<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/NCT01703481</url>
  </required_header>
  <id_info>
    <org_study_id>CR100845</org_study_id>
    <secondary_id>42756493EDI1001</secondary_id>
    <secondary_id>2012-000697-34</secondary_id>
    <nct_id>NCT01703481</nct_id>
  </id_info>
  <brief_title>A Study to Evaluate the Safety, Pharmacokinetics, and Pharmacodynamics of JNJ-42756493 in Adult Participants With Advanced or Refractory Solid Tumors or Lymphoma</brief_title>
  <official_title>A Phase 1 Study to Evaluate the Safety, Pharmacokinetics, and Pharmacodynamics of JNJ-42756493, a Pan-Fibroblast Growth Factor Receptor (FGFR) Tyrosine Kinase Inhibitor, in Subjects With Advanced or Refractory Solid Tumors or Lymphoma</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Janssen Research &amp; Development, LLC</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Janssen Research &amp; Development, LLC</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      The purpose of this study is to evaluate the safety, pharmacokinetics (study of what the body&#xD;
      does to a drug), and pharmacodynamics (study of what a drug does to the body) of&#xD;
      JNJ-42756493, a pan-fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitor, in&#xD;
      adult participants with advanced or refractory solid tumors or lymphoma.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This is a first-in-human, non-randomized (individuals will not be assigned by chance to study&#xD;
      treatments), open-label (individuals will know the identity of study treatments), multicenter&#xD;
      (more than 1 hospital work on a study), Phase 1 study. The study consists of 4 parts. Part 1&#xD;
      is the dose-escalation phase, which will be guided by pharmacokinetics, pharmacodynamics and&#xD;
      safety. In part 1, safe and biologically active Phase 2 doses (recommended Phase 2 doses&#xD;
      [RP2D]) for JNJ-42756493 will be primarily assessed. Participants will be enrolled in&#xD;
      sequential cohorts (first cohort will receive the starting dose and subsequent cohorts will&#xD;
      receive increased doses of JNJ-42756493). Part 2 is the Dose Confirmation Phase, which&#xD;
      consists of a pre and post treatment tumor biopsy cohorts to confirm the RP2D based on the&#xD;
      pharmacodynamic effect of JNJ-42756493 on fibroblast growth factor receptor (FGFR) signaling&#xD;
      pathway in tumor. Part 3 is the first Dose Expansion Phase, which is designed to evaluate&#xD;
      inclusion biomarkers and preliminary clinical activity at the first RP2D. It consists of 4&#xD;
      expansion cohorts, 1 each for squamous cell lung cancer, small cell lung cancer, breast&#xD;
      cancer, other solid tumors (Cohorts A, B, C, and D). Part 4 is the second Dose Expansion&#xD;
      Phase, which is designed to evaluate inclusion biomarkers and preliminary clinical activity&#xD;
      at the second RP2D. Biomarker eligibility has also been refined based on emerging data. It&#xD;
      consists of 2 expansion cohorts, Cohort E for non-small cell lung cancer and Cohort F for&#xD;
      select solid tumors including breast, urothelial, GBM, ovarian, head &amp; neck, esophageal,&#xD;
      gastric, and cholangiocarcinoma (Cohorts E and F). Enrollment of some cohorts may be&#xD;
      discontinued due to lack of enrollment or for futility. The study is estimated to take&#xD;
      approximately 48 months to complete. Participants' safety will be monitored throughout the&#xD;
      study.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">June 15, 2012</start_date>
  <completion_date type="Actual">July 5, 2017</completion_date>
  <primary_completion_date type="Actual">July 5, 2017</primary_completion_date>
  <phase>Phase 1</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Non-Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Part 1: Maximum Tolerated Dose (MTD) of JNJ-42756493</measure>
    <time_frame>Up to Part 1 Day 84 (Cycle 4, Day 21)</time_frame>
    <description>The maximum tolerated dose as determined in Part 1 of the study will be used as the recommended dose for Part 2, 3 and Part 4.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Maximum Observed Plasma Concentration (Cmax) of JNJ-42756493</measure>
    <time_frame>Up to Part 4 Day 84 (Cycle 4, Day 21)</time_frame>
    <description>The Cmax is the maximum observed plasma concentration.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Minimum Observed Plasma Concentration (Cmin) of JNJ-42756493</measure>
    <time_frame>Up to Part 4 Day 84 (Cycle 4, Day 21)</time_frame>
    <description>The Cmin is the minimum observed plasma concentration.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Time to Reach Maximum Observed Plasma Concentration (Tmax) of JNJ-42756493</measure>
