD;
&#xD;
          7. Ability to understand and signing the written PIS/ICF for study treatment eligibility.&#xD;
             Signed informed consent form must be available before any studyspecific procedure for&#xD;
             the respective study parts may begin.&#xD;
&#xD;
          8. Positivity for ERK and/or CDK4/6, defined as showing an H-score above the top-quartile&#xD;
             according to published definitions [1].&#xD;
&#xD;
          9. ECOG performance status of 0-1.&#xD;
&#xD;
         10. Evaluable disease according to RECIST 1.1 criteria.&#xD;
&#xD;
         11. Life expectancy &gt;24 weeks.&#xD;
&#xD;
         12. Adequate bone marrow, liver and renal function as assessed by laboratory requirements&#xD;
             conducted within 7 days before first study drug administration:&#xD;
&#xD;
               1. Absolute neutrophil count (ANC) ≥ 1.500/mm3 (without granulocyte&#xD;
                  colony-stimulating factor support within 2 weeks before the first study drug&#xD;
                  administration)&#xD;
&#xD;
               2. Hemoglobin ≥ 9 g/dL (without transfusion or erythropoietin within 4 weeks before&#xD;
                  the first study drug administration)&#xD;
&#xD;
               3. Platelet count ≥ 100.000/mm3 (without transfusion within 2 weeks before the first&#xD;
                  study drug administration)&#xD;
&#xD;
               4. Total bilirubin ≤ 2 X the upper limit of normal (ULN).&#xD;
&#xD;
               5. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 X ULN&#xD;
                  (≤ 5 times ULN for patients with liver metastases)&#xD;
&#xD;
               6. Glomerular filtration rate (GFR) &gt; 50 mL/min/1.73 m2 according to the&#xD;
                  modification of diet in renal disease (MDRD) abbreviated formula.&#xD;
&#xD;
         13. Patients must have recovered to ≤ Grade 1 in terms of toxicity from prior treatments&#xD;
             (excluding neuropathy which can be ≤ Grade 2, and alopecia).&#xD;
&#xD;
         14. Patients must be able to take oral medications.&#xD;
&#xD;
         15. Patients must have adequate cardiac function, defined as:&#xD;
&#xD;
               1. Left ventricular ejection fraction (LVEF) &gt; 50% as determined by echocardiogram&#xD;
                  or multigated acquisition scan (MUGA).&#xD;
&#xD;
               2. QTc &lt; 480 msec.&#xD;
&#xD;
         16. Negative serum pregnancy test in women of childbearing potential (performed within 7&#xD;
             days before the first treatment). Negative results must be available before the first&#xD;
             study drug administration. Pregnancy test will not be performed in postmenopausal&#xD;
             women.&#xD;
&#xD;
         17. Women of reproductive potential must agree to use adequate contraception when sexually&#xD;
             active. This applies for the time period since the signature of the informed consent&#xD;
             form and until at least 1 month after the last study drug administration. The&#xD;
             definition of adequate contraception will be based on the judgment of the investigator&#xD;
             and on local requirements. Acceptable methods of contraception include, but are not&#xD;
             limited to, (i) condoms (male or female) with or without a spermicidal agent; (ii)&#xD;
             diaphragm or cervical cap with spermicide; (iii) intra-uterine device; (iv)&#xD;
             hormone-based contraception.Zoledronic acid or denosumab started prior to trial&#xD;
             registration is allowed, but in case they are required after initiation of trial&#xD;
             procedures, adequate justification is required.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Participants who have had chemotherapy, radiotherapy, or major surgery within 2 weeks&#xD;
             (6 weeks for nitrosoureas or mitomycin C) prior to entering the study.&#xD;
&#xD;
          2. Patients that received during the metastatic disease setting any of the study drugs,&#xD;
             palbociclib or binimetinib.&#xD;
&#xD;
          3. Participants receiving any other study agents concurrently with the study drugs.&#xD;
             Zoledronic acid or denosumab for bone metastases, started at least 15 days prior to&#xD;
             enrollment are allowed.&#xD;
&#xD;
          4. Participants with symptomatic brain metastases that require chronic steroids. Patients&#xD;
             with a history of brain metastases are permitted to enroll as long as they have been&#xD;
             treated, are off of steroids, and have been stable for a minimum of one month on&#xD;
             imaging.&#xD;
&#xD;
          5. Irradiation of single lesions in the last 28 days prior to trial recruitment, if it is&#xD;
             the only location of the disease and it has not progressed. Patients with radiated&#xD;
             single lesions that has progressed are allowed.&#xD;
&#xD;
          6. Concurrent use of strong CYP3A4 inhibitors/inducers is prohibited due to drug-drug&#xD;