    <time_frame>Up to Part 4 Day 84 (Cycle 4, Day 21)</time_frame>
    <description>The Tmax is defined as actual sampling time to reach maximum observed analyte concentration.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau)</measure>
    <time_frame>Up to Part 4 Day 84 (Cycle 4, Day 21)</time_frame>
    <description>The AUCtau is the measure of the plasma drug concentration from time zero to end of dosing interval (24 hour). It is used to characterize drug absorption.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Elimination Half Life of JNJ-42756493</measure>
    <time_frame>Up to Part 4 Day 84 (Cycle 4, Day 21)</time_frame>
    <description>The elimination half-life (t1/2) is the time measured for the plasma concentration to decrease by 1 half to its original concentration. It is associated with the terminal slope of the semi logarithmic drug concentration-time curve, and is calculated as 0.693/lambda(z).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Apparent Volume of Distribution at Steady-State (Vss) of JNJ-42756493</measure>
    <time_frame>Up to Part 4 Day 84 (Cycle 4, Day 21)</time_frame>
    <description>Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired blood concentration of a drug. Vss is the apparent volume of distribution at steady-state, which is estimated by (D/AUC[0-infinity])*(AUMC[0-infinity])/AUC[0-infinity]) where D is the dose of study drug, AUMC(0-infinity) is the area under the first moment curve extrapolated to infinity and AUC(0-infinity) is the area under the plasma concentration-time curve from time zero to infinite time.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Total Clearance of JNJ-42756493</measure>
    <time_frame>Up to Part 4 Day 84 (Cycle 4, Day 21)</time_frame>
    <description>Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Total clearance of drug is calculated as dose divided by AUCtau at steady-state.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Accumulation Index (AI) of JNJ-42756493</measure>
    <time_frame>Up to Part 4Day 84 (Cycle 4, Day 21)</time_frame>
    <description>Accumulation index is calculated by Cmax on Day 1 of Cycle 2/Cmax on Day 1 of Cycle 1 and/or AUCtau on Day 1 of Cycle 2/AUCtau on Day 1 of Cycle 1, where tau is the length of the dosing interval (24 hour).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of Participants With Objective Tumor Response</measure>
    <time_frame>Up to Part 4 Day 84 (Cycle 4, Day 21)</time_frame>
    <description>Objective response based on assessment of confirmed Complete response (CR) or partial response (PR) according to Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST). CR defined as disappearance of all target lesions. Any pathological lymph nodes must have reduction in short axis to less than 10 millimeter (mm). PR defined as at least 30 percent (%) decrease in sum of the diameters of the target lesions taking as reference the Baseline sum diameters. Confirmed responses are those that persist on repeat imaging study for at least 4 weeks after initial documentation of response.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Progression Free Survival (PFS)</measure>
    <time_frame>Up to Part 4 Day 84 (Cycle 4, Day 21)</time_frame>
    <description>Progression free survival is the time period from start of study medication till the disease progression or death, whichever occurs first.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Duration of Objective Response</measure>
    <time_frame>Up to Part 4 Day 84</time_frame>
    <description>Duration of objective response is time interval from the first date that criteria for complete response or partial response are met to the first date of progression of disease.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of Participants With an Adverse Event</measure>
    <time_frame>Up to Part 4 Day 84 (Cycle 4, Day 21)</time_frame>
    <description>An adverse event is any untoward medical event that occurs in a participant administered an investigational product, and it does not necessarily indicate only events with clear causal relationship with the relevant investigational product.</description>
  </secondary_outcome>
  <number_of_arms>8</number_of_arms>
  <enrollment type="Actual">188</enrollment>
  <condition>Tumor or Lymphoma</condition>
  <arm_group>
    <arm_group_label>Part 1</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Dose Escalation, Part 1: Participants will be enrolled in sequential cohorts to determine recommended Phase 2 doses (RP2D).</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Part 2</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Dose Confirmation, Part 2: Tumor biopsy cohorts will confirm RP2D.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Part 3, Cohort A</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>First dose expansion, Part 3: Participants with squamous non-small cell lung cancer.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Part 3, Cohort B</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>First dose expansion, Part 3: Participants with small cell lung cancer.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Part 3, Cohort C</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>First dose expansion, Part 3: Participants with breast cancer.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Part 3, Cohort D</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>First dose expansion, Part 3: Participants with solid tumors (consisting of one of the following: gastric, head and neck, lung adenocarcinoma, urothelial, glioblastoma multiforme [GBM], ovarian or prostate).</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Part 4, Cohort E</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Second dose expansion, Part 4: Participants with non-small cell lung cancer.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Part 4, Cohort F</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Second dose expansion, Part 4: Participants with solid tumors (consisting of one of the following: breast, urothelial, GBM).</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>JNJ-42756493: Part 1</intervention_name>
    <description>Participants will receive 0.5 mg (starting dose) capsule of JNJ-42756493 orally (by mouth) once daily on Day 1 of Cycle 1. Dose of the study medication will be escalated sequentially till the dose limiting toxicity is achieved to determine the recommended part 2 doses (RP2D).</description>
    <arm_group_label>Part 1</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>JNJ-42756493: Part 2</intervention_name>
    <description>Participants will receive JNJ-42756493 at the RP2D or below RP2D (maximum tolerated dose from Part 1) orally once daily on a 21 days cycle to confirm RP2D (in Part 2).</description>
    <arm_group_label>Part 2</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>JNJ-42756493: Part 3</intervention_name>
    <description>Participants will receive JNJ-42756493 at first RP2D of 9 mg daily in Part 3 orally once daily on a 21 days cycle.</description>
    <arm_group_label>Part 3, Cohort A</arm_group_label>
    <arm_group_label>Part 3, Cohort B</arm_group_label>
    <arm_group_label>Part 3, Cohort C</arm_group_label>
    <arm_group_label>Part 3, Cohort D</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>JNJ-42756493: Part 4</intervention_name>
    <description>Participants will receive JNJ-42756493 second RP2D of 10 mg intermittent dosing in Part 4 (with option to increase to 12 mg intermittent dosing based on phosphate level), orally on an intermittent schedule of daily for 7 days followed by 7 days off with a 28-day cycle.</description>
    <arm_group_label>Part 4, Cohort E</arm_group_label>
    <arm_group_label>Part 4, Cohort F</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Histologically or cytologically confirmed: solid malignancy or lymphoma that is&#xD;
             metastatic or unresectable, and for which standard curative treatment is no longer&#xD;
             effective (Part 1); any type of advanced or refractory solid malignancy (excluding&#xD;
             lymphoma) that is metastatic or unresectable and for which standard curative treatment&#xD;
             is no longer effective (Part 2); advanced or refractory squamous non-small cell lung&#xD;
             cancer (Cohort A, Part 3), advanced or refractory small cell lung cancer (Cohort B,&#xD;
             Part 3), advanced or refractory breast cancer (Cohort C, Part 3), any type of advanced&#xD;
             or refractory solid malignancy (excluding lymphoma) ([consisting of one of the&#xD;
             following: gastric, head and neck, lung adenocarcinoma, urothelial, glioblastoma&#xD;
             multiforme (GBM), ovarian or prostate]) (Cohort D, Part 3), advanced or refractory non&#xD;
             small cell lung cancer(Cohort E, Part 4), any type of advanced or refractory solid&#xD;
             malignancy (consisting of one of the following: Breast, Urothelial, GBM, Ovarian, Head&#xD;
             &amp; Neck, Esophageal, Gastric, and Cholangiocarcinoma) (Cohort F, Part 4)&#xD;
&#xD;
          -  Eastern Cooperative Oncology Group performance status score 0 or 1&#xD;
&#xD;
          -  Adequate bone marrow, liver, and renal function within the 14 days prior to Day 1 of&#xD;
             Cycle 1 of study drug up until pre-dose of Cycle 1&#xD;
&#xD;
          -  Magnesium within 0.85 to 1.25 * institutional normal limits, Sodium greater than or&#xD;