             interactions with palbociclib. Moderate CYP3A4 inhibitors/inducers should be used with&#xD;
             caution.&#xD;
&#xD;
          7. Uncontrolled intercurrent illness including, but not limited to:&#xD;
&#xD;
               1. ongoing or active infection requiring systemic treatment&#xD;
&#xD;
               2. symptomatic congestive heart failure&#xD;
&#xD;
               3. cardiac arrhythmia&#xD;
&#xD;
               4. psychiatric illness/social situations that would limit compliance with study&#xD;
                  requirements&#xD;
&#xD;
               5. hypertension, defined as systolic blood pressure &gt; 160 mmHg despite medical&#xD;
                  management&#xD;
&#xD;
               6. myocardial infarction, unstable angina, coronary artery bypass grafting, coronary&#xD;
                  angioplasty, or stenting &lt; 6 months prior to screening&#xD;
&#xD;
          8. History of QT syndrome, Brugada syndrome, known history of QTc prolongation, or&#xD;
             Torsades de Pointes.&#xD;
&#xD;
          9. History of Gilbert's syndrome.&#xD;
&#xD;
         10. History of neuromuscular disorders that are associated with elevated CK (e.g.&#xD;
             inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis, spinal&#xD;
             muscular atrophy).&#xD;
&#xD;
         11. Previous or concurrent cancer except:&#xD;
&#xD;
               1. cervical carcinoma in situ&#xD;
&#xD;
               2. treated basal-cell carcinoma or squamous cell skin cancer c. any other cancer&#xD;
                  curatively treated &gt; 3 years before the first study drug administration&#xD;
&#xD;
         12. Malabsorption syndrome or uncontrolled nausea, vomiting, or diarrhea that may&#xD;
             interfere with the absorption of oral study medication in the opinion of the&#xD;
             investigator.&#xD;
&#xD;
         13. Pregnant women or breast-feeding.&#xD;
&#xD;
         14. Known HIV-positive individuals on combination antiretroviral therapy.&#xD;
&#xD;
         15. Active hepatitis B virus (HBV; chronic or acute; defined as having a known positive&#xD;
             hepatitis B surface antigen [HBsAg] test at the time of screening) or hepatitis C&#xD;
             infection requiring treatment.&#xD;
&#xD;
               1. Patients with past HBV infection or resolved HBV infection (defined as the&#xD;
                  presence of hepatitis B core antibody [HBcAb] and absence of HBsAg) are eligible&#xD;
                  if HBV DNA is negative.&#xD;
&#xD;
               2. Patients positive for hepatitis C virus (HCV) antibody are eligible only if&#xD;
                  polymerase chain reaction is negative for HCV RNA.&#xD;
&#xD;
         16. Any condition that in the opinion of the investigator would interfere with evaluation&#xD;
             of study treatment or interpretation of patient safety or study results, or inability&#xD;
             to comply with the study and follow-up procedures.&#xD;
&#xD;
         17. Participation in another clinical study with investigational medicinal products within&#xD;
             4 weeks before the first study drug administration.&#xD;
&#xD;
         18. Clinically active infections within 2 weeks before the first study drug&#xD;
             administration.&#xD;
&#xD;
         19. Treatment with therapeutic oral or i.v. antibiotics within 2 weeks before the first&#xD;
             study drug administration. Patients receiving prophylactic antibiotics (e.g. for&#xD;
             prevention of a urinary tract infection or to prevent chronic obstructive pulmonary&#xD;
             disease exacerbation) are eligible.&#xD;
&#xD;
         20. Known hypersensitivity to any of the study drugs, study drug classes, or excipients in&#xD;
             the formulation.&#xD;
&#xD;
         21. Current diagnosis of any retinal disorders including retinal detachment, retinal&#xD;
             pigment epithelial detachment (RPED), serous retinopathy or retinal vein occlusion or&#xD;
             risk factors for RVO (e.g., uncontrolled glaucoma or history of hyperviscosity or&#xD;
             hypercoagulability syndrome).&#xD;
&#xD;
         22. Peripheral sensory neuropathy of CTCAE v.5.0 Grade 2 or higher&#xD;
&#xD;
         23. Major surgery, open biopsy or significant traumatic injury within 4 weeks before the&#xD;
             first study drug administration (central line surgery is not considered major&#xD;
             surgery).&#xD;
&#xD;
         24. Renal failure requiring peritoneal dialysis or hemodialysis.&#xD;
&#xD;
         25. Substance abuse, medical, psychological or social conditions that may interfere with&#xD;
             the patient's participation in the study or evaluation of the study results.&#xD;
      </textblock>
    </criteria>
    <gender>Female</gender>
    <gender_based>Yes</gender_based>