             equal to 130 milli equivalent per liter, Potassium within institutional normal limits&#xD;
             (within 14 days prior to Day 1 of Cycle 1 up until pre-dose of Cycle 1)&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Chemotherapy, targeted therapies, radiotherapy, immunotherapy, or treatment with an&#xD;
             investigational anticancer agent within 2 weeks or at least 5 half-lives of the drug,&#xD;
             whichever is longer and up to a maximum of 4 weeks (in the case of nitrosoureas and&#xD;
             mitomycin C within 6 weeks) before the first administration of study drug. Localized&#xD;
             radiation therapy and ongoing luteinizing hormone-releasing hormone (LHRH) agonists,&#xD;
             bisphosphonates and denosumab, are permitted&#xD;
&#xD;
          -  Participants with GBM can be enrolled 2 weeks after last treatment&#xD;
&#xD;
          -  History or current condition of uncontrolled cardiovascular disease&#xD;
&#xD;
          -  Participants with persistent phosphate greater than upper limit of normal during&#xD;
             screening (within 14 days prior to Day 1 of Cycle 1 up until pre-dose of Cycle 1) and&#xD;
             despite medical management of phosphate levels&#xD;
&#xD;
          -  Participants taking medications known to have a significant risk of causing QTc&#xD;
             prolongation and Torsades de Pointes&#xD;
&#xD;
          -  Left ventricular ejection fraction (LVEF) less than 50 percent as assessed by&#xD;
             echocardiography (or multi-gated acquisition) performed at screening&#xD;
&#xD;
          -  Any medical condition that requires intact wound healing capacity and is expected to&#xD;
             endanger participant safety if wound healing capacity would be severely reduced during&#xD;
             administration of the investigational agent&#xD;
&#xD;
          -  Participants not recovered from reversible toxicity of prior anticancer therapy&#xD;
             (except toxicities which are not clinically significant such as alopecia, skin&#xD;
             discoloration, or Grade 1 neuropathy)&#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>Janssen Research &amp; Development, LLC Clinical Trial</last_name>
    <role>Study Director</role>
    <affiliation>Janssen Research &amp; Development, LLC</affiliation>
  </overall_official>
  <location>
    <facility>
      <address>
        <city>Birmingham</city>
        <state>Alabama</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Tucson</city>
        <state>Arizona</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>La Jolla</city>
        <state>California</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Los Angeles</city>
        <state>California</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Sacramento</city>
        <state>California</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Santa Monica</city>
        <state>California</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Denver</city>
        <state>Colorado</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Tampa</city>
        <state>Florida</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Augusta</city>
        <state>Georgia</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Chicago</city>
        <state>Illinois</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Goshen</city>
        <state>Indiana</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Boston</city>
        <state>Massachusetts</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Detroit</city>
        <state>Michigan</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Saint Louis</city>
        <state>Missouri</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>New Brunswick</city>
        <state>New Jersey</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Albuquerque</city>
        <state>New Mexico</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Charlotte</city>
        <state>North Carolina</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Durham</city>
        <state>North Carolina</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Nashville</city>
        <state>Tennessee</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Dallas</city>
        <state>Texas</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Houston</city>
        <state>Texas</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Tyler</city>
        <state>Texas</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Fairfax</city>
        <state>Virginia</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Bordeaux</city>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Caen Cedex 05</city>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Dijon</city>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Lyon</city>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Marseille</city>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Saint Herblain Cedex</city>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Villejuif</city>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Badalona</city>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Barcelona</city>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Madrid</city>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Málaga</city>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Pamplona</city>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Sevilla</city>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Valencia</city>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>France</country>
    <country>Spain</country>
    <country>United States</country>
  </location_countries>
  <results_reference>
    <citation>Tabernero J, Bahleda R, Dienstmann R, Infante JR, Mita A, Italiano A, Calvo E, Moreno V, Adamo B, Gazzah A, Zhong B, Platero SJ, Smit JW, Stuyckens K, Chatterjee-Kishore M, Rodon J, Peddareddigari V, Luo FR, Soria JC. Phase I Dose-Escalation Study of JNJ-42756493, an Oral Pan-Fibroblast Growth Factor Receptor Inhibitor, in Patients With Advanced Solid Tumors. J Clin Oncol. 2015 Oct 20;33(30):3401-8. doi: 10.1200/JCO.2014.60.7341. Epub 2015 Aug 31.</citation>
    <PMID>26324363</PMID>
  </results_reference>
  <verification_date>April 2019</verification_date>
  <study_first_submitted>March 22, 2012</study_first_submitted>
  <study_first_submitted_qc>October 8, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">October 10, 2012</study_first_posted>
  <last_update_submitted>May 24, 2019</last_update_submitted>
  <last_update_submitted_qc>May 24, 2019</last_update_submitted_qc>
  <last_update_posted type="Actual">May 29, 2019</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Tumor</keyword>
  <keyword>Fibroblast Growth Factor Receptor (FGFR)</keyword>
  <keyword>Non-Small Cell Lung Cancer (NSCLC)</keyword>
  <keyword>Small Cell Lung Cancer (SCLC)</keyword>
  <keyword>JNJ-42756493</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Lymphoma</mesh_term>
  </condition_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/NCT01703481
org study id: CR100845
secondary id: 42756493EDI1001
secondary id: 2012-000697-34
nct id: NCT01703481
lead sponsor: 
has dmc: Yes
is fda regulated device: No
The purpose of this study is to evaluate the safety, pharmacokinetics (study of what the body
      does to a drug), and pharmacodynamics (study of what a drug does to the body) of
      JNJ-42756493, a pan-fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitor, in
      adult participants with advanced or refractory solid tumors or lymphoma.
This is a first-in-human, non-randomized (individuals will not be assigned by chance to study
      treatments), open-label (individuals will know the identity of study treatments), multicenter
      (more than 1 hospital work on a study), Phase 1 study. The study consists of 4 parts. Part 1
      is the dose-escalation phase, which will be guided by pharmacokinetics, pharmacodynamics and
      safety. In part 1, safe and biologically active Phase 2 doses (recommended Phase 2 doses
      [RP2D]) for JNJ-42756493 will be primarily assessed. Participants will be enrolled in
      sequential cohorts (first cohort will receive the starting dose and subsequent cohorts will
      receive increased doses of JNJ-42756493). Part 2 is the Dose Confirmation Phase, which
      consists of a pre and post treatment tumor biopsy cohorts to confirm the RP2D based on the
      pharmacodynamic effect of JNJ-42756493 on fibroblast growth factor receptor (FGFR) signaling
      pathway in tumor. Part 3 is the first Dose Expansion Phase, which is designed to evaluate
      inclusion biomarkers and preliminary clinical activity at the first RP2D. It consists of 4
      expansion cohorts, 1 each for squamous cell lung cancer, small cell lung cancer, breast
      cancer, other solid tumors (Cohorts A, B, C, and D). Part 4 is the second Dose Expansion
      Phase, which is designed to evaluate inclusion biomarkers and preliminary clinical activity
      at the second RP2D. Biomarker eligibility has also been refined based on emerging data. It
      consists of 2 expansion cohorts, Cohort E for non-small cell lung cancer and Cohort F for
      select solid tumors including breast, urothelial, GBM, ovarian, head & neck, esophageal,
      gastric, and cholangiocarcinoma (Cohorts E and F). Enrollment of some cohorts may be
      discontinued due to lack of enrollment or for futility. The study is estimated to take
      approximately 48 months to complete. Participants' safety will be monitored throughout the
      study.