    <gender_description>In this Case, gender is a eligibility criteria because it is a specific cancer in women.</gender_description>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Miguel Ángel Quintela-Fandino, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Centro Nacional de Investigaciones Oncológicas</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Hospital Universitari Arnau de Vilanova de Lleida</name>
      <address>
        <city>Lleida</city>
        <zip>25198</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospìtal Universitario de la Princesa</name>
      <address>
        <city>Madrid</city>
        <zip>28006</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital Ramon y Cajal</name>
      <address>
        <city>Madrid</city>
        <zip>28034</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital Clínico San Carlos</name>
      <address>
        <city>Madrid</city>
        <zip>28040</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital Universitario 12 de Octubre</name>
      <address>
        <city>Madrid</city>
        <zip>28041</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital QuirónSalud Madrid</name>
      <address>
        <city>Madrid</city>
        <zip>28223</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital Universitario de Fuenlabrada</name>
      <address>
        <city>Madrid</city>
        <zip>28942</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital Clínico Universitario de Valencia</name>
      <address>
        <city>Valencia</city>
        <zip>46010</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Spain</country>
  </location_countries>
  <verification_date>March 2023</verification_date>
  <study_first_submitted>July 28, 2020</study_first_submitted>
  <study_first_submitted_qc>July 28, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">July 31, 2020</study_first_posted>
  <last_update_submitted>March 1, 2023</last_update_submitted>
  <last_update_submitted_qc>March 1, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">March 2, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Breast Neoplasms</mesh_term>
    <mesh_term>Triple Negative Breast Neoplasms</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Palbociclib</mesh_term>
  </intervention_browse>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT04494958
org study id: PALBOBIN
nct id: NCT04494958
lead sponsor: 
collaborator: 
collaborator: 
collaborator: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
This study is an interventional, prospective, multicentric, single-arm, open label, phase Ib
      clinical trial. This study will be carried out in patients diagnosed of metastatic or locally
      advanced unresectable triple negative breast cancer with activation of ERK and/or CDK4/6 in
      which the following will be assesed: the overall response rate, the aggregation of antitumor
      effect depending on the different kinome profiles and the safety profile to the combination
      of palbociclib and binimetinib.
allocation: N/A
intervention model: Single Group Assignment
intervention model description: Prospective, multicentric, single-arm, open label, phase IB clinical trial.
primary purpose: Treatment
masking: None (Open Label)
measure: Progression Free survival
time frame: 3 months
description: Time from the date of first dose of study treatment to the date of progression or death (from any cause).
measure: Overall Response Rate
time frame: 1 year
description: Percentage of patients that achieve complete response or partial response according to RECIST 1.1 criteria
measure: Incidence of treatment-Emergent Adverse Event
time frame: 1 year
description: Percentage of patients with each adverse event
arm group label: Palbociclib + Binimetinib
arm group type: Experimental
intervention type: Drug
intervention name: Combination, Palbociclib + Binimetinib
description: Patients will then start treatment with continuous oral binimetinib 45 mg/BID and palbociclib 100 mg daily, 21 days on / 7 days off, until disease progression. Study treatment will continue until disease progression.
If treatment tolerance is good, after a full cycle patients will be allowed to escalate palbociclib to 125 mg, according to the study investigators' decision. Alternatively, patients with non tolerable grade 2 events will resume at 30 mg/BID of binimetinib upon recovery, maintaining palbociclib at 100 mg 21-on/7-off. Depending on the side-effects, in case of clear relationship with palbociclib is established, palbociclib -instead of binimetinib - will be reduced to 75 mg daily.
arm group label: Palbociclib + Binimetinib
criteria: 
gender: Female
gender based: Yes
gender description: In this Case, gender is a eligibility criteria because it is a specific cancer in women.
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Miguel Ángel Quintela-Fandino, MD
role: Principal Investigator
affiliation: Centro Nacional de Investigaciones Oncológicas
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
country: Spain
responsible party type: Sponsor
mesh term: Breast Neoplasms
mesh term: Triple Negative Breast Neoplasms
mesh term: Palbociclib