allocation: Non-Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Part 1: Maximum Tolerated Dose (MTD) of JNJ-42756493
time frame: Up to Part 1 Day 84 (Cycle 4, Day 21)
description: The maximum tolerated dose as determined in Part 1 of the study will be used as the recommended dose for Part 2, 3 and Part 4.
measure: Maximum Observed Plasma Concentration (Cmax) of JNJ-42756493
time frame: Up to Part 4 Day 84 (Cycle 4, Day 21)
description: The Cmax is the maximum observed plasma concentration.
measure: Minimum Observed Plasma Concentration (Cmin) of JNJ-42756493
time frame: Up to Part 4 Day 84 (Cycle 4, Day 21)
description: The Cmin is the minimum observed plasma concentration.
measure: Time to Reach Maximum Observed Plasma Concentration (Tmax) of JNJ-42756493
time frame: Up to Part 4 Day 84 (Cycle 4, Day 21)
description: The Tmax is defined as actual sampling time to reach maximum observed analyte concentration.
measure: Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau)
time frame: Up to Part 4 Day 84 (Cycle 4, Day 21)
description: The AUCtau is the measure of the plasma drug concentration from time zero to end of dosing interval (24 hour). It is used to characterize drug absorption.
measure: Elimination Half Life of JNJ-42756493
time frame: Up to Part 4 Day 84 (Cycle 4, Day 21)
description: The elimination half-life (t1/2) is the time measured for the plasma concentration to decrease by 1 half to its original concentration. It is associated with the terminal slope of the semi logarithmic drug concentration-time curve, and is calculated as 0.693/lambda(z).
measure: Apparent Volume of Distribution at Steady-State (Vss) of JNJ-42756493
time frame: Up to Part 4 Day 84 (Cycle 4, Day 21)
description: Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired blood concentration of a drug. Vss is the apparent volume of distribution at steady-state, which is estimated by (D/AUC[0-infinity])*(AUMC[0-infinity])/AUC[0-infinity]) where D is the dose of study drug, AUMC(0-infinity) is the area under the first moment curve extrapolated to infinity and AUC(0-infinity) is the area under the plasma concentration-time curve from time zero to infinite time.
measure: Total Clearance of JNJ-42756493
time frame: Up to Part 4 Day 84 (Cycle 4, Day 21)
description: Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Total clearance of drug is calculated as dose divided by AUCtau at steady-state.
measure: Accumulation Index (AI) of JNJ-42756493
time frame: Up to Part 4Day 84 (Cycle 4, Day 21)
description: Accumulation index is calculated by Cmax on Day 1 of Cycle 2/Cmax on Day 1 of Cycle 1 and/or AUCtau on Day 1 of Cycle 2/AUCtau on Day 1 of Cycle 1, where tau is the length of the dosing interval (24 hour).
measure: Number of Participants With Objective Tumor Response
time frame: Up to Part 4 Day 84 (Cycle 4, Day 21)
description: Objective response based on assessment of confirmed Complete response (CR) or partial response (PR) according to Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST). CR defined as disappearance of all target lesions. Any pathological lymph nodes must have reduction in short axis to less than 10 millimeter (mm). PR defined as at least 30 percent (%) decrease in sum of the diameters of the target lesions taking as reference the Baseline sum diameters. Confirmed responses are those that persist on repeat imaging study for at least 4 weeks after initial documentation of response.
measure: Progression Free Survival (PFS)
time frame: Up to Part 4 Day 84 (Cycle 4, Day 21)
description: Progression free survival is the time period from start of study medication till the disease progression or death, whichever occurs first.
measure: Duration of Objective Response
time frame: Up to Part 4 Day 84
description: Duration of objective response is time interval from the first date that criteria for complete response or partial response are met to the first date of progression of disease.
measure: Number of Participants With an Adverse Event
time frame: Up to Part 4 Day 84 (Cycle 4, Day 21)
description: An adverse event is any untoward medical event that occurs in a participant administered an investigational product, and it does not necessarily indicate only events with clear causal relationship with the relevant investigational product.
arm group label: Part 1
arm group type: Experimental
description: Dose Escalation, Part 1: Participants will be enrolled in sequential cohorts to determine recommended Phase 2 doses (RP2D).
arm group label: Part 2
arm group type: Experimental
description: Dose Confirmation, Part 2: Tumor biopsy cohorts will confirm RP2D.
arm group label: Part 3, Cohort A
arm group type: Experimental
description: First dose expansion, Part 3: Participants with squamous non-small cell lung cancer.
arm group label: Part 3, Cohort B
arm group type: Experimental
description: First dose expansion, Part 3: Participants with small cell lung cancer.
arm group label: Part 3, Cohort C
arm group type: Experimental
description: First dose expansion, Part 3: Participants with breast cancer.
arm group label: Part 3, Cohort D
arm group type: Experimental
description: First dose expansion, Part 3: Participants with solid tumors (consisting of one of the following: gastric, head and neck, lung adenocarcinoma, urothelial, glioblastoma multiforme [GBM], ovarian or prostate).
arm group label: Part 4, Cohort E
arm group type: Experimental
description: Second dose expansion, Part 4: Participants with non-small cell lung cancer.
arm group label: Part 4, Cohort F
arm group type: Experimental
description: Second dose expansion, Part 4: Participants with solid tumors (consisting of one of the following: breast, urothelial, GBM).
intervention type: Drug
intervention name: JNJ-42756493: Part 1
description: Participants will receive 0.5 mg (starting dose) capsule of JNJ-42756493 orally (by mouth) once daily on Day 1 of Cycle 1. Dose of the study medication will be escalated sequentially till the dose limiting toxicity is achieved to determine the recommended part 2 doses (RP2D).
arm group label: Part 1
intervention type: Drug
intervention name: JNJ-42756493: Part 2
description: Participants will receive JNJ-42756493 at the RP2D or below RP2D (maximum tolerated dose from Part 1) orally once daily on a 21 days cycle to confirm RP2D (in Part 2).
arm group label: Part 2
intervention type: Drug
intervention name: JNJ-42756493: Part 3
description: Participants will receive JNJ-42756493 at first RP2D of 9 mg daily in Part 3 orally once daily on a 21 days cycle.
arm group label: Part 3, Cohort A
arm group label: Part 3, Cohort B
arm group label: Part 3, Cohort C
arm group label: Part 3, Cohort D
intervention type: Drug
intervention name: JNJ-42756493: Part 4
description: Participants will receive JNJ-42756493 second RP2D of 10 mg intermittent dosing in Part 4 (with option to increase to 12 mg intermittent dosing based on phosphate level), orally on an intermittent schedule of daily for 7 days followed by 7 days off with a 28-day cycle.
arm group label: Part 4, Cohort E
arm group label: Part 4, Cohort F
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Janssen Research & Development, LLC Clinical Trial
role: Study Director
affiliation: Janssen Research & Development, LLC
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country: France
country: Spain
country: United States
citation: Tabernero J, Bahleda R, Dienstmann R, Infante JR, Mita A, Italiano A, Calvo E, Moreno V, Adamo B, Gazzah A, Zhong B, Platero SJ, Smit JW, Stuyckens K, Chatterjee-Kishore M, Rodon J, Peddareddigari V, Luo FR, Soria JC. Phase I Dose-Escalation Study of JNJ-42756493, an Oral Pan-Fibroblast Growth Factor Receptor Inhibitor, in Patients With Advanced Solid Tumors. J Clin Oncol. 2015 Oct 20;33(30):3401-8. doi: 10.1200/JCO.2014.60.7341. Epub 2015 Aug 31.
PMID: 26324363
responsible party type: Sponsor
mesh term: Lymphoma